|
Dissociation constant for Dengue virus envelope protein binding by surface plasmon resonance
|
Dengue virus
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the interaction of dengue virus envelope protein with heparin: assessment of glycosaminoglycan-derived inhibitors.
Year : 2001
Volume : 44
Issue : 13
First Page : 2178
Last Page : 2187
Authors : Marks RM, Lu H, Sundaresan R, Toida T, Suzuki A, Imanari T, Hernáiz MJ, Linhardt RJ.
Abstract : A structure-activity relationship study was carried out to facilitate development of inhibitors of dengue virus infectivity. Previous studies demonstrated that a highly charged heparan sulfate, a heparin-like glycosaminoglycan found on the cell surface, serves as a receptor for dengue virus by binding to its envelope protein. Interventions that disrupt this binding effectively inhibit infectivity. A competitive binding assay was developed to screen polyanionic compounds for activity in preventing binding of dengue virus envelope protein to immobilized heparin; compounds tested included drugs, excipients, and larger glycosaminoglycans and their semisynthetic derivatives. Results of this competitive binding assay were used to select agents for detailed evaluation of interactions by surface plasmon resonance spectroscopy, which afforded binding on-rates, off-rates, and dissociation constants. From these data, an understanding of the structural requirements for polyanion binding to dengue virus envelope protein has been established.
|
Evaluated in vivo after intraperitoneal administration by guinea pig assay
|
Cavia porcellus
|
44.0
%
|
|
Journal : J. Med. Chem.
Title : Synthetic modulators of the complement system. 1. Synthesis and biological activity of 5,5',5''-[1,3,6-naphthalenetriyltris(sulfonylimino)]-tris[1,3-benzenedisulfonic acid] hexasodium salt.
Year : 1980
Volume : 23
Issue : 3
First Page : 240
Last Page : 242
Authors : Conrow RB, Bauman N, Brockman JA, Bernstein S.
|
The compound was evaluated for antagonist activity against phospholipase C coupled recombinant human P2Y purinoceptor 6 (P2Y6)
|
None
|
27.0
%
|
|
Journal : J. Med. Chem.
Title : Purine and pyrimidine (P2) receptors as drug targets.
Year : 2002
Volume : 45
Issue : 19
First Page : 4057
Last Page : 4093
Authors : Jacobson KA, Jarvis MF, Williams M.
|
Compound tested for % inhibition of cell-free HIV-1 Reverse Transcriptase at a concentration of 14 uM.
|
Human immunodeficiency virus 1
|
22.0
%
|
|
Journal : J. Med. Chem.
Title : Potential anti-AIDS agents. Synthesis and antiviral activity of naphthalenesulfonic acid derivatives against HIV-1 and HIV-2.
Year : 1991
Volume : 34
Issue : 1
First Page : 212
Last Page : 217
Authors : Mohan P, Singh R, Baba M.
Abstract : Certain naphthalenesulfonic acid analogues have been synthesized and evaluated for their inhibitory effects on HIV-1- and HIV-2-induced cytopathogenicity, HIV-1 giant cell formation, and HIV-1 reverse transcriptase (RT) activity. A bis(naphthalenedisulfonic acid) derivative having a biphenyl spacer emerged as the most potent and selective inhibitor of virus-induced cytopathogenicity in MT-4 cells. The ED50 values for this compound were 7.6 and 36 microM for HIV-1 and HIV-2, respectively. No toxicity to the host cells was detected at 98 microM. This compound also inhibited giant cell formation and was superseded in potency by a bis(naphthalenedisulfonic acid) derivative having a flexible decamethylene spacer. In the cell-free RT assay, a long-chain amide derivative exhibited the most inhibition of RT. All the compounds that achieved complete inhibition of virus-induced cytopathogenicity at concentrations not toxic to host cells were derivatives of 4-amino-5-hydroxy-2,7- naphthalenedisulfonic acid. These analogues represent new leads for the development of anti-HIV agents.
|
Compound tested for % inhibition of cell-free HIV-1 Reverse Transcriptase at a concentration of 2.8 uM
|
Human immunodeficiency virus 1
|
18.0
%
|
|
Journal : J. Med. Chem.
