|
Antiviral activity against A/WSN/33 strain of influenza virus (H1N1 subtype) in MDBK cells using cell protection assay; expressed as 10-100 ppm
|
Bos taurus
|
100.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-influenza virus activities of 2-alkoxyimino-n-(2-isoxazolin-3-ylmethyl)acetamides.
Year : 2001
Volume : 11
Issue : 15
First Page : 1997
Last Page : 2000
Authors : Kai H, Matsumoto H, Hattori N, Takase A, Fujiwara T, Sugimoto H.
Abstract : A series of 2-alkoxyimino-N-(2-isoxazolin-3-ylmethyl)acetamides and related compounds were synthesized and their antiviral activities against human influenza A virus were assessed. Studies of the structure-activity relationships revealed the strongest antiviral activity when position-5 of the isoxazoline ring was substituted with a tert-butyl group. When the alkoxyimino moiety was substituted with a methyl, ethyl, isopropyl or allyl group, good antiviral activity was obtained. Among the geometrical isomers at the oxime moiety, the E-isomers were more active than the Z-isomers. Among the compounds examined, (E)-2-allyloxyimino-2-cyano-N-(5-tert-butyl-2-isoxazolin-3-ylmethyl)acetamide (1j) was the most active inhibitor with an EC(50) of 3 microg/mL in vitro.
|
Binding affinity towards sigma receptor in guinea pig brain membrane was determined by using [3H]DTG as the radioligand
|
Cavia porcellus
|
20.25
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Trishomocubanes, a new class of selective and high affinity ligands for the sigma binding site
Year : 1996
Volume : 6
Issue : 6
First Page : 595
Last Page : 600
Authors : Kassiou M, Nguyen VH, Knott R, Christie MJ, Hambley TW
|
Antiviral activity against Influenza A virus (A/WSN/33/London (H1N1)) in MDCK cells after 72 hrs by neutral red dye uptake assy
|
Influenza A virus
|
15.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Cyclic depsipeptides, ichthyopeptins A and B, from Microcystis ichthyoblabe.
Year : 2007
Volume : 70
Issue : 7
First Page : 1084
Last Page : 1088
Authors : Zainuddin EN, Mentel R, Wray V, Jansen R, Nimtz M, Lalk M, Mundt S.
Abstract : Bioassay-guided isolation of antiviral compounds from the cultured cyanobacterium Microcystis ichthyoblabe provided two novel cyclic depsipeptides, ichthyopeptins A (1) and B (2). Their structures were determined by 1D (1H and 13C) and 2D (COSY, TOCSY, ROESY, HMQC, and HMBC) NMR spectra, ESIMS-MS, and amino acid analysis. The fraction containing both cyclic depsipeptides exhibited antiviral activity against influenza A virus with an IC50 value of 12.5 microg/mL.
|
Antiviral activity against influenza A virus by hemadsorption inhibition assay
|
Influenza A virus
|
0.054
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Two new naphthoquinones with antiviral activity from Rhinacanthus nasutus.
Year : 1996
Volume : 59
Issue : 8
First Page : 808
Last Page : 811
Authors : Sendl A, Chen JL, Jolad SD, Stoddart C, Rozhon E, Kernan M, Nanakorn W, Balick M.
Abstract : Two new naphthoquinones, rhinacanthin-C (1) and rhinacanthin-D (2), exhibit inhibitory activity against cytomegalovirus (CMV), with EC50 values of 0.02 and 0.22 microgram/mL, respectively, against human CMV. They were isolated from the medicinal plant Rhinacanthus nasutus (Acanthaceae). The structures of the compounds were determined by analysis of their spectroscopic data, in particular, 2D NMR.
|
Antiviral activity against influenza H3N2 virus
|
H3N2 subtype
|
630.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks.
Year : 2009
Volume : 17
Issue : 2
First Page : 569
Last Page : 575
Authors : Prado-Prado FJ, Martinez de la Vega O, Uriarte E, Ubeira FM, Chou KC, González-Díaz H.
Abstract : One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the model in practice, we develop a virtual screening recognizing the model as active 92.7%, 102 of 110 antivirus compounds. These compounds were never use in training or predicting series. Next, we obtained and compared the topology of the CNs and their respective GCs based on Euclidean, Manhattan, Chebychey, Pearson and other similarity measures. The GC of the Manhattan network showed the more interesting features for drug-drug similarity search. We also give the procedure for the construction of Back-Projection Maps for the contribution of each drug sub-structure to the antiviral activity against different species.
|
Antiviral activity against influenza A virus NJH1N1 in MDCK cells by hemadsorption-inhibition assay
|
Influenza A virus
|
0.054
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Two new lignans with activity against influenza virus from the medicinal plant Rhinacanthus nasutus.
Year : 1997
Volume : 60
Issue : 6
First Page : 635
Last Page : 637
Authors : Kernan MR, Sendl A, Chen JL, Jolad SD, Blanc P, Murphy JT, Stoddart CA, Nanakorn W, Balick MJ, Rozhon EJ.
Abstract : Two new lignans, rhinacanthin E (1) and rhinacanthin F (2), were isolated from the aerial parts of the plant Rhinacanthus nasutus. Their structures were established by detailed spectroscopic analysis. These compounds show significant antiviral activity against influenza virus type A.
|
Cytotoxicity against MDCK cells by neutral red assay
|
Canis lupus familiaris
|
56.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Two new lignans with activity against influenza virus from the medicinal plant Rhinacanthus nasutus.
Year : 1997
Volume : 60
Issue : 6
First Page : 635
Last Page : 637
Authors : Kernan MR, Sendl A, Chen JL, Jolad SD, Blanc P, Murphy JT, Stoddart CA, Nanakorn W, Balick MJ, Rozhon EJ.
Abstract : Two new lignans, rhinacanthin E (1) and rhinacanthin F (2), were isolated from the aerial parts of the plant Rhinacanthus nasutus. Their structures were established by detailed spectroscopic analysis. These compounds show significant antiviral activity against influenza virus type A.
|
GSK_TCMDC: Inhibition of Plasmodium falciparum 3D7 in whole red blood cells, using parasite LDH activity as an index of growth. Test compounds present at 2uM
|
Plasmodium falciparum
|
98.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Inhibition of Plasmodium falciparum Dd2 in whole red blood cells, using parasite LDH activity as an index of growth. Test compounds present at 2uM
|
Plasmodium falciparum
|
0.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Inhibition of Plasmodium falciparum 3D7 LDH activity, using an LDH reporter assay. Test compounds present at 2uM
|
Plasmodium falciparum
|
0.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Percent inhibition of human HepG2 cell line. Test compounds present at 10uM.
|
Homo sapiens
|
31.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
Antiviral activity against Influenza A virus (A/Hong Kong/7/87(H3N2)) assessed as inhibition of virus-induced cytopathic effect by cell-based assay
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Diazo transfer-click reaction route to new, lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial and anti-influenza virus activity: an aggregation and receptor binding study.
Year : 2009
Volume : 52
Issue : 19
First Page : 6053
Last Page : 6061
Authors : Pintér G, Batta G, Kéki S, Mándi A, Komáromi I, Takács-Novák K, Sztaricskai F, Röth E, Ostorházi E, Rozgonyi F, Naesens L, Herczegh P.
Abstract : Semisynthetic, lipophilic ristocetin and teicoplanin derivatives were prepared starting from ristocetin aglycon and teicoplanin psi-aglycon (N-acetyl-D-glucosaminyl aglycoteicoplanin). The terminal amino functions of the aglycons were converted into azido form by triflic azide. Copper catalyzed 1,3-dipolar cycloaddition reaction with lipophilic alkynes resulted in the title compounds. Two of the teicoplanin derivatives showed very good MIC and MBC values against various Gram-positive bacteria, including vanA enterococci. The aggregation and interaction of a n-decyl derivative with bacterial cell wall components was studied. One of the lipophilic ristocetin derivatives displayed favorable anti-influenza virus activity.
|
Antiviral activity against Influenza A virus (A/Hong Kong/7/87(H3N2)) assessed as cell viability by cell-based MTS assay
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Diazo transfer-click reaction route to new, lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial and anti-influenza virus activity: an aggregation and receptor binding study.
Year : 2009
Volume : 52
Issue : 19
First Page : 6053
Last Page : 6061
Authors : Pintér G, Batta G, Kéki S, Mándi A, Komáromi I, Takács-Novák K, Sztaricskai F, Röth E, Ostorházi E, Rozgonyi F, Naesens L, Herczegh P.
Abstract : Semisynthetic, lipophilic ristocetin and teicoplanin derivatives were prepared starting from ristocetin aglycon and teicoplanin psi-aglycon (N-acetyl-D-glucosaminyl aglycoteicoplanin). The terminal amino functions of the aglycons were converted into azido form by triflic azide. Copper catalyzed 1,3-dipolar cycloaddition reaction with lipophilic alkynes resulted in the title compounds. Two of the teicoplanin derivatives showed very good MIC and MBC values against various Gram-positive bacteria, including vanA enterococci. The aggregation and interaction of a n-decyl derivative with bacterial cell wall components was studied. One of the lipophilic ristocetin derivatives displayed favorable anti-influenza virus activity.
|
Antiviral activity against Influenza A virus H1N1 infected in MDCK cells assessed as inhibition of virus-induced cytopathic effect after 3 days by XTT assay
|
Influenza A virus
|
0.92
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Influenza A (H(1)N(1)) Antiviral and Cytotoxic Agents from Ferula assa-foetida.
