|
In vitro anti-rhinoviral activity against human rhinovirus serotypes 2,3,9,14,16,25 and 39
|
Enterovirus
|
136.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 8. Pharmacological optimization of orally bioavailable 2-pyridone-containing peptidomimetics.
Year : 2003
Volume : 46
Issue : 21
First Page : 4572
Last Page : 4585
Authors : Dragovich PS, Prins TJ, Zhou R, Johnson TO, Hua Y, Luu HT, Sakata SK, Brown EL, Maldonado FC, Tuntland T, Lee CA, Fuhrman SA, Zalman LS, Patick AK, Matthews DA, Wu EY, Guo M, Borer BC, Nayyar NK, Moran T, Chen L, Rejto PA, Rose PW, Guzman MC, Dovalsantos EZ, Lee S, McGee K, Mohajeri M, Liese A, Tao J, Kosa MB, Liu B, Batugo MR, Gleeson JP, Wu ZP, Liu J, Meador JW, Ferre RA.
Abstract : The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).
|
Anti-HRV activity against HRV serotype 14
|
human rhinovirus type 14
|
0.03431
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 15
|
Human rhinovirus 15
|
0.0698
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 16
|
Human rhinovirus 16
|
0.108
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 2
|
human rhinovirus type 2
|
0.02647
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 29
|
Human rhinovirus 29
|
0.0454
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 39
|
Human rhinovirus 39
|
0.04488
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 45
|
Human rhinovirus 45
|
1.908
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 51
|
Human rhinovirus 51
|
0.0304
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 59
|
Human rhinovirus 59
|
0.3873
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 63
|
Human rhinovirus 63
|
0.0623
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 70
|
Human rhinovirus 70
|
0.05387
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 72
|
Human rhinovirus 72
|
0.4687
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 85
|
Human rhinovirus 85
|
0.034
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 86
|
Human rhinovirus 86
|
0.07004
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 89
|
human rhinovirus type 89
|
0.02933
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Anti-HRV activity against HRV serotype 9
|
Human rhinovirus 9
|
0.03716
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
Year : 2003
Volume : 46
Issue : 15
First Page : 3181
Last Page : 3184
Authors : Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW.
Abstract : A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
|
Inhibition of HRV Protease 3CP (serotype 14).
|
Human rhinovirus B
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 6. Structure-activity studies of orally bioavailable, 2-pyridone-containing peptidomimetics.
Year : 2002
Volume : 45
Issue : 8
First Page : 1607
Last Page : 1623
Authors : Dragovich PS, Prins TJ, Zhou R, Brown EL, Maldonado FC, Fuhrman SA, Zalman LS, Tuntland T, Lee CA, Patick AK, Matthews DA, Hendrickson TF, Kosa MB, Liu B, Batugo MR, Gleeson JP, Sakata SK, Chen L, Guzman MC, Meador JW, Ferre RA, Worland ST.
Abstract : The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and a Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The 2-pyridone-containing inhibitors typically display improved 3CP inhibition properties relative to related peptide-derived molecules along with more favorable antiviral properties. The cocrystal structure of one pyridone-derived 3CP inhibitor complexed with HRV-2 3CP is also described along with certain ab initio conformation analyses. Optimization of the 2-pyridone-containing compounds is shown to provide several highly active 3CP inhibitors (k(obs)/[I] > 500,00 M(-1) s(-1)) that function as potent antirhinoviral agents (EC(50) = <0.05 microM) against multiple virus serotypes in cell culture. One 2-pyridone-containing 3CP inhibitor is shown to be bioavailable in the dog after oral dosing (F = 48%).
|
Median effective concentration against HRV serotypes; Number of serotypes 16
|
Human rhinovirus sp.
|
0.04963
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 2 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.02647
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 9 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.03716
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 14 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.03431
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 15 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.0698
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 16 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.108
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 29 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.0454
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 39 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.04488
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 45 (assay was run at least six times)
|
Human rhinovirus sp.
|
1.908
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 51 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.0304
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 59 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.3873
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 63 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.0623
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 70 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.05387
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 72 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.4687
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 85 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.034
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 86 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.07004
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Effective concentration against HRV serotype 89 (assay was run at least six times)
|
Human rhinovirus sp.
|
0.02933
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder.
Year : 2005
Volume : 15
Issue : 8
First Page : 2051
Last Page : 2055
Authors : Brown RN, Cameron R, Chalmers DK, Hamilton S, Luttick A, Krippner GY, McConnell DB, Nearn R, Stanislawski PC, Tucker SP, Watson KG.
Abstract : A series of pyridazinylpiperidinyl capsid-binding compounds with novel bicyclic substituents were synthesized and screened against human rhinovirus (HRV). Several 2-alkoxy- and 2-alkylthio-benzoxazole and benzothiazole derivatives showed excellent anti-HRV activity. When tested against a panel of 16 representative HRV types the 2-ethoxybenzoxazole derivative 13 was found to have superior HRV activity (median EC(50) 3.88ng/mL) to known capsid-binders Pleconaril and Pirodavir. Compound 13 illustrates that a 2-alkoxybenzoxazole group can be an effective bioisostere for a benzoate ester or benzaldehyde oxime ether functionality.
|
Antiviral activity against HRV2 in HeLa cells
|
Human rhinovirus 2
|
0.01
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein.
Year : 2008
Volume : 51
Issue : 4
First Page : 842
Last Page : 851
Authors : Rollinger JM, Steindl TM, Schuster D, Kirchmair J, Anrain K, Ellmerer EP, Langer T, Stuppner H, Wutzler P, Schmidtke M.
Abstract : Inhibitors of the human rhinovirus (HRV) coat protein are promising candidates to treat and prevent a number of upper respiratory diseases. The aim of this study was to find antiviral compounds from nature, focusing on the HRV coat protein. Through computational structure-based screening of an in-house 3D database containing 9676 individual plant metabolites from ancient herbal medicines, combined with knowledge from traditional use, we selected sesquiterpene coumarins from the gum resin asafetida as promising natural products. Chromatographic separation steps resulted in the isolation of microlobidene (1), farnesiferol C (2), farnesiferol B (3), and kellerin (4). Determination of the inhibition of the HRV-induced cytopathic effect for serotypes 1A, 2, 14, and 16 revealed a dose-dependent and selective antirhinoviral activity against serotype 2 for asafetida (IC50 = 11.0 microg/mL) and its virtually predicted constituents 2 (IC50 = 2.5 microM) and 3 (IC50 = 2.6 microM). Modeling studies helped to rationalize the retrieved results.
|
Antiviral activity against HRV1A in HeLa cells
|
Human rhinovirus 1A
|
0.02
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein.
Year : 2008
Volume : 51
Issue : 4
First Page : 842
Last Page : 851
Authors : Rollinger JM, Steindl TM, Schuster D, Kirchmair J, Anrain K, Ellmerer EP, Langer T, Stuppner H, Wutzler P, Schmidtke M.
Abstract : Inhibitors of the human rhinovirus (HRV) coat protein are promising candidates to treat and prevent a number of upper respiratory diseases. The aim of this study was to find antiviral compounds from nature, focusing on the HRV coat protein. Through computational structure-based screening of an in-house 3D database containing 9676 individual plant metabolites from ancient herbal medicines, combined with knowledge from traditional use, we selected sesquiterpene coumarins from the gum resin asafetida as promising natural products. Chromatographic separation steps resulted in the isolation of microlobidene (1), farnesiferol C (2), farnesiferol B (3), and kellerin (4). Determination of the inhibition of the HRV-induced cytopathic effect for serotypes 1A, 2, 14, and 16 revealed a dose-dependent and selective antirhinoviral activity against serotype 2 for asafetida (IC50 = 11.0 microg/mL) and its virtually predicted constituents 2 (IC50 = 2.5 microM) and 3 (IC50 = 2.6 microM). Modeling studies helped to rationalize the retrieved results.
|
Antiviral activity against HRV14 in HeLa cells
|
Human rhinovirus 14
|
0.02
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein.