Title : Potential anti-AIDS agents. Synthesis and antiviral activity of naphthalenesulfonic acid derivatives against HIV-1 and HIV-2.
Year : 1991
Volume : 34
Issue : 1
First Page : 212
Last Page : 217
Authors : Mohan P, Singh R, Baba M.
Abstract : Certain naphthalenesulfonic acid analogues have been synthesized and evaluated for their inhibitory effects on HIV-1- and HIV-2-induced cytopathogenicity, HIV-1 giant cell formation, and HIV-1 reverse transcriptase (RT) activity. A bis(naphthalenedisulfonic acid) derivative having a biphenyl spacer emerged as the most potent and selective inhibitor of virus-induced cytopathogenicity in MT-4 cells. The ED50 values for this compound were 7.6 and 36 microM for HIV-1 and HIV-2, respectively. No toxicity to the host cells was detected at 98 microM. This compound also inhibited giant cell formation and was superseded in potency by a bis(naphthalenedisulfonic acid) derivative having a flexible decamethylene spacer. In the cell-free RT assay, a long-chain amide derivative exhibited the most inhibition of RT. All the compounds that achieved complete inhibition of virus-induced cytopathogenicity at concentrations not toxic to host cells were derivatives of 4-amino-5-hydroxy-2,7- naphthalenedisulfonic acid. These analogues represent new leads for the development of anti-HIV agents.
|
Compound tested for % inhibition of cell-free HIV-1 Reverse Transcriptase at a concentration of 350 uM
|
Human immunodeficiency virus 1
|
92.0
%
|
|
Journal : J. Med. Chem.
Title : Potential anti-AIDS agents. Synthesis and antiviral activity of naphthalenesulfonic acid derivatives against HIV-1 and HIV-2.
Year : 1991
Volume : 34
Issue : 1
First Page : 212
Last Page : 217
Authors : Mohan P, Singh R, Baba M.
Abstract : Certain naphthalenesulfonic acid analogues have been synthesized and evaluated for their inhibitory effects on HIV-1- and HIV-2-induced cytopathogenicity, HIV-1 giant cell formation, and HIV-1 reverse transcriptase (RT) activity. A bis(naphthalenedisulfonic acid) derivative having a biphenyl spacer emerged as the most potent and selective inhibitor of virus-induced cytopathogenicity in MT-4 cells. The ED50 values for this compound were 7.6 and 36 microM for HIV-1 and HIV-2, respectively. No toxicity to the host cells was detected at 98 microM. This compound also inhibited giant cell formation and was superseded in potency by a bis(naphthalenedisulfonic acid) derivative having a flexible decamethylene spacer. In the cell-free RT assay, a long-chain amide derivative exhibited the most inhibition of RT. All the compounds that achieved complete inhibition of virus-induced cytopathogenicity at concentrations not toxic to host cells were derivatives of 4-amino-5-hydroxy-2,7- naphthalenedisulfonic acid. These analogues represent new leads for the development of anti-HIV agents.
|
Compound tested for % inhibition of giant cell formation at a concentration of 70 uM
|
Human immunodeficiency virus 1
|
83.0
%
|
|
Journal : J. Med. Chem.
Title : Potential anti-AIDS agents. Synthesis and antiviral activity of naphthalenesulfonic acid derivatives against HIV-1 and HIV-2.
Year : 1991
Volume : 34
Issue : 1
First Page : 212
Last Page : 217
Authors : Mohan P, Singh R, Baba M.