Year : 2009
Volume : 72
Issue : 9
First Page : 1568
Last Page : 1572
Authors : Lee CL, Chiang LC, Cheng LH, Liaw CC, Abd El-Razek MH, Chang FR, Wu YC.
Abstract : Two new sesquiterpene coumarins, designated 5'-acetoxy-8'-hydroxyumbelliprenin (1) and 10'R-acetoxy-11'-hydroxyumbelliprenin (2), and a new diterpene, 15-hydroxy-6-en-dehydroabietic acid (3), along with 27 known compounds, were isolated from a CHCl(3)-soluble extract of Ferula assa-foetida through bioassay-guided fractionation. The structures of the new metabolites 1-3 were identified by spectroscopic data interpretation and by the Mosher ester method. Compounds 4 and 6-13 showed greater potency against influenza A virus (H(1)N(1)) (IC(50) 0.26-0.86 microg/mL) than amantadine (IC(50) 0.92 microg/mL), and 11 exhibited the best potency (IC(50) 0.51, 2.6, and 3.4 microg/mL) of these compounds against the HepG2, Hep3B, and MCF-7 cancer cell lines, respectively.
|
Binding affinity to Influenza A Weybridge(H7N7) virus Matrix protein 2 by spectrophotometry
|
Influenza A virus (A/chicken/FPV/Weybridge(H7N7))
|
320.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Interaction of aminoadamantane derivatives with the influenza A virus M2 channel-docking using a pore blocking model.
Year : 2010
Volume : 20
Issue : 14
First Page : 4182
Last Page : 4187
Authors : Eleftheratos S, Spearpoint P, Ortore G, Kolocouris A, Martinelli A, Martin S, Hay A.
Abstract : Interaction of aminoadamantanes with the influenza A virus M2 proton channel was analyzed by docking simulations of a series of synthetic aminoadamantane derivatives, of differing binding affinity, into the crystal structure of the transmembrane (M2TM) pore. The pore blocking model tested in the 'gas phase' describes qualitatively the changes on the relative binding affinities of the compounds (although a series of highly hydrophobic ligands which seem to have little capacity for different specific interactions with their receptor). The docking calculations predicted poses in which the adamantane ring is surrounded mainly by the alkyl side chains of Val27 or Ala30 and the ligand's amino group is generally hydrogen bonded with hydroxyls of Ser31 or carbonyls of Val27 or carbonyls of Ala30, the former (Ser31) being the most stable and most frequently observed. The binding of the ligand is a compromise between hydrogen bonding ability, which is elevated by a primary amino group, and apolar interactions, which are increased by the ability of the lipophilic moiety to adequately fill a hydrophobic pocket within the M2TM pore. A delicate balance of these hydrophobic contributions is required for optimal interaction.
|
Antiviral activity against influenza A virus H1N1 infected in MDCK cells assessed as protection against virus-induced cytopathogenicity after 2 days
|
Influenza A virus
|
101.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4(3)H-ones.
Year : 2010
Volume : 45
Issue : 11
First Page : 5474
Last Page : 5479
Authors : Kumar KS, Ganguly S, Veerasamy R, De Clercq E.
Abstract : A new series of 3-(benzylideneamino)-2-phenylquinazoline-4(3H)-ones were prepared through Schiff base formation of 3-amino-2-phenyl quinazoline-4(3)H-one with various substituted carbonyl compounds. Their chemical structures were elucidated by spectral studies. Cytotoxicity and antiviral activity were evaluated against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK- KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1N1 subtype, influenza A H3N2 subtype, and influenza B virus. Compound 2a showed better antiviral activity against the entire tested virus.
|
Antiviral activity against Influenza A virus H3N2 infected in MDCK cells assessed as protection against virus-induced cytopathogenicity after 2 days
|
Influenza A virus H3N2
|
117.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4(3)H-ones.
Year : 2010
Volume : 45
Issue : 11
First Page : 5474
Last Page : 5479
Authors : Kumar KS, Ganguly S, Veerasamy R, De Clercq E.
Abstract : A new series of 3-(benzylideneamino)-2-phenylquinazoline-4(3H)-ones were prepared through Schiff base formation of 3-amino-2-phenyl quinazoline-4(3)H-one with various substituted carbonyl compounds. Their chemical structures were elucidated by spectral studies. Cytotoxicity and antiviral activity were evaluated against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK- KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1N1 subtype, influenza A H3N2 subtype, and influenza B virus. Compound 2a showed better antiviral activity against the entire tested virus.
|
Antiviral activity against influenza A virus H1N1 infected in MDCK cells assessed as cell viability after 2 days by MTS assay
|
Influenza A virus
|
87.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4(3)H-ones.
Year : 2010
Volume : 45
Issue : 11
First Page : 5474
Last Page : 5479
Authors : Kumar KS, Ganguly S, Veerasamy R, De Clercq E.
Abstract : A new series of 3-(benzylideneamino)-2-phenylquinazoline-4(3H)-ones were prepared through Schiff base formation of 3-amino-2-phenyl quinazoline-4(3)H-one with various substituted carbonyl compounds. Their chemical structures were elucidated by spectral studies. Cytotoxicity and antiviral activity were evaluated against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK- KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1N1 subtype, influenza A H3N2 subtype, and influenza B virus. Compound 2a showed better antiviral activity against the entire tested virus.
|
Antiviral activity against Influenza A virus H3N2 infected in MDCK cells assessed as cell viability after 2 days by MTS assay
|
Influenza A virus H3N2
|
115.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4(3)H-ones.
Year : 2010
Volume : 45
Issue : 11
First Page : 5474
Last Page : 5479
Authors : Kumar KS, Ganguly S, Veerasamy R, De Clercq E.
Abstract : A new series of 3-(benzylideneamino)-2-phenylquinazoline-4(3H)-ones were prepared through Schiff base formation of 3-amino-2-phenyl quinazoline-4(3)H-one with various substituted carbonyl compounds. Their chemical structures were elucidated by spectral studies. Cytotoxicity and antiviral activity were evaluated against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK- KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1N1 subtype, influenza A H3N2 subtype, and influenza B virus. Compound 2a showed better antiviral activity against the entire tested virus.
|
Antiviral activity against Influenza A H1N1 virus subtype infected in MDCK cells assessed as inhibition of virus induced cytopathicity by visual scoring of CPE
|
Influenza A virus
|
18.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation.
Year : 2010
Volume : 45
Issue : 12
First Page : 5985
Last Page : 5997
Authors : Yadav S, Kumar P, De Clercq E, Balzarini J, Pannecouque C, Dewan SK, Narasimhan B.
Abstract : A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2χv) in describing the antimicrobial activity of synthesized compounds (1-20).
|
Antiviral activity against Influenza A H1N1 virus subtype infected in MDCK cells assessed as inhibition of virus induced cytopathicity after 2 to 4 days by MTS assay
|
Influenza A virus
|
44.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation.
Year : 2010
Volume : 45
Issue : 12
First Page : 5985
Last Page : 5997
Authors : Yadav S, Kumar P, De Clercq E, Balzarini J, Pannecouque C, Dewan SK, Narasimhan B.
Abstract : A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2χv) in describing the antimicrobial activity of synthesized compounds (1-20).
|
Antiviral activity against Influenza A H3N2 virus subtype infected in MDCK cells assessed as inhibition of virus induced cytopathicity by visual scoring of CPE
|
Influenza A virus H3N2
|
0.3
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation.
Year : 2010
Volume : 45
Issue : 12
First Page : 5985
Last Page : 5997
Authors : Yadav S, Kumar P, De Clercq E, Balzarini J, Pannecouque C, Dewan SK, Narasimhan B.
Abstract : A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2χv) in describing the antimicrobial activity of synthesized compounds (1-20).
|
Antiviral activity against Influenza A H3N2 virus subtype infected in MDCK cells assessed as inhibition of virus induced cytopathicity after 2 to 4 days by MTS assay
|
Influenza A virus H3N2
|
0.2
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation.
Year : 2010
Volume : 45
Issue : 12
First Page : 5985
Last Page : 5997
Authors : Yadav S, Kumar P, De Clercq E, Balzarini J, Pannecouque C, Dewan SK, Narasimhan B.
Abstract : A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2χv) in describing the antimicrobial activity of synthesized compounds (1-20).
|
Antiviral activity against Influenza B virus infected in MDCK cells assessed as inhibition of virus induced cytopathicity by visual scoring of CPE
|
Influenza B virus
|
200.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation.
Year : 2010
Volume : 45
Issue : 12
First Page : 5985
Last Page : 5997
Authors : Yadav S, Kumar P, De Clercq E, Balzarini J, Pannecouque C, Dewan SK, Narasimhan B.
Abstract : A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2χv) in describing the antimicrobial activity of synthesized compounds (1-20).
|
Antiviral activity against Influenza B virus infected in MDCK cells assessed as inhibition of virus induced cytopathicity after 2 to 4 days by MTS assay
|
Influenza B virus
|
200.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : 4-[1-(Substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzenesulfonic acids: synthesis, antimicrobial activity, QSAR studies, and antiviral evaluation.
Year : 2010
Volume : 45
Issue : 12
First Page : 5985
Last Page : 5997
Authors : Yadav S, Kumar P, De Clercq E, Balzarini J, Pannecouque C, Dewan SK, Narasimhan B.