Year : 2008
Volume : 51
Issue : 4
First Page : 842
Last Page : 851
Authors : Rollinger JM, Steindl TM, Schuster D, Kirchmair J, Anrain K, Ellmerer EP, Langer T, Stuppner H, Wutzler P, Schmidtke M.
Abstract : Inhibitors of the human rhinovirus (HRV) coat protein are promising candidates to treat and prevent a number of upper respiratory diseases. The aim of this study was to find antiviral compounds from nature, focusing on the HRV coat protein. Through computational structure-based screening of an in-house 3D database containing 9676 individual plant metabolites from ancient herbal medicines, combined with knowledge from traditional use, we selected sesquiterpene coumarins from the gum resin asafetida as promising natural products. Chromatographic separation steps resulted in the isolation of microlobidene (1), farnesiferol C (2), farnesiferol B (3), and kellerin (4). Determination of the inhibition of the HRV-induced cytopathic effect for serotypes 1A, 2, 14, and 16 revealed a dose-dependent and selective antirhinoviral activity against serotype 2 for asafetida (IC50 = 11.0 microg/mL) and its virtually predicted constituents 2 (IC50 = 2.5 microM) and 3 (IC50 = 2.6 microM). Modeling studies helped to rationalize the retrieved results.
|
Antiviral activity against HRV16 in HeLa cells
|
Human rhinovirus 16
|
0.02
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein.
Year : 2008
Volume : 51
Issue : 4
First Page : 842
Last Page : 851
Authors : Rollinger JM, Steindl TM, Schuster D, Kirchmair J, Anrain K, Ellmerer EP, Langer T, Stuppner H, Wutzler P, Schmidtke M.
Abstract : Inhibitors of the human rhinovirus (HRV) coat protein are promising candidates to treat and prevent a number of upper respiratory diseases. The aim of this study was to find antiviral compounds from nature, focusing on the HRV coat protein. Through computational structure-based screening of an in-house 3D database containing 9676 individual plant metabolites from ancient herbal medicines, combined with knowledge from traditional use, we selected sesquiterpene coumarins from the gum resin asafetida as promising natural products. Chromatographic separation steps resulted in the isolation of microlobidene (1), farnesiferol C (2), farnesiferol B (3), and kellerin (4). Determination of the inhibition of the HRV-induced cytopathic effect for serotypes 1A, 2, 14, and 16 revealed a dose-dependent and selective antirhinoviral activity against serotype 2 for asafetida (IC50 = 11.0 microg/mL) and its virtually predicted constituents 2 (IC50 = 2.5 microM) and 3 (IC50 = 2.6 microM). Modeling studies helped to rationalize the retrieved results.
|
Inhibition of HRV2 absorption on HeLa cells assessed as reduction in plaques at 0.25 ug/ml after 2 hrs
|
Human rhinovirus 2
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein.
Year : 2008
Volume : 51
Issue : 4
First Page : 842
Last Page : 851
Authors : Rollinger JM, Steindl TM, Schuster D, Kirchmair J, Anrain K, Ellmerer EP, Langer T, Stuppner H, Wutzler P, Schmidtke M.
Abstract : Inhibitors of the human rhinovirus (HRV) coat protein are promising candidates to treat and prevent a number of upper respiratory diseases. The aim of this study was to find antiviral compounds from nature, focusing on the HRV coat protein. Through computational structure-based screening of an in-house 3D database containing 9676 individual plant metabolites from ancient herbal medicines, combined with knowledge from traditional use, we selected sesquiterpene coumarins from the gum resin asafetida as promising natural products. Chromatographic separation steps resulted in the isolation of microlobidene (1), farnesiferol C (2), farnesiferol B (3), and kellerin (4). Determination of the inhibition of the HRV-induced cytopathic effect for serotypes 1A, 2, 14, and 16 revealed a dose-dependent and selective antirhinoviral activity against serotype 2 for asafetida (IC50 = 11.0 microg/mL) and its virtually predicted constituents 2 (IC50 = 2.5 microM) and 3 (IC50 = 2.6 microM). Modeling studies helped to rationalize the retrieved results.
|
Inhibition of HRV2 replication cycle progression
|
Human rhinovirus 2
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein.
Year : 2008
Volume : 51
Issue : 4
First Page : 842
Last Page : 851
Authors : Rollinger JM, Steindl TM, Schuster D, Kirchmair J, Anrain K, Ellmerer EP, Langer T, Stuppner H, Wutzler P, Schmidtke M.
Abstract : Inhibitors of the human rhinovirus (HRV) coat protein are promising candidates to treat and prevent a number of upper respiratory diseases. The aim of this study was to find antiviral compounds from nature, focusing on the HRV coat protein. Through computational structure-based screening of an in-house 3D database containing 9676 individual plant metabolites from ancient herbal medicines, combined with knowledge from traditional use, we selected sesquiterpene coumarins from the gum resin asafetida as promising natural products. Chromatographic separation steps resulted in the isolation of microlobidene (1), farnesiferol C (2), farnesiferol B (3), and kellerin (4). Determination of the inhibition of the HRV-induced cytopathic effect for serotypes 1A, 2, 14, and 16 revealed a dose-dependent and selective antirhinoviral activity against serotype 2 for asafetida (IC50 = 11.0 microg/mL) and its virtually predicted constituents 2 (IC50 = 2.5 microM) and 3 (IC50 = 2.6 microM). Modeling studies helped to rationalize the retrieved results.
|
Inhibition of HRV16 replication cycle progression
|
Human rhinovirus 16
|
570.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein.
Year : 2008
Volume : 51
Issue : 4
First Page : 842
Last Page : 851
Authors : Rollinger JM, Steindl TM, Schuster D, Kirchmair J, Anrain K, Ellmerer EP, Langer T, Stuppner H, Wutzler P, Schmidtke M.
Abstract : Inhibitors of the human rhinovirus (HRV) coat protein are promising candidates to treat and prevent a number of upper respiratory diseases. The aim of this study was to find antiviral compounds from nature, focusing on the HRV coat protein. Through computational structure-based screening of an in-house 3D database containing 9676 individual plant metabolites from ancient herbal medicines, combined with knowledge from traditional use, we selected sesquiterpene coumarins from the gum resin asafetida as promising natural products. Chromatographic separation steps resulted in the isolation of microlobidene (1), farnesiferol C (2), farnesiferol B (3), and kellerin (4). Determination of the inhibition of the HRV-induced cytopathic effect for serotypes 1A, 2, 14, and 16 revealed a dose-dependent and selective antirhinoviral activity against serotype 2 for asafetida (IC50 = 11.0 microg/mL) and its virtually predicted constituents 2 (IC50 = 2.5 microM) and 3 (IC50 = 2.6 microM). Modeling studies helped to rationalize the retrieved results.
|
Antiviral activity against HRV-14
|
Human rhinovirus 14
|
0.03
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacophore-based design, synthesis, and biological evaluation of novel chloro-pyridazine piperazines as human rhinovirus (HRV-3) inhibitors.
Year : 2011
Volume : 21
Issue : 3
First Page : 1057
Last Page : 1059
Authors : Wang H, Xiao J, Gao D, Zhang X, Yan H, Gong Z, Sun T, Li S.