Abstract : Certain naphthalenesulfonic acid analogues have been synthesized and evaluated for their inhibitory effects on HIV-1- and HIV-2-induced cytopathogenicity, HIV-1 giant cell formation, and HIV-1 reverse transcriptase (RT) activity. A bis(naphthalenedisulfonic acid) derivative having a biphenyl spacer emerged as the most potent and selective inhibitor of virus-induced cytopathogenicity in MT-4 cells. The ED50 values for this compound were 7.6 and 36 microM for HIV-1 and HIV-2, respectively. No toxicity to the host cells was detected at 98 microM. This compound also inhibited giant cell formation and was superseded in potency by a bis(naphthalenedisulfonic acid) derivative having a flexible decamethylene spacer. In the cell-free RT assay, a long-chain amide derivative exhibited the most inhibition of RT. All the compounds that achieved complete inhibition of virus-induced cytopathogenicity at concentrations not toxic to host cells were derivatives of 4-amino-5-hydroxy-2,7- naphthalenedisulfonic acid. These analogues represent new leads for the development of anti-HIV agents.
|
Inhibitory concentration against brucei variant 221 was determined in vitro
|
Trypanosoma brucei
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antitubulin activity of N1- and N4-substituted 3,5-dinitro sulfanilamides against African trypanosomes and Leishmania.
Year : 2004
Volume : 47
Issue : 7
First Page : 1823
Last Page : 1832
Authors : Bhattacharya G, Herman J, Delfín D, Salem MM, Barszcz T, Mollet M, Riccio G, Brun R, Werbovetz KA.
Abstract : Thirty analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide (GB-II-5, compound 3), a new antikinetoplastid antimitotic agent, have been synthesized and evaluated. The addition of simple functional groups to the N1 aromatic ring generally decreases antiparasitic and antimitotic potency, but placement of a dibutyl substituent at the N4 nitrogen to give N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (compound 35) augments antitrypanosomal and antileishmanial activity. Compound 35 possesses IC(50) values of 0.12 and 2.6 microM against cultured T. brucei and L. donovani amastigote-like forms, surpassing the activity of compound 3 against these parasites by 3.4- and 1.9-fold, respectively. Compound 35 inhibits the assembly of leishmanial tubulin with an IC(50) of 6.9 microM and displays antimitotic effects in cultured T. brucei as assessed by flow cytometry, but shows little effect on purified mammalian tubulin, and displays 100-fold selectivity for trypanosomes over two mammalian cell lines. Although 3 and 35 were not effective in initial in vivo antitrypanosomal assays, the in vitro potency and selectivity of these compounds make N(1)-aryl-3,5-dinitro-N(4),N(4)-dialkylsulfanilamides a promising new class of antikinetoplastid agents that act on parasite tubulin.
|
Effective concentration in vitro against the bloodstream trypomastigote form of Trypanosoma brucei
|
Trypanosoma brucei
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of nitro heterocycles analogous to megazol, a trypanocidal lead.
Year : 2003
Volume : 46
Issue : 3
First Page : 427
Last Page : 440
Authors : Chauvière G, Bouteille B, Enanga B, de Albuquerque C, Croft SL, Dumas M, Périé J.
Abstract : As part of our efforts to develop new compounds aimed at the therapy of parasitic infections, we synthesized and assayed analogues of a lead compound megazol, 5-(1-methyl-5-nitro-1H-2-imidazolyl)-1,3,4-thiadiazol-2-amine, CAS no. 19622-55-0), in vitro. We first developed a new route for the synthesis of megazol. Subsequently several structural changes were introduced, including substitutions on the two rings of the basic nucleus, replacement of the thiadiazole by an oxadiazole, replacement of the nitroimidazole part by a nitrofurane or a nitrothiophene, and substitutions on the exocyclic nitrogen atom for evaluation of an improved import by the glucose or the purine transporters. Assays of the series of compounds on the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, as either extracellular cells or infected macrophages, indicated that megazol was more active than the derivatives. Megazol was then evaluated on primates infected with Trypanosoma brucei gambiense, including late-stage central nervous system infections in combination with suramin. Full recovery was observed in five monkeys in the study with no relapse of parasitemia within a 2 year follow-up. Because there is a lack of efficacious treatments for sleeping sickness in Africa and Chagas disease in South America, megazol is proposed as a potential alternative. The mutagenicity of this compound is at present being reevaluated, and metabolism is also under investigation prior to possible further developments.
|
In vitro anti protozoal activity against Trypanosoma brucei strain S427 was determined
|
Trypanosoma brucei
|
900.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biological evaluation of substituted quinolines.