Abstract : A series of 4-[1-(substituted aryl/alkyl carbonyl)-benzoimidazol-2-yl]-benzene sulphonic acids (1-20) was synthesized and evaluated, in vitro, for their antimicrobial activity and the results indicated that compounds 4-[1-(4-Nitrobenzoyl)-1H-benzoimidazol-2-yl]-benzenesulfonic acid (9) and 4-(1-octadec-9-enoyl-1H-benzoimidazol-2-yl)-benzenesulfonic acid (18) were found to be the most active ones. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial activity over the one-target QSAR models. Further the mt-QSAR model indicated the importance of the topological parameter, Balaban index (J) followed by the electronic parameter, LUMO and topological parameter, valence second order molecular connectivity index (2χv) in describing the antimicrobial activity of synthesized compounds (1-20).
|
Antiviral activity against Influenza A virus/NWS/1933(H1N1) infected in BALB/c mouse assessed as reduction in mortality rate at 2 mg, ip administered once daily for 10 days and dosed 30 mins post infection relative to untreated control
|
Influenza A virus (A/NWS/1933(H1N1))
|
77.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Therapeutic activity of an anti-idiotypic antibody-derived killer peptide against influenza A virus experimental infection.
Year : 2008
Volume : 52
Issue : 12
First Page : 4331
Last Page : 4337
Authors : Conti G, Magliani W, Conti S, Nencioni L, Sgarbanti R, Palamara AT, Polonelli L.
Abstract : The in vitro and in vivo activities of a killer decapeptide (KP) against influenza A virus is described, and the mechanisms of action are suggested. KP represents the functional internal image of a yeast killer toxin that proved to exert antimicrobial and anti-human immunodeficiency virus type 1 (HIV-1) activities. Treatment with KP demonstrated a significant inhibitory activity on the replication of two strains of influenza A virus in different cell lines, as evaluated by hemagglutination, hemadsorption, and plaque assays. The complete inhibition of virus particle production and a marked reduction of the synthesis of viral proteins (membrane protein and hemagglutinin, in particular) were observed at a KP concentration of 4 microg/ml. Moreover, KP administered intraperitoneally at a dose of 100 microg/mice once a day for 10 days to influenza A/NWS/33 (H1N1) virus-infected mice improved the survival of the animals by 40% and significantly decreased the viral titers in their lungs. Overall, KP appears to be the first anti-idiotypic antibody-derived peptide that displays inhibitory activity and that has a potential therapeutic effect against pathogenic microorganisms, HIV-1, and influenza A virus by different mechanisms of action.
|
Inhibition of Influenza A virus (A/Udorn/72) wild type matrix protein 2 expressed in xenopus oocytes at 100 uM after 2 mins by two-electrode voltage clamp assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
91.0
%
|
|
Journal : J. Med. Chem.
Title : Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.
Year : 2011
Volume : 54
Issue : 8
First Page : 2646
Last Page : 2657
Authors : Duque MD, Ma C, Torres E, Wang J, Naesens L, Juárez-Jiménez J, Camps P, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.
|
Inhibition of Influenza A virus (A/Udorn/72) matrix protein 2 S31N mutant expressed in xenopus oocytes at 100 uM after 2 mins by two-electrode voltage clamp assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
35.6
%
|
|
Journal : J. Med. Chem.
Title : Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.
Year : 2011
Volume : 54
Issue : 8
First Page : 2646
Last Page : 2657
Authors : Duque MD, Ma C, Torres E, Wang J, Naesens L, Juárez-Jiménez J, Camps P, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.
|
Inhibition of Influenza A virus (A/Udorn/72) matrix protein 2 V27A mutant expressed in xenopus oocytes at 100 uM after 2 mins by two-electrode voltage clamp assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
10.8
%
|
|
Journal : J. Med. Chem.
Title : Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.
Year : 2011
Volume : 54
Issue : 8
First Page : 2646
Last Page : 2657
Authors : Duque MD, Ma C, Torres E, Wang J, Naesens L, Juárez-Jiménez J, Camps P, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.
|
Inhibition of Influenza A virus matrix protein 2
|
Influenza A virus
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.
Year : 2011
Volume : 54
Issue : 8
First Page : 2646
Last Page : 2657
Authors : Duque MD, Ma C, Torres E, Wang J, Naesens L, Juárez-Jiménez J, Camps P, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.
|
Antagonist activity at VGCC in Sprague-Dawley rat brain synaptoneurosomes assessed as inhibition of Kcl-induced calcium flux at 100 uM after 5 mins using FURA-2AM by fluorescent spectrometer analysis relative to control
|
Rattus norvegicus
|
86.13
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents.
Year : 2011
Volume : 19
Issue : 13
First Page : 3935
Last Page : 3944
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.
|
Antagonist activity at NMDAR in Sprague-Dawley rat brain synaptoneurosomes assessed as inhibition of NMDA/glycine-induced calcium flux at 100 uM after 5 mins using FURA-2AM by fluorescent spectrometer analysis relative to control
|
Rattus norvegicus
|
83.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents.
Year : 2011
Volume : 19
Issue : 13
First Page : 3935
Last Page : 3944
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.
|
Antioxidant activity assessed as inhibition of DPPH free radicals at 0.01 mM after 30 mins by UV-visible spectrophotometer analysis relative to control
|
None
|
0.55
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents.
Year : 2011
Volume : 19
Issue : 13
First Page : 3935
Last Page : 3944
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.
|
Antioxidant activity assessed as inhibition of DPPH free radicals at 0.1 mM after 30 mins by UV-visible spectrophotometer analysis relative to control
|
None
|
2.11
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents.
Year : 2011
Volume : 19
Issue : 13
First Page : 3935
Last Page : 3944
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.
|
Antioxidant activity assessed as inhibition of DPPH free radicals at 1 mM after 30 mins by UV-visible spectrophotometer analysis relative to control
|
None
|
2.32
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents.
Year : 2011
Volume : 19
Issue : 13
First Page : 3935
Last Page : 3944
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.
|
Antioxidant activity assessed as inhibition of ABTS free radicals at 0.01 mM after 30 mins by UV-visible spectrophotometer analysis relative to control
|
None
|
0.49
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents.
Year : 2011
Volume : 19
Issue : 13
First Page : 3935
Last Page : 3944
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.
|
Antioxidant activity assessed as inhibition of ABTS free radicals at 0.1 mM after 30 mins by UV-visible spectrophotometer analysis relative to control
|
None
|
1.34
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents.
Year : 2011
Volume : 19
Issue : 13
First Page : 3935
Last Page : 3944
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.
|
Antioxidant activity assessed as inhibition of ABTS free radicals at 1 mM after 30 mins by UV-visible spectrophotometer analysis relative to control
|
None
|
1.62
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents.
Year : 2011
Volume : 19
Issue : 13
First Page : 3935
Last Page : 3944
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N-adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H-isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection.
|
Antagonist activity at voltage gated calcium channel in Sprague-Dawley rat striatal synaptoneurosomes assessed as inhibition of KCl-induced calcium flux at 100 uM by spectrofluorimetric analysis relative to control
|
Rattus norvegicus
|
86.13
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-D-aspartate receptor and voltage gated calcium channel ligands.
Year : 2011
Volume : 46
Issue : 10
First Page : 5010
Last Page : 5020
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of polycyclic fluorescent ligands were synthesised and evaluated in murine striatal synaptoneurosomes for N-methyl-D-aspartate receptor (NMDAR) mediated calcium flux inhibition and inhibition of calcium influx through voltage gated calcium channels (VGCC). Amantadine (a) and N-(1-adamantyl)-1,3-propanediamine (c) substituted with 1-cyanoisoindole (3), indazole (5), dinitrobenzene (7, 8), dansyl (9, 10) and coumarin (11) moieties showed moderate to high inhibition of the NMDAR. A high degree of VGCC inhibition was observed for the cyanoisoindole compounds (3, 4) the dansyl compounds (9, 10) and the coumarin compound (12). Fluorophores conjugated to hydroxy-4-aza-8-oxoheptacyclotetradecane (13, 14) did not exhibit any significant VGCC inhibition, but the indazole conjugate (14) showed promising NMDAR activity. Dose response curves were calculated for selected NMDAR inhibitors (8-11) and N-[3-(1-adamantylamino)propyl]-5-dimethylaminonaphthalene-1-sulfonamide (10) exhibited the highest activity of the novel compounds. Compound 10 was further used as a fluorescent NMDAR ligand in a fluorescent competition assay utilizing MK-801, NGP1-01 and amantadine as known NMDAR inhibitors to demonstrate the possible applications of the novel fluorescent compounds. These small molecule fluorescent ligands can be considered as possible pharmacological tools in assay development and/or other investigations in the study of neurodegeneration.
|
Antagonist activity at voltage gated calcium channel in Sprague-Dawley rat striatal synaptoneurosomes assessed as inhibition of NMDA/glycine-induced calcium flux at 100 uM by spectrofluorimetric analysis relative to control
|
Rattus norvegicus
|
83.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-D-aspartate receptor and voltage gated calcium channel ligands.
Year : 2011
Volume : 46
Issue : 10
First Page : 5010
Last Page : 5020
Authors : Joubert J, van Dyk S, Green IR, Malan SF.