Abstract : A series of chloro-pyridazine piperazines were developed based on the structure of human rhinovirus (HRV) capsid-binding inhibitors with proven activity using a pharmacophore model. A preliminary evaluation demonstrated potent activity against HRV-3 with low cytotoxicity. A docking analysis indicated that 8a could fit into, and form tight interactions (e.g., H-bonds, σ-π effect) with the active site in VP1.
|
Antiviral activity against Human rhinovirus 14 infected in human HeLa Ohio cells assessed as inhibition of virus-induced cytopathic effect by CellTiter-Glo assay
|
Human rhinovirus 14
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Effect of lipophilicity modulation on inhibition of human rhinovirus capsid binders.
Year : 2011
Volume : 21
Issue : 20
First Page : 6031
Last Page : 6035
Authors : Morley A, Tomkinson N, Cook A, MacDonald C, Weaver R, King S, Jenkinson L, Unitt J, McCrae C, Phillips T.
Abstract : To try and generate broad spectrum human rhinovirus VP1 inhibitors with more attractive physicochemical, DMPK and safety profiles, we explored the current SAR of known VP1 compounds. This lead to the identification of specific structural regions where reduction in polarity can be achieved, so guiding chemistry to analogues with significantly superior profiles to previously reported inhibitors.
|
Antiviral activity against Human rhinovirus 2 infected in human HeLa Ohio cells assessed as inhibition of virus-induced cytopathic effect by CellTiter-Glo assay
|
Human rhinovirus 2
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Effect of lipophilicity modulation on inhibition of human rhinovirus capsid binders.
Year : 2011
Volume : 21
Issue : 20
First Page : 6031
Last Page : 6035
Authors : Morley A, Tomkinson N, Cook A, MacDonald C, Weaver R, King S, Jenkinson L, Unitt J, McCrae C, Phillips T.
Abstract : To try and generate broad spectrum human rhinovirus VP1 inhibitors with more attractive physicochemical, DMPK and safety profiles, we explored the current SAR of known VP1 compounds. This lead to the identification of specific structural regions where reduction in polarity can be achieved, so guiding chemistry to analogues with significantly superior profiles to previously reported inhibitors.
|
Activation of human PXR expressed in african green monkey CV1 cells transfected with pSG5-hPXRDATG and (ER6)3-tk-CAT reporter
|
Homo sapiens
|
251.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Effect of lipophilicity modulation on inhibition of human rhinovirus capsid binders.
Year : 2011
Volume : 21
Issue : 20
First Page : 6031
Last Page : 6035
Authors : Morley A, Tomkinson N, Cook A, MacDonald C, Weaver R, King S, Jenkinson L, Unitt J, McCrae C, Phillips T.
Abstract : To try and generate broad spectrum human rhinovirus VP1 inhibitors with more attractive physicochemical, DMPK and safety profiles, we explored the current SAR of known VP1 compounds. This lead to the identification of specific structural regions where reduction in polarity can be achieved, so guiding chemistry to analogues with significantly superior profiles to previously reported inhibitors.
|
Antirhinoviral activity against Human rhinovirus A infected in human HeLa cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human rhinovirus sp.
|
0.0374
ug.mL-1
|
|
Journal : ACS Med. Chem. Lett.
Title : An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus.
Year : 2012
Volume : 3
Issue : 4
First Page : 303
Last Page : 307
Authors : Feil SC, Hamilton S, Krippner GY, Lin B, Luttick A, McConnell DB, Nearn R, Parker MW, Ryan J, Stanislawski PC, Tucker SP, Watson KG, Morton CJ.
Abstract : Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus-compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.
|
Antirhinoviral activity against Human rhinovirus B infected in human HeLa cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human rhinovirus sp.
|
0.2241
ug.mL-1
|
|
Journal : ACS Med. Chem. Lett.
Title : An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus.
Year : 2012
Volume : 3
Issue : 4
First Page : 303
Last Page : 307
Authors : Feil SC, Hamilton S, Krippner GY, Lin B, Luttick A, McConnell DB, Nearn R, Parker MW, Ryan J, Stanislawski PC, Tucker SP, Watson KG, Morton CJ.
Abstract : Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus-compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.
|
Antirhinoviral activity against antiviral-resistant Human rhinovirus A infected in human HeLa cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human rhinovirus sp.
|
0.3876
ug.mL-1
|
|
Journal : ACS Med. Chem. Lett.
Title : An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus.
Year : 2012
Volume : 3
Issue : 4
First Page : 303
Last Page : 307
Authors : Feil SC, Hamilton S, Krippner GY, Lin B, Luttick A, McConnell DB, Nearn R, Parker MW, Ryan J, Stanislawski PC, Tucker SP, Watson KG, Morton CJ.
Abstract : Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus-compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.
|
Antirhinoviral activity against antiviral-resistant Human rhinovirus B infected in human HeLa cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human rhinovirus sp.
|
0.0338
ug.mL-1
|
|
Journal : ACS Med. Chem. Lett.
Title : An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus.
Year : 2012
Volume : 3
Issue : 4
First Page : 303
Last Page : 307
Authors : Feil SC, Hamilton S, Krippner GY, Lin B, Luttick A, McConnell DB, Nearn R, Parker MW, Ryan J, Stanislawski PC, Tucker SP, Watson KG, Morton CJ.
Abstract : Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus-compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.
|
Antirhinoviral activity against major receptor-resistant Human rhinovirus infected in human HeLa cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human rhinovirus sp.
|
0.0492
ug.mL-1
|
|
Journal : ACS Med. Chem. Lett.
Title : An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus.
Year : 2012
Volume : 3
Issue : 4
First Page : 303
Last Page : 307
Authors : Feil SC, Hamilton S, Krippner GY, Lin B, Luttick A, McConnell DB, Nearn R, Parker MW, Ryan J, Stanislawski PC, Tucker SP, Watson KG, Morton CJ.
Abstract : Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus-compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.
|
Antirhinoviral activity against minor receptor-resistant Human rhinovirus infected in human HeLa cells assessed as inhibition of virus-induced cytopathic effect after 5 days by MTT assay
|
Human rhinovirus sp.
|
0.0232
ug.mL-1
|
|
Journal : ACS Med. Chem. Lett.
Title : An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus.
Year : 2012
Volume : 3
Issue : 4
First Page : 303
Last Page : 307
Authors : Feil SC, Hamilton S, Krippner GY, Lin B, Luttick A, McConnell DB, Nearn R, Parker MW, Ryan J, Stanislawski PC, Tucker SP, Watson KG, Morton CJ.
Abstract : Respiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus-compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans.
|
Antiviral activity against Coxsackievirus B3 assessed as inhibition of viral replication
|
Human coxsackievirus B3
|
410.0
nM
|
|
Journal : J. Nat. Prod.
Title : Alkaloids from the root of Isatis indigotica.
Year : 2012
Volume : 75
Issue : 6
First Page : 1167
Last Page : 1176
Authors : Chen M, Gan L, Lin S, Wang X, Li L, Li Y, Zhu C, Wang Y, Jiang B, Jiang J, Yang Y, Shi J.