Year : 2004
Volume : 14
Issue : 14
First Page : 3635
Last Page : 3638
Authors : Franck X, Fournet A, Prina E, Mahieux R, Hocquemiller R, Figadère B.
Abstract : Several quinolines were synthesized and evaluated in vitro against several parasites (Trypanosoma brucei, T. cruzi, Leishmania infantum, L. amazonensis, Plasmodium falciparum). Then, they were evaluated in vitro (at 10 microM), against HTLV-1 transformed cells. A few of them displayed interesting activities, comparable to the reference drugs.
|
Inhibitory concentration against P2Y purinoceptor 11 expressed in 1321N1 astrocytoma cells; n=3
|
Homo sapiens
|
112.2
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency.
Year : 2005
Volume : 48
Issue : 22
First Page : 7040
Last Page : 7048
Authors : Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, Communi D, Boeynaems JM, Wolf C, Hausmann R, Schmalzing G, Kassack MU.
Abstract : Selective and potent P2Y(11) receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y(11), P2Y(1), and P2Y(2) receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y(11) antagonist (8f, NF157, pK(i): 7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y(11) over P2Y(1) (>650-fold), P2Y(2) (>650-fold), P2X(2) (3-fold), P2X(3) (8-fold), P2X(4) (>22-fold), and P2X(7) (>67-fold) but no selectivity over P2X(1). QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y(11) receptors.
|
Inhibitory concentration against P2Y purinoceptor 11 expressed in 1321N1 astrocytoma cells; n=6
|
Homo sapiens
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency.
Year : 2005
Volume : 48
Issue : 22
First Page : 7040
Last Page : 7048
Authors : Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, Communi D, Boeynaems JM, Wolf C, Hausmann R, Schmalzing G, Kassack MU.
Abstract : Selective and potent P2Y(11) receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y(11), P2Y(1), and P2Y(2) receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y(11) antagonist (8f, NF157, pK(i): 7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y(11) over P2Y(1) (>650-fold), P2Y(2) (>650-fold), P2X(2) (3-fold), P2X(3) (8-fold), P2X(4) (>22-fold), and P2X(7) (>67-fold) but no selectivity over P2X(1). QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y(11) receptors.
|
Percent inhibition of agonist-induced calcium mobilization at P2Y purinoceptor 2 recombinantly expressed in human HEK293 cells at 100 uM dose
|
Homo sapiens
|
31.6
%
|
|
Percent inhibition of agonist-induced calcium mobilization at P2Y purinoceptor 2 recombinantly expressed in human HEK293 cells at 100 uM dose
|
Homo sapiens
|
50.5
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency.
Year : 2005
Volume : 48
Issue : 22
First Page : 7040
Last Page : 7048
Authors : Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, Communi D, Boeynaems JM, Wolf C, Hausmann R, Schmalzing G, Kassack MU.
Abstract : Selective and potent P2Y(11) receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y(11), P2Y(1), and P2Y(2) receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y(11) antagonist (8f, NF157, pK(i): 7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y(11) over P2Y(1) (>650-fold), P2Y(2) (>650-fold), P2X(2) (3-fold), P2X(3) (8-fold), P2X(4) (>22-fold), and P2X(7) (>67-fold) but no selectivity over P2X(1). QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y(11) receptors.
|
Percent inhibition of agonist-induced calcium mobilization at P2Y purinoceptor 1 recombinantly expressed in human HEK293 cells at 100 uM dose
|
Homo sapiens
|
59.3
%
|
|
Percent inhibition of agonist-induced calcium mobilization at P2Y purinoceptor 1 recombinantly expressed in human HEK293 cells at 100 uM dose
|
Homo sapiens
|
54.5
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency.