Abstract : A series of polycyclic fluorescent ligands were synthesised and evaluated in murine striatal synaptoneurosomes for N-methyl-D-aspartate receptor (NMDAR) mediated calcium flux inhibition and inhibition of calcium influx through voltage gated calcium channels (VGCC). Amantadine (a) and N-(1-adamantyl)-1,3-propanediamine (c) substituted with 1-cyanoisoindole (3), indazole (5), dinitrobenzene (7, 8), dansyl (9, 10) and coumarin (11) moieties showed moderate to high inhibition of the NMDAR. A high degree of VGCC inhibition was observed for the cyanoisoindole compounds (3, 4) the dansyl compounds (9, 10) and the coumarin compound (12). Fluorophores conjugated to hydroxy-4-aza-8-oxoheptacyclotetradecane (13, 14) did not exhibit any significant VGCC inhibition, but the indazole conjugate (14) showed promising NMDAR activity. Dose response curves were calculated for selected NMDAR inhibitors (8-11) and N-[3-(1-adamantylamino)propyl]-5-dimethylaminonaphthalene-1-sulfonamide (10) exhibited the highest activity of the novel compounds. Compound 10 was further used as a fluorescent NMDAR ligand in a fluorescent competition assay utilizing MK-801, NGP1-01 and amantadine as known NMDAR inhibitors to demonstrate the possible applications of the novel fluorescent compounds. These small molecule fluorescent ligands can be considered as possible pharmacological tools in assay development and/or other investigations in the study of neurodegeneration.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
26.4
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
10.0
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
17.0
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Antiviral activity against Influenza A virus (A/Hong Kong/7/1987(H3N2)) H1N1 infected in MDCK cells assessed as inhibition of virus-induced cytopathic effect
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
450.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of isoindole and benzoisoindole derivatives of teicoplanin pseudoaglycon with remarkable antibacterial and antiviral activities.
Year : 2012
Volume : 22
Issue : 23
First Page : 7092
Last Page : 7096
Authors : Sipos A, Török Z, Rőth E, Kiss-Szikszai A, Batta G, Bereczki I, Fejes Z, Borbás A, Ostorházi E, Rozgonyi F, Naesens L, Herczegh P.
Abstract : The primary amino function of teicoplanin pseudoaglycon has been transformed into arylthioisoindole or benzoisoindole and glycosylthioisoindole derivatives, in a reaction with o-phthalaldehyde or naphtalene-2,3-dicarbaldehyde and various thiols. All of the obtained semisynthetic antibiotics exhibited potent antibacterial activities against Gram-positive bacteria in the ng per ml concentration range. A few of them showed antiviral activity, in particular against influenza virus.
|
Inhibition of human MATE1-mediated ASP+ uptake expressed in HEK293 cells at 20 uM after 1.5 mins by fluorescence assay
|
Homo sapiens
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.
Year : 2013
Volume : 56
Issue : 3
First Page : 781
Last Page : 795
Authors : Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM.
Abstract : The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
|
Antiviral activity against Influenza A virus (A/Taiwan/1/1986(H1N1)) infected in MDCK cells assessed as inhibition of virus-induced cytopathogenicity at 1 hr post-infection measured after 3 days by fluorescein-diacetate based fluorimetric analysis
|
Influenza A virus (A/Taiwan/1/1986(H1N1))
|
600.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Efficient synthesis of 3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3,3'-dione as novel skeletons specifically for influenza virus type B inhibition.
Year : 2013
Volume : 62
First Page : 534
Last Page : 544
Authors : Malpani Y, Achary R, Kim SY, Jeong HC, Kim P, Han SB, Kim M, Lee CK, Kim JN, Jung YS.
Abstract : An efficient and novel two step synthetic procedure to prepare various substituted 3H,3'H-spiro[benzofuran-2,1'-isobenzofuran]-3,3'-diones A, was established from very simple and easily available starting materials. The developed method is a robust and general approach for the synthesis of these structures. The prepared compounds were tested against influenza virus type A viz., A/Taiwan/1/86 (H1N1), A/Hong Kong/8/68 (H3N2) and type B viz., B/Panama/45/90, B/Taiwan/2/62, B/Lee/40, B/Brisbane/60/2008. Among 31 compounds tested, some of them showed good activity (selective index values >10) against these influenza viruses preferentially for type B. The most active compound 3b showed activity in 3.0-16.1 μM range with a selectivity index value between 30 and 166 against these type B viruses, in which it was comparable to the antiviral agent favipiravir. Also, 3b is found to be inactive against other enveloped viruses (viz., HIV and HSV) showing its specificity for influenza viruses.
|
Antiviral activity against influenza A virus H3N3 subtype infected in dog MDCK cells assessed as reduction of virus-induced cytopathogenicity by MTS assay
|
Influenza A virus
|
300.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of 4-aminoquinoline-pyrimidine hybrids as potent antimalarials and their mode of action studies.
Year : 2013
Volume : 66
First Page : 314
Last Page : 323
Authors : Singh K, Kaur H, Chibale K, Balzarini J.
Abstract : One of the most viable options to tackle the growing resistance to the antimalarial drugs such as artemisinin is to resort to synthetic drugs. The multi-target strategy involving the use of hybrid drugs has shown promise. In line with this, new hybrids of quinoline with pyrimidine have been synthesized and evaluated for their antiplasmodial activity against both CQ(S) and CQ(R) strains of Plasmodium falciparum. These depicted activity in nanomolar range and were found to bind to heme as well as AT rich pUC18 DNA.
|
Antiviral activity against Influenza A virus H3N3 infected in MDCK cells assessed as reduction in virus-induced cytopathogenicity
|
Influenza A virus
|
800.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Regioselective synthesis of 6-substituted-2-amino-5-bromo-4(3H)-pyrimidinones and evaluation of their antiviral activity.
Year : 2013
Volume : 67
First Page : 428
Last Page : 433
Authors : Singh K, Singh K, Balzarini J.
Abstract : A series of 2-amino-5-bromo-4(3H)-pyrimidinone derivatives bearing different substituents at the C-6 position were synthesized using a highly regioselective lithiation-substitution protocol, and the effect of structural variation at the C-6 position on their antiviral activity in cell culture was evaluated. Although some of the derivatives were found to be active against various virus strains, they were effective only close to their toxicity threshold.
|
Antiviral activity against Influenza A virus (A/Hong Kong/7/1987(H3N2)) harboring wild type M2 channel infected in MDCK cells assessed as reduction of cytopathic effect after 72 hrs by MTS assay
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
820.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-Azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane derivatives: from wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant.
Year : 2013
Volume : 56
Issue : 22
First Page : 9265
Last Page : 9274
Authors : Rey-Carrizo M, Torres E, Ma C, Barniol-Xicota M, Wang J, Wu Y, Naesens L, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.
|
Antiviral activity against Influenza A virus (A/Hong Kong/7/1987(H3N2)) harboring wild type M2 channel infected in MDCK cells assessed as reduction of cytopathic effect after 72 hrs by microsocopic analysis
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
840.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-Azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane derivatives: from wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant.
Year : 2013
Volume : 56
Issue : 22
First Page : 9265
Last Page : 9274
Authors : Rey-Carrizo M, Torres E, Ma C, Barniol-Xicota M, Wang J, Wu Y, Naesens L, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.
|
Inhibition of Influenza A virus Udorn/72 M2 ion channel V27A mutant expressed in Xenopus oocyte plasma membranes at 100 uM after 2 mins by two-electrode voltage clamp assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
10.8
%
|
|
Journal : J. Med. Chem.
Title : 3-Azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane derivatives: from wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant.
Year : 2013
Volume : 56
Issue : 22
First Page : 9265
Last Page : 9274
Authors : Rey-Carrizo M, Torres E, Ma C, Barniol-Xicota M, Wang J, Wu Y, Naesens L, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.
|
Inhibition of Influenza A virus Udorn/72 M2 ion channel S31N mutant expressed in Xenopus oocyte plasma membranes at 100 uM after 2 mins by two-electrode voltage clamp assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
35.6
%
|
|
Journal : J. Med. Chem.
Title : 3-Azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane derivatives: from wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant.
Year : 2013
Volume : 56
Issue : 22
First Page : 9265
Last Page : 9274
Authors : Rey-Carrizo M, Torres E, Ma C, Barniol-Xicota M, Wang J, Wu Y, Naesens L, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.
|
Inhibition of Influenza A virus Udorn/72 wild type M2 ion channel expressed in Xenopus oocyte plasma membranes at 100 uM after 2 mins by two-electrode voltage clamp assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
91.0
%
|
|
Journal : J. Med. Chem.
Title : 3-Azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane derivatives: from wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant.
Year : 2013
Volume : 56
Issue : 22
First Page : 9265
Last Page : 9274
Authors : Rey-Carrizo M, Torres E, Ma C, Barniol-Xicota M, Wang J, Wu Y, Naesens L, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.
|
Antiviral activity against Influenza A virus A2/Taiwan/1/64(H2N2) infected in MDCK cells expressing wild type M2 after overnight incubation by fluorescence-based miniplaque assay
|
influenza A virus
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Aminoadamantanes with persistent in vitro efficacy against H1N1 (2009) influenza A.
Year : 2014
Volume : 57
Issue : 11
First Page : 4629
Last Page : 4639
Authors : Kolocouris A, Tzitzoglaki C, Johnson FB, Zell R, Wright AK, Cross TA, Tietjen I, Fedida D, Busath DD.