Abstract : Seventeen new alkaloids (1-17) and 14 known analogues have been isolated from an aqueous extract of the root of Isatis indigotica. The structures and absolute configurations of these compounds were determined by extensive spectroscopic data analysis, including 2D NMR, single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation, and electronic circular dichroism spectra calculations based on the quantum-mechanical time-dependent density functional theory. Compounds 1, 2, and 3 are the first examples of natural products with unique linkages between a molecule of 2-(4-methoxy-1H-indol-3-yl)acetonitrile and 2-(1H-indol-3-yl)acetonitrile, 2-(4-methoxy-1H-indol-3-yl)acetonitrile, and 4-hydroxyphenylethane, respectively. Compounds (-)-4 and (+)-4 represent the first natural products with the pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline skeleton. Some structural assignments for the new alkaloids suggest that the assignments made for certain previously reported alkaloids require revision. Compounds 1-3 and arvelexin (18) show antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2), with IC(50) values of 3.70-12.35 μM, and 17 inhibits Coxsackie virus B3 replication with an IC(50) of 6.87 μM.
|
Antienteroviral activity against poliovirus 3 infected in african green monkey Vero cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human poliovirus 3
|
84.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Coxsackievirus A9 infected in african green monkey Vero cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human coxsackievirus A9
|
33.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 89 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 89
|
75.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 86 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 86
|
89.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 85 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 85
|
883.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 70 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 70
|
578.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 63 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 63
|
85.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 59 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus A59
|
471.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 41 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 41
|
655.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 39 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 39
|
44.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 29 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 29
|
26.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 15 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 15
|
166.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 9 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 9
|
83.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 2 infected in human HeLa Rh cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 2
|
7.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antienteroviral activity against Human rhinovirus 14 infected in human HeLa cells assessed as protection against virus-induced cytopathic effect after 2 to 3 days by MTS assay
|
Human rhinovirus 14
|
177.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.
Year : 2013
Volume : 4
Issue : 7
First Page : 585
Last Page : 589
Authors : MacLeod AM, Mitchell DR, Palmer NJ, Van de Poël H, Conrath K, Andrews M, Leyssen P, Neyts J.
Abstract : Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
|
Antiviral activity against Coxsackie virus B3 assessed as inhibition of viral replication
|
Human coxsackievirus B3
|
300.0
nM
|
|
Journal : J. Nat. Prod.
Title : Homosecoiridoid alkaloids with amino acid units from the flower buds of Lonicera japonica.
Year : 2013
Volume : 76
Issue : 12
First Page : 2226
Last Page : 2233
Authors : Yu Y, Zhu C, Wang S, Song W, Yang Y, Shi J.
Abstract : Nine new homosecoiridoid alkaloids, named lonijaposides O-W (1-9), along with 19 known compounds, were isolated from an aqueous extract of the flower buds of Lonicera japonica. Their structures and absolute configurations were determined by spectroscopic data analysis and chemical methods. Lonijaposides O-W have structural features that involve amino acid units sharing the N atom with a pyridinium (1-5) or nicotinic acid (6-9) moiety. The absolute configurations of the amino acid units were determined by oxidation of each pyridinium ring moiety with potassium ferricyanide, hydrolysis of the oxidation product, and Marfey's analysis of the hydrolysate. This procedure was validated by oxidizing and hydrolyzing synthetic model compounds. The phenylalanine units in compounds 4, 5, and 9 have the d-configuration, and the other amino acid units in 1-3 and 6-8 possess the l-configuration. Compounds 1, 4, 6, and 9 and the known compounds 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, and 5'-O-methyladenosine exhibited antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2) with IC50 values of 3.4-11.6 μM, and 4 inhibited Coxsackie virus B3 replication with an IC50 value of 12.3 μM.
|
Antiviral activity against Coxsackievirus B5 infected in African green monkey Vero 76 cells after 3 days by plaque reduction assay
|
Human coxsackievirus B5
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-((1,3-Diphenyl-1H-pyrazol-4-yl)methyl)anilines: A novel class of anti-RSV agents.
Year : 2015
Volume : 25
Issue : 11
First Page : 2401
Last Page : 2404
Authors : Fioravanti R, Desideri N, Biava M, Droghini P, Atzori EM, Ibba C, Collu G, Sanna G, Delogu I, Loddo R.
Abstract : A series of N-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)anilines were synthesized and evaluated in vitro for cytotoxicity and antiviral activity against a large panel of viruses. Most of the tested compounds interfered with RSV replication in the micromolar concentrations (EC50s ranging from 5 μM to 28 μM). SAR studies suggested that the presence of a trifluoromethyl group in R(1) abolished the anti-RSV activity and enhanced the cytotoxicity while the best results in term of both anti-RSV activity and selectivity were obtained by the introduction in R(1) of a chlorine or a bromine atom.
|
Antiviral activity against Coxsackievirus B3 infected in African green monkey Vero cells assessed as inhibition of virus-induced cytopathic effect
|
Human coxsackievirus B3
|
2.5
nM
|
|
Journal : J. Nat. Prod.
Title : Bioactive Sesquiterpenes and Lignans from the Fruits of Xanthium sibiricum.
Year : 2015
Volume : 78
Issue : 7
First Page : 1526
Last Page : 1535
Authors : Shi YS, Liu YB, Ma SG, Li Y, Qu J, Li L, Yuan SP, Hou Q, Li YH, Jiang JD, Yu SS.
Abstract : Seven new sesquiterpenes (1, 3-8), a new sesquiterpene natural product (2), and two new lignans (9 and 10), together with 15 known compounds, were isolated from the fruits of Xanthium sibiricum. The structures of the new compounds were established by NMR spectroscopic analysis, ECD calculations, and Mo2(OAc)4-induced circular dichroism, with the structures of 1 and 4 confirmed by single-crystal X-ray diffraction. Compound 1 is the first example of a 3/5/6/5 tetracyclic eudesmane sesquiterpene lactone formed at C-6 and C-7. In turn, compound 4 is the first example of a natural xanthane tetranorsesquiterpene, while compounds 5-8 are the first xanthane trinorsesquiterpenes found to date. Compounds 8, 11-15, 17, and 24 exhibited indirect anti-inflammatory activity by suppressing the lipopolysaccharide-induced proinflammatory factors in BV2 microglial cells, with IC50 values between 1.6 and 8.5 μM. Furthermore, compounds 13 and 17 exhibited anti-inflammatory activity against ear edema in mice produced by croton oil, with inhibition rates of 46.9% and 37.7%, respectively. Compounds 8, 11, 12, 23, and 24 exhibited potent activity against influenza A virus (A/FM/1/47, H1N1) with IC50 values between 3.7 and 8.4 μM.
|
Antiviral activity against human CVB5 infected in african green monkey Vero76 cells assessed as inhibition of virus-induced cytopathogenicity after 3 days by plaque reduction assay
|
Human coxsackievirus B5
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antiviral activity of benzotriazole derivatives. 5-[4-(Benzotriazol-2-yl)phenoxy]-2,2-dimethylpentanoic acids potently and selectively inhibit Coxsackie Virus B5.
Year : 2015
Volume : 23
Issue : 21
First Page : 7024
Last Page : 7034
Authors : Loddo R, Novelli F, Sparatore A, Tasso B, Tonelli M, Boido V, Sparatore F, Collu G, Delogu I, Giliberti G, La Colla P.