Year : 2005
Volume : 48
Issue : 22
First Page : 7040
Last Page : 7048
Authors : Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, Communi D, Boeynaems JM, Wolf C, Hausmann R, Schmalzing G, Kassack MU.
Abstract : Selective and potent P2Y(11) receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y(11), P2Y(1), and P2Y(2) receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y(11) antagonist (8f, NF157, pK(i): 7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y(11) over P2Y(1) (>650-fold), P2Y(2) (>650-fold), P2X(2) (3-fold), P2X(3) (8-fold), P2X(4) (>22-fold), and P2X(7) (>67-fold) but no selectivity over P2X(1). QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y(11) receptors.
|
Percent inhibition of agonist-induced calcium mobilization at P2Y purinoceptor 11 recombinantly expressed in human HEK293 cells at 100 uM dose
|
Homo sapiens
|
89.5
%
|
|
Percent inhibition of agonist-induced calcium mobilization at P2Y purinoceptor 11 recombinantly expressed in human HEK293 cells at 100 uM dose
|
Homo sapiens
|
93.7
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency.
Year : 2005
Volume : 48
Issue : 22
First Page : 7040
Last Page : 7048
Authors : Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, Communi D, Boeynaems JM, Wolf C, Hausmann R, Schmalzing G, Kassack MU.
Abstract : Selective and potent P2Y(11) receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y(11), P2Y(1), and P2Y(2) receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y(11) antagonist (8f, NF157, pK(i): 7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y(11) over P2Y(1) (>650-fold), P2Y(2) (>650-fold), P2X(2) (3-fold), P2X(3) (8-fold), P2X(4) (>22-fold), and P2X(7) (>67-fold) but no selectivity over P2X(1). QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y(11) receptors.
|
Antiprotozoal activity against Trypanosoma brucei rhodesiense STIB900
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiprotozoal activities of new bis-chlorophenyl derivatives of bicyclic octanes and aza-nonanes.
Year : 2006
Volume : 16
Issue : 20
First Page : 5457
Last Page : 5461
Authors : Berger H, Seebacher W, Saf R, Kaiser M, Brun R, Weis R.
Abstract : The in vitro activity of newly synthesized bis-(chlorophenyl)-azabicyclo[3.2.2]nonanes and bis-(chlorophenyl)-bicyclo[2.2.2]octanes against Plasmodium falciparum K(1) (resistant to chloroquine and pyrimethamine) and Trypanosoma brucei rhodesiense was investigated. Especially the bis-(chlorophenyl)-azabicyclo[3.2.2]nonanes exhibit promising antitrypanosomal activity and were tested in vivo against Trypanosoma brucei brucei featuring moderate activities.
|
Growth inhibition against Trypanosoma brucei brucei
|
Trypanosoma brucei brucei
|
77.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation, and molecular modeling of 3,5-substituted-N1-phenyl-N4,N4-di-n-butylsulfanilamides as antikinetoplastid antimicrotubule agents.
Year : 2007
Volume : 15
Issue : 18
First Page : 6071
Last Page : 6079
Authors : George TG, Endeshaw MM, Morgan RE, Mahasenan KV, Delfín DA, Mukherjee MS, Yakovich AJ, Fotie J, Li C, Werbovetz KA.