Abstract : A series of 2-adamantanamines with alkyl adducts of various lengths were examined for efficacy against strains of influenza A including those having an S31N mutation in M2 proton channel that confer resistance to amantadine and rimantadine. The addition of as little as one CH2 group to the methyl adduct of the amantadine/rimantadine analogue, 2-methyl-2-aminoadamantane, led to activity in vitro against two M2 S31N viruses A/Calif/07/2009 (H1N1) and A/PR/8/34 (H1N1) but not to a third A/WS/33 (H1N1). Solid state NMR of the transmembrane domain (TMD) with a site mutation corresponding to S31N shows evidence of drug binding. But electrophysiology using the full length S31N M2 protein in HEK cells showed no blockade. A wild type strain, A/Hong Kong/1/68 (H3N2) developed resistance to representative drugs within one passage with mutations in M2 TMD, but A/Calif/07/2009 S31N was slow (>8 passages) to develop resistance in vitro, and the resistant virus had no mutations in M2 TMD. The results indicate that 2-alkyl-2-aminoadamantane derivatives with sufficient adducts can persistently block p2009 influenza A in vitro through an alternative mechanism. The observations of an HA1 mutation, N160D, near the sialic acid binding site in both 6-resistant A/Calif/07/2009(H1N1) and the broadly resistant A/WS/33(H1N1) and of an HA1 mutation, I325S, in the 6-resistant virus at a cell-culture stable site suggest that the drugs tested here may block infection by direct binding near these critical sites for virus entry to the host cell.
|
Inhibition of wild type Influenza A virus (A/udorn/72(H3N2)) M2 channel expressed in Xenopus oocyte plasma membrane at 100 uM incubated for 2 mins measured over 48 to 72 hrs by two-electrode voltage clamp method relative to control
|
Influenza A virus (A/udorn/1972(H3N2))
|
91.0
%
|
|
Journal : J. Med. Chem.
Title : Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus.
Year : 2014
Volume : 57
Issue : 13
First Page : 5738
Last Page : 5747
Authors : Rey-Carrizo M, Barniol-Xicota M, Ma C, Frigolé-Vivas M, Torres E, Naesens L, Llabrés S, Juárez-Jiménez J, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.
|
Inhibition of amantadine-resistant Influenza A virus (A/udorn/72(H3N2)) M2 S31N mutant channel expressed in Xenopus oocyte plasma membrane at 100 uM incubated for 2 mins measured over 48 to 72 hrs by two-electrode voltage clamp method relative to control
|
Influenza A virus (A/udorn/1972(H3N2))
|
35.6
%
|
|
Journal : J. Med. Chem.
Title : Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus.
Year : 2014
Volume : 57
Issue : 13
First Page : 5738
Last Page : 5747
Authors : Rey-Carrizo M, Barniol-Xicota M, Ma C, Frigolé-Vivas M, Torres E, Naesens L, Llabrés S, Juárez-Jiménez J, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.
|
Inhibition of amantadine-resistant Influenza A virus (A/udorn/72(H3N2)) M2 V27A mutant channel expressed in Xenopus oocyte plasma membrane at 100 uM incubated for 2 mins measured over 48 to 72 hrs by two-electrode voltage clamp method relative to control
|
Influenza A virus (A/udorn/1972(H3N2))
|
10.8
%
|
|
Journal : J. Med. Chem.
Title : Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus.
Year : 2014
Volume : 57
Issue : 13
First Page : 5738
Last Page : 5747
Authors : Rey-Carrizo M, Barniol-Xicota M, Ma C, Frigolé-Vivas M, Torres E, Naesens L, Llabrés S, Juárez-Jiménez J, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vázquez S.
Abstract : Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.
|
Antiviral activity against Influenza A virus (A/HK/7/1987(H3N2)) infected in MDCK cells assessed as virus-induced cytopathic effect after 72 hrs by microscopy
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
450.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semisynthetic teicoplanin derivatives as new influenza virus binding inhibitors: synthesis and antiviral studies.
Year : 2014
Volume : 24
Issue : 15
First Page : 3251
Last Page : 3254
Authors : Bereczki I, Kicsák M, Dobray L, Borbás A, Batta G, Kéki S, Nikodém ÉN, Ostorházi E, Rozgonyi F, Vanderlinden E, Naesens L, Herczegh P.
Abstract : In order to obtain new, cluster-forming antibiotic compounds, teicoplanin pseudoaglycone derivatives containing two lipophilic n-octyl chains have been synthesized. The compounds proved to be poor antibacterials, but, surprisingly, they exhibited potent anti-influenza virus activity against influenza A strains. This antiviral action was related to inhibition of the binding interaction between the virus and the host cell. Related analogs bearing methyl substituents in lieu of the octyl chains, displayed no anti-influenza virus activity. Hence, an interaction between the active, dually n-octylated compounds and the lipid bilayer of the host cell can be postulated, to explain the observed inhibition of influenza virus attachment.
|
Antiviral activity against Influenza A virus (A/HK/7/1987(H3N2)) infected in MDCK cells assessed as reduction in host cell viability after 72 hrs by MTS assay
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semisynthetic teicoplanin derivatives as new influenza virus binding inhibitors: synthesis and antiviral studies.
Year : 2014
Volume : 24
Issue : 15
First Page : 3251
Last Page : 3254
Authors : Bereczki I, Kicsák M, Dobray L, Borbás A, Batta G, Kéki S, Nikodém ÉN, Ostorházi E, Rozgonyi F, Vanderlinden E, Naesens L, Herczegh P.
Abstract : In order to obtain new, cluster-forming antibiotic compounds, teicoplanin pseudoaglycone derivatives containing two lipophilic n-octyl chains have been synthesized. The compounds proved to be poor antibacterials, but, surprisingly, they exhibited potent anti-influenza virus activity against influenza A strains. This antiviral action was related to inhibition of the binding interaction between the virus and the host cell. Related analogs bearing methyl substituents in lieu of the octyl chains, displayed no anti-influenza virus activity. Hence, an interaction between the active, dually n-octylated compounds and the lipid bilayer of the host cell can be postulated, to explain the observed inhibition of influenza virus attachment.
|
Antiviral activity against Influenza A virus (A/HK/7/87(H3N2)) infected in MDCK cells assessed as virus plaque reduction preincubated for 1 hr followed by compound wash out and incubated for 72 hrs by crystal violet staining
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
140.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode.
Year : 2015
Volume : 96
First Page : 318
Last Page : 329
Authors : Rey-Carrizo M, Gazzarrini S, Llabrés S, Frigolé-Vivas M, Juárez-Jiménez J, Font-Bardia M, Naesens L, Moroni A, Luque FJ, Vázquez S.
Abstract : Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.0(2,10).0(3,7).0(9,11)]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.0(2,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.
|
Antiviral activity against OSV-resistant influenza A virus A/LiaoNing-ZhenXing/1109/2010 (H1N1) strain
|
influenza A virus
|
820.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Neoechinulin B and its analogues as potential entry inhibitors of influenza viruses, targeting viral hemagglutinin.
Year : 2015
Volume : 93
First Page : 182
Last Page : 195
Authors : Chen X, Si L, Liu D, Proksch P, Zhang L, Zhou D, Lin W.
Abstract : A class of prenylated indole diketopiperazine alkaloids including 15 new compounds namely rubrumlines A-O obtained from marine-derived fungus Eurotium rubrum, were tested against influenza A/WSN/33 virus. Neoechinulin B (18) exerted potent inhibition against H1N1 virus infected in MDCK cells, and is able to inhibit a panel of influenza virus strains including amantadine- and oseltamivir-resistant clinical isolates. Mechanism of action studies indicated that neoechinulin B binds to influenza envelope hemagglutinin, disrupting its interaction with the sialic acid receptor and the attachment of viruses to host cells. In addition, neoechinulin B was still efficient in inhibiting influenza A/WSN/33 virus propagation even after a fifth passage. The high potency and broad-spectrum activities against influenza viruses with less drug resistance make neoechinulin B as a new lead for the development of potential inhibitor of influenza viruses.
|
ST_JUDE_LEISH: Cytotoxicity at 2uM final concentration against transgenic Leishmania Mexicana promastigotes LmGLUT1 that are glucose transport deficient and complemented with the human glucose transporter GLUT1. Activity is measured by DNA content using SYBR green in vitro
|
Leishmania mexicana
|
5.47
%
|
|
Title : St. Jude Leishmania screening dataset.
|
ST_JUDE_LEISH: Cytotoxicity at 2uM final concentration against transgenic Leishmania Mexicana promastigotes LmPfHT that are glucose transport deficient and complemented with the Plasmodium falciparum hexose transporter. Activity is measured by by DNA content using SYBR green in vitro
|
Leishmania mexicana
|
5.42
%
|
|
Title : St. Jude Leishmania screening dataset.
|
ST_JUDE_LEISH: Cytotoxicity at 2uM final concentration against transgenic Leishmania Mexicana promastigotes LmGT2 that are glucose transport deficient and complemented with the L. Mexicana glucose transporter 2. Activity is measured by by DNA content using SYBR green in vitro
|
Leishmania mexicana
|
4.45
%
|
|
Title : St. Jude Leishmania screening dataset.
|
Inhibition of NMDA receptor in mouse synaptoneurosomes assessed as reduction of NMDA/glycine-induced calcium influx at 100 uM after 30 mins using Fura-2 AM by fluorescence assay relative to control
|
Mus musculus
|
84.6
%
|
|
Journal : MedChemComm
Title : Adamantane amine derivatives as dual acting NMDA receptor and voltage-gated calcium channel inhibitors for neuroprotection
Year : 2014
Volume : 5
Issue : 11
First Page : 1678
Last Page : 1684
Authors : Kadernani YE, Zindo FT, Kapp E, Malan SF, Joubert J
|
Inhibition of voltage-gated calcium channel in mouse synaptoneurosomes assessed as reduction of KCl-induced calcium influx at 100 uM after 30 mins using Fura-2 AM by fluorescence assay relative to control
|
Mus musculus
|
2.76
%
|
|
Journal : MedChemComm
Title : Adamantane amine derivatives as dual acting NMDA receptor and voltage-gated calcium channel inhibitors for neuroprotection
Year : 2014
Volume : 5
Issue : 11
First Page : 1678
Last Page : 1684
Authors : Kadernani YE, Zindo FT, Kapp E, Malan SF, Joubert J
|
Antiviral activity against wild type M2 ion channel expressing Influenza A virus (A/Hong Kong/1968(H3N2)) infected in MDCK cells preincubated for 30 mins followed by viral infection measured after 72 hrs by CCK-8 assay
|
Influenza A virus H3N2
|
500.0
nM
|
|
Journal : MedChemComm
Title : Identification of camphor derivatives as novel M2 ion channel inhibitors of influenza A virus
Year : 2015
Volume : 6
Issue : 4
First Page : 727
Last Page : 731
Authors : Zhao X, Zhang Z, Cui W, Chen S, Zhou Y, Dong J, Jie Y, Wan J, Xu Y, Hu W
|
Inhibition of Influenza A virus wild type M2 ion channel expressed in Xenopus oocytes at 100 uM after 2 mins by two-electrode voltage clamp assay
|
influenza A virus
|
93.8
%
|
|
Journal : Eur. J. Med. Chem.