Abstract : A library of 64 benzotriazole derivatives (17 of which were [4-(benzotriazol-2-yl)phenoxy]alkanoic acids) were screened for antiviral activity against a panel of twelve DNA and RNA viruses. Twenty-six compounds (12 of which were [4-(benzotriazol-2-yl)phenoxy]alkanoic acids) displayed activity against one or more viruses. CVB-5, RSV, BVDV, Sb-1 and YFV were, in decreasing order, the more frequently and effectively affected viruses; DENV-2, WNV, HIV-1 and Reo-1 were only occasionally and modestly affected, while the remaining viruses were not affected by any of the tested compounds. Worth of note were compounds 33 and 35; the former for the activity against Sb-1 (EC50=7 μM) and the latter for the large spectrum of activity including six viruses with a mean EC50=12 μM. Even more interesting were the alkanoic acids 45-48 and 50-57 for their activity against RSV and/or CVB-5. In particular, compound 56 displayed a potent and selective activity against CVB-5 with EC50=0.15 μM and SI=100, thus representing a valuable hit compound for the development of antiviral agents for the treatment of human pathologies related to this virus.
|
Antiviral activity against Human Rhinovirus B serotype 14 infected in HeLa Rh cells assessed as reduction of virus-induced cytopathic effect after 3 days by MTS assay
|
Rhinovirus B
|
200.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : VP1 crystal structure-guided exploration and optimization of 4,5-dimethoxybenzene-based inhibitors of rhinovirus 14 infection.
Year : 2016
Volume : 115
First Page : 453
Last Page : 462
Authors : Da Costa L, Roche M, Scheers E, Coluccia A, Neyts J, Terme T, Leyssen P, Silvestri R, Vanelle P.
Abstract : Human rhinoviruses (HRV) are the predominant cause of common colds and flu-like illnesses, but are also responsible for virus-induced exacerbations of asthma and chronic obstructive pulmonary disease. However, to date, no drug has been approved yet for clinical use. In this study, we present the results of the structure-based lead optimization of a class of new small-molecule inhibitors that we previously reported to bind into the pocket beneath the canyon of the VP1 protein. A small series of analogues that we designed based on the available structure and interaction data were synthesized and evaluated for their potency to inhibit the replication of HRV serotype 14. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(4-(pyridin-4-yl)phenyl)ethanol (3v) was found to be a potent inhibitor exhibiting micromolar activity (EC50 = 3.4 ± 1.0 μM) with a toxicity for HeLa cells that was significantly lower than that of our previous hit (LPCRW_0005, CC50 = 104.0 ± 22.2 μM; 3v, CC50 > 263 μM).
|
Antiviral activity against Coxsackievirus B3 infected in African green monkey Vero cells assessed as inhibition of virus-induced cytopathic effect
|
Human coxsackievirus B3
|
1.0
nM
|
|
Journal : J Nat Prod
Title : Antiviral Triterpenes from the Twigs and Leaves of Lyonia ovalifolia.
Year : 2016
Volume : 79
Issue : 11
First Page : 2824
Last Page : 2837
Authors : Lv XJ, Li Y, Ma SG, Qu J, Liu YB, Li YH, Zhang D, Li L, Yu SS.
Abstract : Eleven new 9,10-seco-cycloartan triterpene glycosides (1-11), seven new lanostane triterpene glycosides (12-18), and two new ursane triterpenoids (19-20) were isolated from the twigs and leaves of Lyonia ovalifolia. The structures of these compounds were elucidated by extensive MS and NMR spectroscopic analysis. The absolute configuration of compound 1a (the aglycone of 1) was established by X-ray crystallography, and that of C-24 in compounds 2, 7, and 12 was established by Mo2(OAc)4-induced electronic circular dichroism experiments. All compounds were evaluated for their antiviral [herpes simplex virus-1 (HSV-1), influenza A/95-359 (A/95-359), and Coxsackie B3 (CVB3)] activity. Compounds 1, 1a, 2a, 12a, 13, and 16 exhibited potent activity against HSV-1, with IC50 values from 2.1 to 14.3 μM, while compounds 1a, 2a, 12a, 13, and 12-2a exhibited potent activity against A/95-359, with IC50 values from 2.1 to 11.1 μM. In turn, compounds 1, 1a, 2a, 12a, and 13 exhibited potent activity against CVB3, with IC50 values from 2.1 to 11.1 μM.
|
Antiviral activity against Human rhinovirus B14 infected in human H1HeLa cells assessed as protection against virus induced cytopathic effect after 3 days by MTT assay
|
Human rhinovirus B14
|
75.0
nM
|
|
Journal : J Med Chem
Title : A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication.
Year : 2017
Volume : 60
Issue : 13
First Page : 5472
Last Page : 5492
Authors : Kim J, Jung YK, Kim C, Shin JS, Scheers E, Lee JY, Han SB, Lee CK, Neyts J, Ha JD, Jung YS.
Abstract : Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 μM. The results of a time-of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that 6g acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that 6g has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species.
|
Antiviral activity against Human rhinovirus A21 infected in human H1HeLa cells assessed as protection against virus induced cytopathic effect after 3 days by MTT assay
|
Human rhinovirus A21
|
73.0
nM
|
|
Journal : J Med Chem
Title : A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication.
Year : 2017
Volume : 60
Issue : 13
First Page : 5472
Last Page : 5492
Authors : Kim J, Jung YK, Kim C, Shin JS, Scheers E, Lee JY, Han SB, Lee CK, Neyts J, Ha JD, Jung YS.
Abstract : Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 μM. The results of a time-of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that 6g acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that 6g has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species.
|
Antiviral activity against Human rhinovirus A71 infected in human H1HeLa cells assessed as protection against virus induced cytopathic effect after 3 days by MTT assay
|
Human rhinovirus A71
|
9.4
nM
|
|
Journal : J Med Chem
Title : A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication.
Year : 2017
Volume : 60
Issue : 13
First Page : 5472
Last Page : 5492
Authors : Kim J, Jung YK, Kim C, Shin JS, Scheers E, Lee JY, Han SB, Lee CK, Neyts J, Ha JD, Jung YS.
Abstract : Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 μM. The results of a time-of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that 6g acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that 6g has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species.
|
Antiviral activity against Human rhinovirus A16 infected in human H1HeLa cells assessed as protection against virus induced cytopathic effect after 3 days by MTT assay
|
Human rhinovirus A16
|
350.0
nM
|
|
Journal : J Med Chem
Title : A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication.
Year : 2017
Volume : 60
Issue : 13
First Page : 5472
Last Page : 5492
Authors : Kim J, Jung YK, Kim C, Shin JS, Scheers E, Lee JY, Han SB, Lee CK, Neyts J, Ha JD, Jung YS.
Abstract : Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 μM. The results of a time-of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that 6g acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that 6g has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species.
|
Antiviral activity against human poliovirus 3 infected in human HeLa cells assessed as reduction in virus-induced cytopathicity incubated for 3 days by MTT assay
|
Human poliovirus 3
|
510.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones.
Year : 2017
Volume : 27
Issue : 15
First Page : 3582
Last Page : 3585
Authors : Kumar Biswas B, Malpani YR, Ha N, Kwon DH, Soo Shin J, Kim HS, Kim C, Bong Han S, Lee CK, Jung YS.
Abstract : Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85μM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6μM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively.
|
Antiviral activity against human coxsackievirus B1 infected in human HeLa cells assessed as reduction in virus-induced cytopathicity incubated for 3 days by MTT assay
|
Human coxsackievirus B1
|
130.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones.
Year : 2017
Volume : 27
Issue : 15
First Page : 3582
Last Page : 3585
Authors : Kumar Biswas B, Malpani YR, Ha N, Kwon DH, Soo Shin J, Kim HS, Kim C, Bong Han S, Lee CK, Jung YS.
Abstract : Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85μM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6μM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively.
|
Antiviral activity against human rhinovirus 14 infected in human H1HeLa cells assessed as reduction in virus-induced cytopathicity incubated for 3 days by MTT assay
|
Human rhinovirus 14
|
310.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones.
Year : 2017
Volume : 27
Issue : 15
First Page : 3582
Last Page : 3585
Authors : Kumar Biswas B, Malpani YR, Ha N, Kwon DH, Soo Shin J, Kim HS, Kim C, Bong Han S, Lee CK, Jung YS.