Abstract : Dinitroanilines are of interest as antiprotozoal lead compounds because of their selective activity against the tubulin of these organisms, but concern has been raised due to the potentially mutagenic nitro groups. Analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (GB-II-150, compound 2b), a selective antimitotic agent against African trypanosomes and Leishmania, have been prepared where the nitro groups are replaced with amino, chloro, cyano, carboxylate, methyl ester, amide, and methyl ketone moieties. Dicyano compound 5 displays IC(50) values that are comparable to 2b against purified leishmanial tubulin assembly (6.6 vs 7.4 microM), Trypanosoma brucei brucei growth in vitro (0.26 vs 0.18 microM), Leishmania donovani axenic amastigote growth in vitro (4.4 vs 2.3 microM), and in vitro toxicity against Vero cells (16 vs 9.7 microM). Computational studies provide a rationale for the antiparasitic order of activity of these analogues and further insight into the role of the substituents at the 3 and 5 positions of the sulfanilamide ring.
|
Antitrypanosomal activity against Trypanosoma brucei brucei bloodstream trypomastigotes by alamar blue assay
|
Trypanosoma brucei brucei
|
41.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antitrypanosomal activity of triterpenoids and sterols from the leaves of Strychnos spinosa and related compounds.
Year : 2007
Volume : 70
Issue : 8
First Page : 1360
Last Page : 1363
Authors : Hoet S, Pieters L, Muccioli GG, Habib-Jiwan JL, Opperdoes FR, Quetin-Leclercq J.
Abstract : Fractionation of an antitrypanosomal lipophilic leaf extract from Strychnos spinosa led to the isolation of eight triterpenoids and sterols in this plant part for the first time. Two of these were found to possess in vitro antitrypanosomal activity, namely, saringosterol (14) and 24-hydroperoxy-24-vinylcholesterol (15), with IC(50) values of 7.8 +/- 1.2 and 3.2 +/- 1.2 microM, respectively. The latter compound was isolated from a plant source for the first time. A comparative study on the antitrypanosomal activity of the isolated triterpenoids and sterols and some related compounds has indicated that the presence of an oxygenated function at C-28 or an oxygenated side chain at C-17 seems to be important for the antitrypanosomal activity of triterpenoids and sterols, respectively.
|
Antitrypanosomal activity against Trypanosoma brucei brucei MITat 1.2 variant 221
|
Trypanosoma brucei brucei
|
200.0
nM
|
|
Journal : J. Nat. Prod.
Title : Trypanocidal and antileishmanial dihydrochelerythrine derivatives from Garcinia lucida.
Year : 2007
Volume : 70
Issue : 10
First Page : 1650
Last Page : 1653
Authors : Fotie J, Bohle DS, Olivier M, Adelaida Gomez M, Nzimiro S.
Abstract : Three benzo[ c]phenanthridine alkaloids have been isolated from the stem bark of Garcinia lucida: dihydrochelerythrine ( 1), 6-acetonyldihydrochelerythrine ( 2), and its new derivative, ( S)1''-(9,10-dihydro-2',3'-dihydroxy-7,8-dimethoxy-10-methyl-1,2-benzophenanthridin-9-yl)propan-2''-one (lucidamine A) ( 3). The new diisoprenylated derivative of lucidamine B ( 4) was obtained by semisynthesis. These dihydrochelerythrine derivatives as well as the crude extract displayed attractive antiprotozoal activity against Trypanosoma brucei brucei and Leishmania donovani, with little toxicity to Vero cells and the host cells. This is the first trypanocidal and antileishmanial bioguided study of G. lucida, and the activity of the crude extract as well as of the dihydrochelerythrine derivatives are reported for the first time.
|
Antitrypanosomal activity against Trypanosoma brucei
|
Trypanosoma brucei
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB.
Year : 2008
Volume : 51
Issue : 3
First Page : 545
Last Page : 552
Authors : Mallari JP, Shelat AA, Obrien T, Caffrey CR, Kosinski A, Connelly M, Harbut M, Greenbaum D, McKerrow JH, Guy RK.