Title : Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus.
Year : 2016
Volume : 108
First Page : 605
Last Page : 615
Authors : Dong J, Chen S, Li R, Cui W, Jiang H, Ling Y, Yang Z, Hu W.
Abstract : We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak. To further increase its potency, a structure-activity relationship study of a series of imidazole-linked pinanamine derivatives was conducted by modifying the imidazole ring of this compound. Several compounds of this series inhibited the amantadine-sensitive virus at low micromolar concentrations. Among them, 33 was the most potent compound, which was identified as being active on an amantadine-sensitive virus through blocking of the viral M2 ion channel. Furthermore, 33 markedly inhibited the amantadine-resistant virus (IC50 = 3.4 μM) and its activity increased by almost 24-fold compared to initial compound, with its action mechanism being not M2 channel mediated.
|
Inhibition of Influenza A virus M2 S31N mutant ion channel expressed in Xenopus oocytes at 100 uM after 2 mins by two-electrode voltage clamp assay
|
influenza A virus
|
24.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus.
Year : 2016
Volume : 108
First Page : 605
Last Page : 615
Authors : Dong J, Chen S, Li R, Cui W, Jiang H, Ling Y, Yang Z, Hu W.
Abstract : We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak. To further increase its potency, a structure-activity relationship study of a series of imidazole-linked pinanamine derivatives was conducted by modifying the imidazole ring of this compound. Several compounds of this series inhibited the amantadine-sensitive virus at low micromolar concentrations. Among them, 33 was the most potent compound, which was identified as being active on an amantadine-sensitive virus through blocking of the viral M2 ion channel. Furthermore, 33 markedly inhibited the amantadine-resistant virus (IC50 = 3.4 μM) and its activity increased by almost 24-fold compared to initial compound, with its action mechanism being not M2 channel mediated.
|
Antiviral activity against Influenza A virus A/udorn/72(H3N2) expressing wild type M2 proton channel infected in MDCK cells assessed as reduction in plaque formation preincubated for 30 mins followed by infection measured on day 2 post infection by naphthalene black dye-based assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Highly Potent Inhibitors Targeting the Predominant Drug-Resistant S31N Mutant of the Influenza A Virus M2 Proton Channel.
Year : 2016
Volume : 59
Issue : 3
First Page : 1207
Last Page : 1216
Authors : Li F, Ma C, DeGrado WF, Wang J.
Abstract : With the emergence of highly pathogenic avian influenza (HPAI) H7N9 and H5N1 strains, there is a pressing need to develop direct-acting antivirals (DAAs) to combat such deadly viruses. The M2-S31N proton channel of the influenza A virus (A/M2) is one of the validated and most conserved proteins encoded by the current circulating influenza A viruses; thus, it represents a high-profile drug target for therapeutic intervention. We recently discovered a series of S31N inhibitors with the general structure of adamantyl-1-NH2(+)CH2-aryl, but they generally had poor physical properties and some showed toxicity in vitro. In this study, we sought to optimize both the adamantyl as well as the aryl/heteroaryl group. Several compounds from this study exhibited submicromolar EC50 values against S31N-containing A/WSN/33 influenza viruses in antiviral plaque reduction assays with a selectivity index greater than 100, indicating that these compounds are promising candidates for in-depth preclinical pharmacology.
|
Inhibition of Influenza A virus A/udorn/72(H3N2) wild type M2 proton channel expressed in yeast assessed as growth restoration measured after 44 hrs by turbidometric assay
|
Influenza A virus (A/udorn/1972(H3N2))
|
100.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel spirothiazamenthane inhibitors of the influenza A M2 proton channel.
Year : 2016
Volume : 120
First Page : 64
Last Page : 73
Authors : Arns S, Balgi AD, Shimizu Y, Pfeifer TA, Kumar N, Shidmoossavee FS, Sun S, Tai SS, Agafitei O, Jaquith JB, Bourque E, Niikura M, Roberge M.
Abstract : The development of treatments for influenza that inhibit the M2 proton channel without being susceptible to the widespread resistance mechanisms associated with the adamantanes is an ongoing challenge. Using a yeast high-throughput yeast growth restoration assay designed to identify M2 channel inhibitors, a single screening hit was uncovered. This compound (3), whose structure was incorrectly identified in the literature, is an inhibitor with similar potency to amantadine against WT M2. A library of derivatives of 3 was prepared and activity against WT M2 and the two principal mutant strains (V27A and S31N) was assessed in the yeast assay. The best compounds were further evaluated in an antiviral plaque reduction assay using engineered WT, V27A and S31N M2 influenza A strains with otherwise identical genetic background. Compound 63 was found to inhibit all three virus strains in this cell based antiviral assay at micromolar concentrations, possibly through a mechanism other than M2 inhibition.
|
Antiviral activity against Influenza A virus A/Puerto Rico/8/34 expressing wild type M2 proton channel infected in MDCK cells assessed as inhibition of viral replication measured after 10 hrs by miniplaque assay
|
Influenza A virus (A/Puerto Rico/8/1934(H1N1))
|
40.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel spirothiazamenthane inhibitors of the influenza A M2 proton channel.
Year : 2016
Volume : 120
First Page : 64
Last Page : 73
Authors : Arns S, Balgi AD, Shimizu Y, Pfeifer TA, Kumar N, Shidmoossavee FS, Sun S, Tai SS, Agafitei O, Jaquith JB, Bourque E, Niikura M, Roberge M.
Abstract : The development of treatments for influenza that inhibit the M2 proton channel without being susceptible to the widespread resistance mechanisms associated with the adamantanes is an ongoing challenge. Using a yeast high-throughput yeast growth restoration assay designed to identify M2 channel inhibitors, a single screening hit was uncovered. This compound (3), whose structure was incorrectly identified in the literature, is an inhibitor with similar potency to amantadine against WT M2. A library of derivatives of 3 was prepared and activity against WT M2 and the two principal mutant strains (V27A and S31N) was assessed in the yeast assay. The best compounds were further evaluated in an antiviral plaque reduction assay using engineered WT, V27A and S31N M2 influenza A strains with otherwise identical genetic background. Compound 63 was found to inhibit all three virus strains in this cell based antiviral assay at micromolar concentrations, possibly through a mechanism other than M2 inhibition.
|
Antiviral activity against Influenza A virus A/Puerto Rico/8/34 expressing wild type M2 proton channel infected in MDCK cells assessed as inhibition of viral replication at >= 0.8 uM measured after 10 hrs by miniplaque assay
|
Influenza A virus (A/Puerto Rico/8/1934(H1N1))
|
90.0
%
|
|
Journal : Eur J Med Chem
Title : Novel spirothiazamenthane inhibitors of the influenza A M2 proton channel.
Year : 2016
Volume : 120
First Page : 64
Last Page : 73
Authors : Arns S, Balgi AD, Shimizu Y, Pfeifer TA, Kumar N, Shidmoossavee FS, Sun S, Tai SS, Agafitei O, Jaquith JB, Bourque E, Niikura M, Roberge M.
Abstract : The development of treatments for influenza that inhibit the M2 proton channel without being susceptible to the widespread resistance mechanisms associated with the adamantanes is an ongoing challenge. Using a yeast high-throughput yeast growth restoration assay designed to identify M2 channel inhibitors, a single screening hit was uncovered. This compound (3), whose structure was incorrectly identified in the literature, is an inhibitor with similar potency to amantadine against WT M2. A library of derivatives of 3 was prepared and activity against WT M2 and the two principal mutant strains (V27A and S31N) was assessed in the yeast assay. The best compounds were further evaluated in an antiviral plaque reduction assay using engineered WT, V27A and S31N M2 influenza A strains with otherwise identical genetic background. Compound 63 was found to inhibit all three virus strains in this cell based antiviral assay at micromolar concentrations, possibly through a mechanism other than M2 inhibition.
|
Inhibition of Influenza A virus (A/California/07/2009(H1N1)) M2 proton channel S31N mutant expressed in HEK cells assessed as inhibition of low-pH-dependent inward proton currents at 10 uM and pH 5.5 measured after 3 mins in presence of CaCl2 by electrophysiology method
|
Influenza A virus (A/California/07/2009(H1N1))
|
75.0
%
|
|
Journal : J Med Chem
Title : Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained.
Year : 2017
Volume : 60
Issue : 5
First Page : 1716
Last Page : 1733
Authors : Tzitzoglaki C, Wright A, Freudenberger K, Hoffmann A, Tietjen I, Stylianakis I, Kolarov F, Fedida D, Schmidtke M, Gauglitz G, Cross TA, Kolocouris A.