Abstract : Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85μM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6μM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively.
|
Antiviral activity against human rhinovirus 21 infected in human H1HeLa cells assessed as reduction in virus-induced cytopathicity incubated for 3 days by MTT assay
|
Human rhinovirus A21
|
83.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones.
Year : 2017
Volume : 27
Issue : 15
First Page : 3582
Last Page : 3585
Authors : Kumar Biswas B, Malpani YR, Ha N, Kwon DH, Soo Shin J, Kim HS, Kim C, Bong Han S, Lee CK, Jung YS.
Abstract : Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85μM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6μM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively.
|
Antiviral activity against human rhinovirus 71 infected in human H1HeLa cells assessed as reduction in virus-induced cytopathicity incubated for 3 days by MTT assay
|
Human rhinovirus A71
|
13.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones.
Year : 2017
Volume : 27
Issue : 15
First Page : 3582
Last Page : 3585
Authors : Kumar Biswas B, Malpani YR, Ha N, Kwon DH, Soo Shin J, Kim HS, Kim C, Bong Han S, Lee CK, Jung YS.
Abstract : Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85μM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6μM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively.
|
Antiviral activity against Human enterovirus B Faulkner ATCC VR 185 infected in African green monkey Vero 76 cells assessed as protection against virus-induced cytopathic effect after 3 days by crystal violet staining-based plaque reduction assay
|
Human enterovirus B
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Inhibitors of Yellow Fever Virus replication based on 1,3,5-triphenyl-4,5-dihydropyrazole scaffold: Design, synthesis and antiviral evaluation.
Year : 2017
Volume : 141
First Page : 15
Last Page : 25
Authors : Fioravanti R, Desideri N, Carta A, Atzori EM, Delogu I, Collu G, Loddo R.
Abstract : By the antiviral screening of an in house library of pyrazoline compounds, 4-(3-(4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide (5a) was identified as a promising hit compound for the development of anti- Yellow Fever Virus (YFV) agents. Structural optimization studies were focused on the development of 5a analogues which retain the potency as YFV inhibitors and show a reduced cytotoxicity. The synthesized 1-3,5-triphenyl-pyrazolines (4a-j, 5a-j, 6a-j) were evaluated in cell based assays for cytotoxicity and antiviral activity against representative viruses of two of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV) and Flavivirus (YFV). These compounds were also tested against a large panel of different pathogenic RNA and DNA viruses. Most of the new 1-3,5-triphenyl-pyrazolines (4a-j, 5a-j, 6a-j) exhibited a specific activity against YFV, showing EC50 values in the low micromolar range with almost a 10-fold improvement in potency compared to the reference inhibitor 6-azauridine. However, the selectivity indexes of the unsubstituted (4a-j) and the phenoxy (5a-j) analogues were generally modest due to the pronounced cytotoxicity against BHK-21 cells. Otherwise, the benzyloxy derivatives (6a-j) generally coupled high potency and selectivity. On the basis of both anti-YFV activity and selectivity index, pyrazolines 6a and 6b were chosen for time of addition experiments. The selected pyrazolines and the reference inhibitor 6-azauridine displayed maximal inhibition when added in the pretreatment or during the infection.
|
Antiviral activity against Human rhinovirus serotype 14 infected in human HeLa cells assessed as reduction in virus-induced cytopathic effect after 24 to 36 hrs by MTT assay
|
Human rhinovirus B14
|
300.0
nM
|
|
Journal : J Nat Prod
Title : Phenylpropenoids from Bupleurum fruticosum as Anti-Human Rhinovirus Species A Selective Capsid Binders.
Year : 2017
Volume : 80
Issue : 10
First Page : 2799
Last Page : 2806
Authors : Fois B, Bianco G, Sonar VP, Distinto S, Maccioni E, Meleddu R, Melis C, Marras L, Pompei R, Floris C, Caboni P, Cottiglia F.
Abstract : The dichloromethane extract of the leaves of Bupleurum fruticosum was found to inhibit the replication of human rhinovirus (HRV) serotypes 14 and 39. Bioassay-guided fractionation led to the isolation of seven phenylpropenol derivatives (3-9), two polyacetylenes (1 and 2), and one monoterpene (10). Compounds 1 and 10 were identified as previously undescribed secondary metabolites after extensive 1D and 2D NMR experiments as well as high-resolution mass spectrometry. Compounds 2, 4, and 5 showed a selective inhibition of viral replication against HRV39 serotype, with 2 and 4 being the most active, with EC50 values of 1.8 ± 0.02 and 2.4 ± 0.04 μM. Mechanism of action studies indicated that 4 behaves not only as a capsid binder, interfering with the early phases of virus replication, but also as a late-phase replication inhibitor. Docking experiments were performed to confirm the ability of the antiviral phenylpropenoids to selectively fit into the hydrophobic pocket of VP1-HRV39.
|
Antiviral activity against Human rhinovirus serotype 39 infected in human HeLa cells assessed as reduction in virus-induced cytopathic effect after 24 to 36 hrs by MTT assay
|
Human rhinovirus A39
|
100.0
nM
|
|
Journal : J Nat Prod
Title : Phenylpropenoids from Bupleurum fruticosum as Anti-Human Rhinovirus Species A Selective Capsid Binders.
Year : 2017
Volume : 80
Issue : 10
First Page : 2799
Last Page : 2806
Authors : Fois B, Bianco G, Sonar VP, Distinto S, Maccioni E, Meleddu R, Melis C, Marras L, Pompei R, Floris C, Caboni P, Cottiglia F.
Abstract : The dichloromethane extract of the leaves of Bupleurum fruticosum was found to inhibit the replication of human rhinovirus (HRV) serotypes 14 and 39. Bioassay-guided fractionation led to the isolation of seven phenylpropenol derivatives (3-9), two polyacetylenes (1 and 2), and one monoterpene (10). Compounds 1 and 10 were identified as previously undescribed secondary metabolites after extensive 1D and 2D NMR experiments as well as high-resolution mass spectrometry. Compounds 2, 4, and 5 showed a selective inhibition of viral replication against HRV39 serotype, with 2 and 4 being the most active, with EC50 values of 1.8 ± 0.02 and 2.4 ± 0.04 μM. Mechanism of action studies indicated that 4 behaves not only as a capsid binder, interfering with the early phases of virus replication, but also as a late-phase replication inhibitor. Docking experiments were performed to confirm the ability of the antiviral phenylpropenoids to selectively fit into the hydrophobic pocket of VP1-HRV39.
|
Antiviral activity against Coxsackievirus B5 Ohio-1 ATCC VR 29 infected in African green monkey Vero 76 cells after 3 days by plaque reduction assay
|
Coxsackievirus B5
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Quinoxaline derivatives as new inhibitors of coxsackievirus B5.
Year : 2018
Volume : 145
First Page : 559
Last Page : 569
Authors : Carta A, Sanna G, Briguglio I, Madeddu S, Vitale G, Piras S, Corona P, Peana AT, Laurini E, Fermeglia M, Pricl S, Serra A, Carta E, Loddo R, Giliberti G.