Abstract : While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2 pore when N31 is present, which, in contrast to wild-type (WT), leads (A) to the loss of the V27 pocket for the adamantyl cage and to a predominant orientation of the ligand's ammonium group toward the N-terminus and (B) to the lack of a helical kink upon ligand binding. The kink, which reduces the tilt of the C-terminal helical domain relative to the bilayer normal, includes the W41 primary gate for proton conductance and may prevent the gate from opening, representing an alternative view for how these drugs prevent proton conductance.
|
Inhibition of Influenza A virus (A/California/07/2009(H1N1)) M2 proton channel S31N mutant expressed in HEK cells assessed as inhibition of low-pH-dependent inward proton currents at pH 5.5 in presence of CaCl2 by electrophysiology method
|
Influenza A virus (A/California/07/2009(H1N1))
|
2.0
%
|
|
Journal : J Med Chem
Title : Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained.
Year : 2017
Volume : 60
Issue : 5
First Page : 1716
Last Page : 1733
Authors : Tzitzoglaki C, Wright A, Freudenberger K, Hoffmann A, Tietjen I, Stylianakis I, Kolarov F, Fedida D, Schmidtke M, Gauglitz G, Cross TA, Kolocouris A.
Abstract : While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2 pore when N31 is present, which, in contrast to wild-type (WT), leads (A) to the loss of the V27 pocket for the adamantyl cage and to a predominant orientation of the ligand's ammonium group toward the N-terminus and (B) to the lack of a helical kink upon ligand binding. The kink, which reduces the tilt of the C-terminal helical domain relative to the bilayer normal, includes the W41 primary gate for proton conductance and may prevent the gate from opening, representing an alternative view for how these drugs prevent proton conductance.
|
Antiviral activity against Influenza A virus (A/WSN/1933(H1N1)) expressing M2 proton channel S31N mutant infected in MDCK cells assessed as reduction in cytopathic effect after 48 hrs by crystal violet staining-based microscopic analysis
|
Influenza A virus (A/WSN/1933(H1N1))
|
270.0
nM
|
|
Journal : J Med Chem
Title : Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained.
Year : 2017
Volume : 60
Issue : 5
First Page : 1716
Last Page : 1733
Authors : Tzitzoglaki C, Wright A, Freudenberger K, Hoffmann A, Tietjen I, Stylianakis I, Kolarov F, Fedida D, Schmidtke M, Gauglitz G, Cross TA, Kolocouris A.
Abstract : While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2 pore when N31 is present, which, in contrast to wild-type (WT), leads (A) to the loss of the V27 pocket for the adamantyl cage and to a predominant orientation of the ligand's ammonium group toward the N-terminus and (B) to the lack of a helical kink upon ligand binding. The kink, which reduces the tilt of the C-terminal helical domain relative to the bilayer normal, includes the W41 primary gate for proton conductance and may prevent the gate from opening, representing an alternative view for how these drugs prevent proton conductance.
|
Antiviral activity against Influenza A virus A//HK/7/87 (H3N2) expressing wild-type M2 proton channel infected in MDCK cells assessed as reduction in plaque formation preincubated with virus for 1 hr followed by addition to cells measured after 72 hrs by crystal violet staining based assay
|
Influenza A virus (A/Hong Kong/7/1987(H3N2))
|
140.0
nM
|
|
Journal : J Med Chem
Title : Slow but Steady Wins the Race: Dissimilarities among New Dual Inhibitors of the Wild-Type and the V27A Mutant M2 Channels of Influenza A Virus.
Year : 2017
Volume : 60
Issue : 9
First Page : 3727
Last Page : 3738
Authors : Barniol-Xicota M, Gazzarrini S, Torres E, Hu Y, Wang J, Naesens L, Moroni A, Vázquez S.
Abstract : New insights on the amantadine resistance mechanism of the V27A mutant were obtained through the study of novel, easily accessible 4-(1- and 2-adamantyl)piperidines, identified as dual binders of the wild-type and V27A mutant M2 channels of influenza A virus. Their antiviral activity and channel blocking ability were determined using cell-based assays and two-electrode voltage clamp (TEVC) technique on M2 channels, respectively. In addition, electrophysiology experiments revealed two interesting findings: (i) these inhibitors display a different behavior against the wild-type versus V27A mutant A/M2 channels, and (ii) the compounds display antiviral activity when they have kd equal or smaller than 10-6 while they do not exhibit antiviral activity when kd is 10-5 or higher although they may show blocking activity in the TEV assay. Thus, caution must be taken when predicting antiviral activity based on percent channel blockage in electrophysiological assays. These findings provide experimental evidence of the resistance mechanism of the V27A mutation to wild-type inhibitors, previously predicted in silico, offer an explanation for the lack of antiviral activity of compounds active in the TEV assay, and may help design new and more effective drugs.
|
Antiviral activity against Influenza A virus A/Udorn/72 H3N2 infected in MDCK cells assessed as reduction in virus-induced cytopathic effect by crystal violet staining based light-microscopic analysis
|
Influenza A virus (A/udorn/1972(H3N2))
|
780.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.
Year : 2018
Volume : 9
Issue : 3
First Page : 198
Last Page : 203
Authors : Drakopoulos A, Tzitzoglaki C, McGuire K, Hoffmann A, Konstantinidi A, Kolokouris D, Ma C, Freudenberger K, Hutterer J, Gauglitz G, Wang J, Schmidtke M, Busath DD, Kolocouris A.
Abstract : Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
|
Antiviral activity against Influenza A virus A/WSN/33 H1N1 harboring N31S mutant infected in MDCK cells assessed as reduction in virus-induced cytopathic effect by crystal violet staining based light-microscopic analysis
|
Influenza A virus (A/WSN/1933(H1N1))
|
480.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.
Year : 2018
Volume : 9
Issue : 3
First Page : 198
Last Page : 203
Authors : Drakopoulos A, Tzitzoglaki C, McGuire K, Hoffmann A, Konstantinidi A, Kolokouris D, Ma C, Freudenberger K, Hutterer J, Gauglitz G, Wang J, Schmidtke M, Busath DD, Kolocouris A.
Abstract : Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
|
Inhibition of Influenza A virus A/Udorn/72 wild-type M2 proton channel expressed in Xenopus laevis oocytes assessed as blockade of inward currents at 100 uM at pH 5.5 after 2 mins by two-electrode voltage clamp assay relative to control
|
Influenza A virus (A/udorn/1972(H3N2))
|
90.0
%
|
|
Journal : ACS Med Chem Lett
Title : Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.
Year : 2018
Volume : 9
Issue : 3
First Page : 198
Last Page : 203
Authors : Drakopoulos A, Tzitzoglaki C, McGuire K, Hoffmann A, Konstantinidi A, Kolokouris D, Ma C, Freudenberger K, Hutterer J, Gauglitz G, Wang J, Schmidtke M, Busath DD, Kolocouris A.
Abstract : Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
|
Inhibition of Influenza A virus A/Udorn/72 wild-type M2 proton channel expressed in Xenopus laevis oocytes assessed as blockade of inward currents at 100 uM at pH 5.5 after 5 mins by two-electrode voltage clamp assay relative to control
|
Influenza A virus (A/udorn/1972(H3N2))
|
95.0
%
|
|
Journal : ACS Med Chem Lett
Title : Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.
Year : 2018
Volume : 9
Issue : 3
First Page : 198
Last Page : 203
Authors : Drakopoulos A, Tzitzoglaki C, McGuire K, Hoffmann A, Konstantinidi A, Kolokouris D, Ma C, Freudenberger K, Hutterer J, Gauglitz G, Wang J, Schmidtke M, Busath DD, Kolocouris A.
Abstract : Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
|
Inhibition of Influenza A virus A/Udorn/72 M2 proton channel S31N mutant expressed in Xenopus laevis oocytes assessed as blockade of inward currents at 100 uM at pH 5.5 after 2 mins by two-electrode voltage clamp assay relative to control
|
Influenza A virus (A/udorn/1972(H3N2))
|
35.0
%
|
|
Journal : ACS Med Chem Lett
Title : Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.
Year : 2018
Volume : 9
Issue : 3
First Page : 198
Last Page : 203
Authors : Drakopoulos A, Tzitzoglaki C, McGuire K, Hoffmann A, Konstantinidi A, Kolokouris D, Ma C, Freudenberger K, Hutterer J, Gauglitz G, Wang J, Schmidtke M, Busath DD, Kolocouris A.
Abstract : Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
|
Inhibition of Influenza A virus A/Udorn/72 M2 proton channel S31N mutant expressed in Xenopus laevis oocytes assessed as blockade of inward currents at 100 uM at pH 5.5 after 5 mins by two-electrode voltage clamp assay relative to control
|
Influenza A virus (A/udorn/1972(H3N2))
|
36.0
%
|
|
Journal : ACS Med Chem Lett
Title : Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.
Year : 2018
Volume : 9
Issue : 3
First Page : 198
Last Page : 203
Authors : Drakopoulos A, Tzitzoglaki C, McGuire K, Hoffmann A, Konstantinidi A, Kolokouris D, Ma C, Freudenberger K, Hutterer J, Gauglitz G, Wang J, Schmidtke M, Busath DD, Kolocouris A.
Abstract : Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
|
Inhibition of Influenza A virus A/Udorn/72 M2 proton channel S31N mutant expressed in Xenopus laevis oocytes assessed as blockade of inward currents at 100 uM at pH 5.5 after 10 mins by two-electrode voltage clamp assay relative to control
|
Influenza A virus (A/udorn/1972(H3N2))
|
36.3
%
|
|
Journal : ACS Med Chem Lett
Title : Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants.
Year : 2018
Volume : 9
Issue : 3
First Page : 198
Last Page : 203
Authors : Drakopoulos A, Tzitzoglaki C, McGuire K, Hoffmann A, Konstantinidi A, Kolokouris D, Ma C, Freudenberger K, Hutterer J, Gauglitz G, Wang J, Schmidtke M, Busath DD, Kolocouris A.
Abstract : Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
|
Antiviral activity against Influenza A virus (A/chicken/Hubei/327/2004(H5N1)) infected in MDCK cells after 40 mins by crystal violet staining-based plaque reduction assay
|
influenza A virus
|
230.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and structure-activity relationship study of arylsulfonamides as novel potent H5N1 inhibitors.
Year : 2018
Volume : 159
First Page : 206
Last Page : 216
Authors : Yu Y, Tang Q, Xu Z, Li S, Jin M, Zhao Z, Dong C, Wu S, Zhou HB.
Abstract : H5N1 virus, one subtype of highly pathogenic influenza A virus in human infection, has recently received attention due to its unpredictable and high mortality. In this study, a series of arylsulfonamide derivatives were identified as improved H5N1 inhibitors for the influenza treatment by systematic structure-activity relationship investigation. Among them, the most potent H5N1 inhibitor 3h exhibited excellent antiviral activity against H5N1 virus with EC50 value of 0.006 μM and selectivity index 33543.3. Moreover, the molecular docking of 3h with M2 proton channel protein provides practical way for understanding the inhibition of H5N1 with this kind of compounds.
|
Inhibition of wild type Influenza A virus (A/chicken/Hubei/327/2004(H5N1)) M2 channel expressed in yeast after 46 to 48 hrs by yeast growth restoration assay
|
influenza A virus
|
660.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and structure-activity relationship study of arylsulfonamides as novel potent H5N1 inhibitors.
Year : 2018
Volume : 159
First Page : 206
Last Page : 216
Authors : Yu Y, Tang Q, Xu Z, Li S, Jin M, Zhao Z, Dong C, Wu S, Zhou HB.
Abstract : H5N1 virus, one subtype of highly pathogenic influenza A virus in human infection, has recently received attention due to its unpredictable and high mortality. In this study, a series of arylsulfonamide derivatives were identified as improved H5N1 inhibitors for the influenza treatment by systematic structure-activity relationship investigation. Among them, the most potent H5N1 inhibitor 3h exhibited excellent antiviral activity against H5N1 virus with EC50 value of 0.006 μM and selectivity index 33543.3. Moreover, the molecular docking of 3h with M2 proton channel protein provides practical way for understanding the inhibition of H5N1 with this kind of compounds.
|
Antiviral activity against Hepatitis A virus infected in HepG2 cells assessed as virus inhibition at 40 ug/L incubated overnight with virus followed by inoculation and measured after 1 hr by crystal violet staining based plaque reduction assay
|
Hepatitis A virus
|
55.0
%
|
|
Journal : Bioorg Med Chem
Title : Thieno[2,3-d]pyrimidine as a promising scaffold in medicinal chemistry: Recent advances.
Year : 2019
Volume : 27
Issue : 7
First Page : 1159
Last Page : 1194
Authors : Ali EMH, Abdel-Maksoud MS, Oh CH.
Abstract : Thienopyrimidine scaffold is a fused heterocyclic ring system that structurally can be considered as adenine, the purine base that is found in both DNA and RNA-bioisosteres. Thienopyrimidines exist in three distinct isomeric forms. The current review discusses thieno[2,3-d]pyrimidine as a one of the opulent heterocycles in drug discovery. Its broad range of medical applications such as anticancer, anti-inflammatory, anti-microbial, and CNS protective agents has inspired us to study its structure-activity relationship (SAR), along with its relevant synthetic strategies. The present review briefly summarizes synthetic approaches for the preparation of thieno[2,3-d]pyrimidine derivatives. In addition, the promising biological activities of this scaffold are also illustrated with explanatory diagrams for their SAR studies.
|
Antiviral activity against Influenza A virus (A/HK/7/87(H3N2)) infected in dog MDCK cells assessed as reduction in virus-induced cytopathogenicity incubated for 7 days by microscopic analysis
|
Influenza A virus
|
200.0
nM
|
|
Journal : Eur J Med Chem
Title : Antitumor and antiviral activities of 4-substituted 1,2,3-triazolyl-2,3-dibenzyl-L-ascorbic acid derivatives.
Year : 2019
Volume : 184
First Page : 111739
Last Page : 111739
Authors : Macan AM, Harej A, Cazin I, Klobučar M, Stepanić V, Pavelić K, Pavelić SK, Schols D, Snoeck R, Andrei G, Raić-Malić S.
Abstract : Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.
|
Antiviral activity against Influenza A virus (A/HK/7/87(H3N2)) infected in dog MDCK cells assessed as reduction in virus-induced cytopathogenicity incubated for 7 days by MTS assay
|
Influenza A virus
|
30.0
nM
|
|
Journal : Eur J Med Chem
Title : Antitumor and antiviral activities of 4-substituted 1,2,3-triazolyl-2,3-dibenzyl-L-ascorbic acid derivatives.
Year : 2019
Volume : 184
First Page : 111739
Last Page : 111739
Authors : Macan AM, Harej A, Cazin I, Klobučar M, Stepanić V, Pavelić K, Pavelić SK, Schols D, Snoeck R, Andrei G, Raić-Malić S.
Abstract : Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.
|
Inhibition of F1F0-ATP synthase in Escherichia coli after 60 mins relative to control
|
Escherichia coli
|
100.0
%
|
|
Journal : Eur J Med Chem
Title : Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent.
Year : 2019
Volume : 182
First Page : 111644
Last Page : 111644
Authors : Narang R, Kumar R, Kalra S, Nayak SK, Khatik GL, Kumar GN, Sudhakar K, Singh SK.
Abstract : The emergence of drug resistance in infectious microbial strains can be overcome by development of novel drug molecules against unexploited microbial target. The success of Bedaquiline in recent years, as FoF1 ATP synthase inhibitor against XDR and MDR mycobacterium strains, has resulted in further exploration to identify more potent and safe drug molecules against resistant strains. FoF1 ATP synthase is the main energy production enzyme in almost all eukaryotes and prokaryotes. Development of bacterial ATP synthase inhibitors is a safe approach, without causing harm to mammalian cells due to structural difference between bacterial and mammalian ATP synthase target sites. This review emphasizes on providing the structural insights for FoF1 ATP synthase of different prokaryotes and will help in the design of new potent antimicrobial agents with better efficacy. Further, applications of synthetic and natural active antimicrobial ATP synthase inhibitors, reported by different research groups are summarized. Their SAR and mode of actions are also analysed.
|
Antiviral activity against amantadine-sensitive Influenza A virus (A/chicken/Hubei/327/2004(H5N1)) infected in MDCK cells after 40 mins by crystal violet staining-based plaque reduction assay
|
influenza A virus
|
430.0
nM
|
|
Journal : MedChemComm
Title : Design and synthesis of heteroaromatic-based benzenesulfonamide derivatives as potent inhibitors of H5N1 influenza A virus.
Year : 2019
Volume : 10
Issue : 1
First Page : 89
Last Page : 100
Authors : Yu Y, Tazeem, Xu Z, Du L, Jin M, Dong C, Zhou HB, Wu S.
Abstract : Influenza A virus is an enveloped negative single-stranded RNA virus that causes febrile respiratory infection and represents a clinically challenging threat to human health and even lives worldwide. Even more alarming is the emergence of highly pathogenic avian influenza (HPAI) strains such as H5N1, which possess much higher mortality rate (60%) than seasonal influenza strains in human infection. In this study, a novel series of heteroaromatic-based benzenesulfonamide derivatives were identified as M2 proton channel inhibitors. A systematic investigation of the structure-activity relationships and a molecular docking study demonstrated that the sulfonamide moiety and 2,5-dimethyl-substituted thiophene as the core structure played significant roles in the anti-influenza activity. Among the derivatives, compound 11k exhibited excellent antiviral activity against H5N1 virus with an EC50 value of 0.47 μM and selectivity index of 119.9, which are comparable to those of the reference drug amantadine.
|
Inhibition of wild type Influenza A virus (A/chicken/Hubei/327/2004(H5N1)) M2 expressed in yeast cells after 46 to 48 hrs
|
influenza A virus
|
660.0
nM
|
|
Journal : MedChemComm
Title : Design and synthesis of heteroaromatic-based benzenesulfonamide derivatives as potent inhibitors of H5N1 influenza A virus.
Year : 2019
Volume : 10
Issue : 1
First Page : 89
Last Page : 100
Authors : Yu Y, Tazeem, Xu Z, Du L, Jin M, Dong C, Zhou HB, Wu S.
Abstract : Influenza A virus is an enveloped negative single-stranded RNA virus that causes febrile respiratory infection and represents a clinically challenging threat to human health and even lives worldwide. Even more alarming is the emergence of highly pathogenic avian influenza (HPAI) strains such as H5N1, which possess much higher mortality rate (60%) than seasonal influenza strains in human infection. In this study, a novel series of heteroaromatic-based benzenesulfonamide derivatives were identified as M2 proton channel inhibitors. A systematic investigation of the structure-activity relationships and a molecular docking study demonstrated that the sulfonamide moiety and 2,5-dimethyl-substituted thiophene as the core structure played significant roles in the anti-influenza activity. Among the derivatives, compound 11k exhibited excellent antiviral activity against H5N1 virus with an EC50 value of 0.47 μM and selectivity index of 119.9, which are comparable to those of the reference drug amantadine.