Abstract : Enteroviruses are among the most common and important human pathogens for which there are no specific antiviral agents approved by the US Food and Drug Administration so far. Particularly, coxsackievirus infections have a worldwide distribution and can cause many important diseases. We here report the synthesis of new 14 quinoxaline derivatives and the evaluation of their cytotoxicity and antiviral activity against representatives of ssRNA, dsRNA and dsDNA viruses. Promisingly, three compounds showed a very potent and selective antiviral activity against coxsackievirus B5, with EC50 in the sub-micromolar range (0.3-0.06 μM). A combination of experimental techniques (i.e. virucidal activity, time of drug addition and adsorption assays) and in silico modeling studies were further performed, aiming to understand the mode of action of the most active, selective and not cytotoxic compound, the ethyl 4-[(2,3-dimethoxyquinoxalin-6-yl)methylthio]benzoate (6).
|
Antiviral activity against Human rhinovirus B14 infected in human HeLa Rh cells assessed as protection against virus induced cytopathic effect after 3 days in presence of 10% inactivated FBS by MTT assay
|
Human rhinovirus B14
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Heterocyclic pharmacochemistry of new rhinovirus antiviral agents: A combined computational and experimental study.
Year : 2017
Volume : 140
First Page : 528
Last Page : 541
Authors : Da Costa L, Scheers E, Coluccia A, Rosetti A, Roche M, Neyts J, Terme T, Cirilli R, Mirabelli C, Silvestri R, Vanelle P.
Abstract : Rhinovirus (RV), member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in molecular biology, rhinoviruses have also been associated with exacerbations of chronic pulmonary diseases (e.g. asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis). In the current investigation, we develop a novel series of 4,5-dimethoxybenzyl derivatives that potently inhibits rhinovirus replication. Compound (S)-7f blocks RV-B14 replication with an EC50 value of 0.25 μM and shows a low toxicity in HeLa cells (CC50 > 271 μM). Enantioseparation followed by an absolute configuration determination by a Mosher's method revealed the interest of enantiopure compounds. Molecular docking studies permitted the identification of key biological interactions within the drug-binding pocket and an in silico drug-like study revealed a good potential for the development of these derivatives.
|
Antiviral activity against Human rhinovirus B14 infected in human H1HeLa cells assessed as inhibition of viral replication after 3 days by MTT assay
|
Human rhinovirus B14
|
92.0
nM
|
|
Journal : ACS Med Chem Lett
Title : 3-Aryl-1,2,4-oxadiazole Derivatives Active Against Human Rhinovirus.
Year : 2018
Volume : 9
Issue : 7
First Page : 667
Last Page : 672
Authors : Kim J, Shin JS, Ahn S, Han SB, Jung YS.
Abstract : The human rhinovirus (hRV) is the causative agent of the common cold that often aggravates respiratory complications in patients with asthma or chronic obstructive pulmonary disease. The high rate of mutations and variety of serotypes are limiting the development of anti-hRV drugs, which emphasizes the need for the discovery of novel lead compounds. Previously, we identified antiviral compound 1 that we used here as the starting material for developing a novel compound series with high efficacy against hRV-A and -B. Improved metabolic stability was achieved by substituting an ester moiety with a 1,2,4-oxadiazole group. Specifically, compound 3k exhibited a high efficacy against hRV-B14, hRV-A21, and hRV-A71, with EC50 values of 66.0, 22.0, and 3.7 nM, respectively, and a relevant hepatic stability (59.6 and 40.7% compound remaining after 30 min in rat and human liver microsomes, respectively). An in vivo study demonstrated that 3k possessed a desirable pharmacokinetic profile with low systemic clearance (0.158 L·h-1·kg-1) and modest oral bioavailability (27.8%). Hence, 3k appears to be an interesting candidate for the development of antiviral lead compounds.
|
Antiviral activity against Human rhinovirus A21 infected in human H1HeLa cells assessed as inhibition of viral replication after 3 days by MTT assay
|
Human rhinovirus A21
|
73.0
nM
|
|
Journal : ACS Med Chem Lett
Title : 3-Aryl-1,2,4-oxadiazole Derivatives Active Against Human Rhinovirus.
Year : 2018
Volume : 9
Issue : 7
First Page : 667
Last Page : 672
Authors : Kim J, Shin JS, Ahn S, Han SB, Jung YS.
Abstract : The human rhinovirus (hRV) is the causative agent of the common cold that often aggravates respiratory complications in patients with asthma or chronic obstructive pulmonary disease. The high rate of mutations and variety of serotypes are limiting the development of anti-hRV drugs, which emphasizes the need for the discovery of novel lead compounds. Previously, we identified antiviral compound 1 that we used here as the starting material for developing a novel compound series with high efficacy against hRV-A and -B. Improved metabolic stability was achieved by substituting an ester moiety with a 1,2,4-oxadiazole group. Specifically, compound 3k exhibited a high efficacy against hRV-B14, hRV-A21, and hRV-A71, with EC50 values of 66.0, 22.0, and 3.7 nM, respectively, and a relevant hepatic stability (59.6 and 40.7% compound remaining after 30 min in rat and human liver microsomes, respectively). An in vivo study demonstrated that 3k possessed a desirable pharmacokinetic profile with low systemic clearance (0.158 L·h-1·kg-1) and modest oral bioavailability (27.8%). Hence, 3k appears to be an interesting candidate for the development of antiviral lead compounds.
|
Antiviral activity against Human rhinovirus A71 infected in human H1HeLa cells assessed as inhibition of viral replication after 3 days by MTT assay
|
Human rhinovirus A71
|
9.4
nM
|
|
Journal : ACS Med Chem Lett
Title : 3-Aryl-1,2,4-oxadiazole Derivatives Active Against Human Rhinovirus.
Year : 2018
Volume : 9
Issue : 7
First Page : 667
Last Page : 672
Authors : Kim J, Shin JS, Ahn S, Han SB, Jung YS.
Abstract : The human rhinovirus (hRV) is the causative agent of the common cold that often aggravates respiratory complications in patients with asthma or chronic obstructive pulmonary disease. The high rate of mutations and variety of serotypes are limiting the development of anti-hRV drugs, which emphasizes the need for the discovery of novel lead compounds. Previously, we identified antiviral compound 1 that we used here as the starting material for developing a novel compound series with high efficacy against hRV-A and -B. Improved metabolic stability was achieved by substituting an ester moiety with a 1,2,4-oxadiazole group. Specifically, compound 3k exhibited a high efficacy against hRV-B14, hRV-A21, and hRV-A71, with EC50 values of 66.0, 22.0, and 3.7 nM, respectively, and a relevant hepatic stability (59.6 and 40.7% compound remaining after 30 min in rat and human liver microsomes, respectively). An in vivo study demonstrated that 3k possessed a desirable pharmacokinetic profile with low systemic clearance (0.158 L·h-1·kg-1) and modest oral bioavailability (27.8%). Hence, 3k appears to be an interesting candidate for the development of antiviral lead compounds.
|
Inhibition of Rhinovirus B14 capsid infected in human HeLa Rh cells assessed as reduction in virus-induced cytopathic effect after 3 days by MTS assay
|
Human rhinovirus B14
|
30.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication.
Year : 2018
Volume : 61
Issue : 18
First Page : 8402
Last Page : 8416
Authors : Da Costa L, Scheers E, Coluccia A, Casulli A, Roche M, Di Giorgio C, Neyts J, Terme T, Cirilli R, La Regina G, Silvestri R, Mirabelli C, Vanelle P.
Abstract : Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.
|
Inhibition of Rhinovirus A02 capsid infected in human HeLa Rh cells assessed as reduction in virus-induced cytopathic effect after 3 days by MTS assay
|
Human rhinovirus A2
|
15.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication.
Year : 2018
Volume : 61
Issue : 18
First Page : 8402
Last Page : 8416
Authors : Da Costa L, Scheers E, Coluccia A, Casulli A, Roche M, Di Giorgio C, Neyts J, Terme T, Cirilli R, La Regina G, Silvestri R, Mirabelli C, Vanelle P.
Abstract : Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.
|
Inhibition of Rhinovirus A08 capsid infected in human HeLa Rh cells assessed as reduction in virus-induced cytopathic effect after 3 days by MTS assay
|
Human rhinovirus A8
|
490.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication.
Year : 2018
Volume : 61
Issue : 18
First Page : 8402
Last Page : 8416
Authors : Da Costa L, Scheers E, Coluccia A, Casulli A, Roche M, Di Giorgio C, Neyts J, Terme T, Cirilli R, La Regina G, Silvestri R, Mirabelli C, Vanelle P.
Abstract : Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.
|
Inhibition of Rhinovirus A28 capsid infected in human HeLa Rh cells assessed as reduction in virus-induced cytopathic effect after 3 days by MTS assay
|
Rhinovirus A
|
15.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication.
Year : 2018
Volume : 61
Issue : 18
First Page : 8402
Last Page : 8416
Authors : Da Costa L, Scheers E, Coluccia A, Casulli A, Roche M, Di Giorgio C, Neyts J, Terme T, Cirilli R, La Regina G, Silvestri R, Mirabelli C, Vanelle P.
Abstract : Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.
|
Inhibition of Rhinovirus A85 capsid infected in human HeLa Rh cells assessed as reduction in virus-induced cytopathic effect after 3 days by MTS assay
|
Human rhinovirus A85
|
11.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication.
Year : 2018
Volume : 61
Issue : 18
First Page : 8402
Last Page : 8416
Authors : Da Costa L, Scheers E, Coluccia A, Casulli A, Roche M, Di Giorgio C, Neyts J, Terme T, Cirilli R, La Regina G, Silvestri R, Mirabelli C, Vanelle P.
Abstract : Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.
|
Inhibition of Rhinovirus A89 capsid infected in human HeLa Rh cells assessed as reduction in virus-induced cytopathic effect after 3 days by MTS assay
|
Human rhinovirus A89
|
4.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication.
Year : 2018
Volume : 61
Issue : 18
First Page : 8402
Last Page : 8416
Authors : Da Costa L, Scheers E, Coluccia A, Casulli A, Roche M, Di Giorgio C, Neyts J, Terme T, Cirilli R, La Regina G, Silvestri R, Mirabelli C, Vanelle P.
Abstract : Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.
|
Inhibition of Rhinovirus B70 capsid infected in human HeLa Rh cells assessed as reduction in virus-induced cytopathic effect after 3 days by MTS assay
|
Human rhinovirus 70
|
167.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication.
Year : 2018
Volume : 61
Issue : 18
First Page : 8402
Last Page : 8416
Authors : Da Costa L, Scheers E, Coluccia A, Casulli A, Roche M, Di Giorgio C, Neyts J, Terme T, Cirilli R, La Regina G, Silvestri R, Mirabelli C, Vanelle P.
Abstract : Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-2.6
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Antiviral activity against Enterovirus clinical isolate
|
Enterovirus
|
30.0
nM
|
|
Journal : Eur J Med Chem
Title : Back to the future: Advances in development of broad-spectrum capsid-binding inhibitors of enteroviruses.
Year : 2019
Volume : 178
First Page : 606
Last Page : 622
Authors : Egorova A, Ekins S, Schmidtke M, Makarov V.
Abstract : The hydrophobic pocket within viral capsid protein 1 is a target to combat the rhino- and enteroviruses (RV and EV) using small molecules. The highly conserved amino acids lining this pocket enable the development of antivirals with broad-spectrum of activity against numerous RVs and EVs. Inhibitor binding blocks: the attachment of the virion to the host cell membrane, viral uncoating, and/or production of infectious virus particles. Syntheses and biological studies of the most well-known antipicornaviral capsid binders have been reviewed and we propose next steps in this research.
|
Cytotoxicity against human HeLa cells after 3 days by MTT assay
|
Homo sapiens
|
180.0
nM
|
|
Journal : Eur J Med Chem
Title : Back to the future: Advances in development of broad-spectrum capsid-binding inhibitors of enteroviruses.
Year : 2019
Volume : 178
First Page : 606
Last Page : 622
Authors : Egorova A, Ekins S, Schmidtke M, Makarov V.
Abstract : The hydrophobic pocket within viral capsid protein 1 is a target to combat the rhino- and enteroviruses (RV and EV) using small molecules. The highly conserved amino acids lining this pocket enable the development of antivirals with broad-spectrum of activity against numerous RVs and EVs. Inhibitor binding blocks: the attachment of the virion to the host cell membrane, viral uncoating, and/or production of infectious virus particles. Syntheses and biological studies of the most well-known antipicornaviral capsid binders have been reviewed and we propose next steps in this research.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
26.3
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.7
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
3.549
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.02
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.11
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.11
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.02
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Antiviral activity against Coxsackievirus B3 infected in Vero cells assessed as reduction in virus-induced cytopathic effect incubated for 48 hrs by Reed-Muench method
|
Human coxsackievirus B3
|
2.0
nM
|
|
Journal : J Med Chem
Title : 2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action.
Year : 2020
Volume : 63
Issue : 11
First Page : 5972
Last Page : 5989
Authors : Jiang X, Tan J, Wang Y, Chen J, Li J, Jiang Z, Quan Y, Jin J, Li Y, Cen S, Li Y, Peng Z, Li Z.
Abstract : Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, 35 (L0909, EC50 = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that L0909 could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that L0909 is long-lasting, is orally available, and has low toxicity in vivo. These results show L0909 as a promising HCV entry inhibitor for single or combinational therapeutic potential.
|
Antiviral activity against wild type Coxsackievirus B3 97927 infected in human HeLa cell line assessed as inhibition of virus-induced cytopathic effect measured after 48 hrs by crystal violet uptake assay
|
Human coxsackievirus B3
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses.
Year : 2020
Volume : 188
First Page : 112007
Last Page : 112007
Authors : Egorova A,Kazakova E,Jahn B,Ekins S,Makarov V,Schmidtke M
Abstract : Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 10g was among the compounds exhibiting the strongest activity against pleconaril-resistant as well as pleconaril-susceptible enteroviruses with IC values from 0.02 to 5.25 μM in this series. Compound 10g demonstrated markedly less CYP3A4 induction than pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations.
|
Antiviral activity against Rhinovirus A2 infected in human HeLa cell line assessed as inhibition of virus-induced cytopathic effect measured after 72 hrs by crystal violet uptake assay
|
Human rhinovirus A2
|
40.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses.
Year : 2020
Volume : 188
First Page : 112007
Last Page : 112007
Authors : Egorova A,Kazakova E,Jahn B,Ekins S,Makarov V,Schmidtke M
Abstract : Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 10g was among the compounds exhibiting the strongest activity against pleconaril-resistant as well as pleconaril-susceptible enteroviruses with IC values from 0.02 to 5.25 μM in this series. Compound 10g demonstrated markedly less CYP3A4 induction than pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations.
|
Antiviral activity against Rhinovirus B14 infected in human HeLa cell line assessed as inhibition of virus-induced cytopathic effect measured after 72 hrs by crystal violet uptake assay
|
Human rhinovirus B14
|
70.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses.
Year : 2020
Volume : 188
First Page : 112007
Last Page : 112007
Authors : Egorova A,Kazakova E,Jahn B,Ekins S,Makarov V,Schmidtke M
Abstract : Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 10g was among the compounds exhibiting the strongest activity against pleconaril-resistant as well as pleconaril-susceptible enteroviruses with IC values from 0.02 to 5.25 μM in this series. Compound 10g demonstrated markedly less CYP3A4 induction than pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations.