Abstract : Human African trypanosomiasis (HAT), a major health concern in sub-Saharan Africa, is caused by the protozoan parasite Trypanosoma brucei. Recent studies have shown that a cathepsin B like protease, TbcatB, is essential to the survival of T. brucei in vitro (Mackey, Z. B.; O'Brien, T. C.; Greenbaum, D. C.; Blank, R. B.; McKerrow, J. H. J. Biol. Chem. 2004, 279, 48426-48433). Herein, we describe the first inhibitors of TbcatB, a series of purine nitriles. The compounds are potent trypanocides, killing the parasite with a high degree of selectivity over a panel of three human cell lines. In addition, a predictive model of trypanocidal activity was developed on the basis of potency against TbcatB and various calculated physical property descriptors.
|
Inhibition of HIV1 recombinant reverse transcriptase p66/p51 expressed in Escherichia coli
|
Human immunodeficiency virus 1
|
18.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : In vitro anti-HIV activity of biflavonoids isolated from Rhus succedanea and Garcinia multiflora.
Year : 1997
Volume : 60
Issue : 9
First Page : 884
Last Page : 888
Authors : Lin YM, Anderson H, Flavin MT, Pai YH, Mata-Greenwood E, Pengsuparp T, Pezzuto JM, Schinazi RF, Hughes SH, Chen FC.
Abstract : Eleven biflavonoids, including amentoflavone (1), agathisflavone (2), robustaflavone (3), hinokiflavone (4), volkensiflavone (5), morelloflavone (7), rhusflavanone (9), succedaneaflavanone (10), GB-1a (11), GB-1a 7"-O-beta-glucoside (13), and GB-2a (14) isolated from Rhus succedanea and Garcinia multiflora, as well as their methyl ethers, volkensiflavone hexamethyl ether (6), morelloflavone heptamethyl ether (8), and GB-1a hexamethyl ether (12), were evaluated for their anti-HIV-1 RT activity. The results indicated that compounds 3 and 4 demonstrated similar activity against HIV-1 reverse transcriptase (RT), with IC50 values of 65 microM. Compounds 1, 2, 7, 11, and 14 were moderately active against HIV-1 RT, with IC50 values of 119 microM, 100 microM, 116 microM, 236 microM, and 170 microM, respectively. Morelloflavone (7) also demonstrated significant antiviral activity against HIV-1 (strain LAV-1) in phytohemagglutinin-stimulated primary human peripheral blood mononuclear cells at an EC50 value of 6.9 microM and a selectivity index value of approximately 10. The other biflavonoids were either weakly active, inactive, or not selective against HIV-1 in human lymphocytes.
|
Antitrypanosomal activity against blood stream-form of Trypanosoma brucei brucei MITat1.2 after 72 hrs by MTT assay
|
Trypanosoma brucei brucei
|
0.193
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antiprotozoal compounds from Psorothamnus polydenius.
Year : 2005
Volume : 68
Issue : 1
First Page : 108
Last Page : 111
Authors : Salem MM, Werbovetz KA.
Abstract : Bioactivity-guided fractionation of the methanolic extract of Psorothamnus polydenius yielded the new chalcone 2,2',4'-trihydroxy-6'-methoxy-3',5'-dimethylchalcone (2), together with six other known compounds, 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (1), dalrubone (3), demethoxymatteucinol (4), eriodictyol (5), and photodalrubone (6a and 6b). This is the first report of chalcones in P. polydenius. The extracts and isolated compounds were tested in vitro for their antiprotozoal activity against Leishmania donovani and Trypanosoma brucei. Chalcones 1 and 2 and dalrubone (3) exhibited leishmanicidal (IC(50) 5.0, 7.5, and 7.5 microg/mL, respectively) and trypanocidal (IC(50) 6.3, 6.8, and 21.6 microg/mL, respectively) properties. Dalrubone (3) displayed 6-fold selectivity for axenic L. donovani parasites over Vero cells. Furthermore, treatment of L. mexicana-preinfected macrophages with chalcones 1 and 2 and dalrubone (3) (12.5, 12.5, and 25 microg/mL, respectively) reduced the number of infected macrophages by at least 96% while posing no toxicity to the host cell.
|
Antitrypanosomal activity against Trypanosoma brucei brucei MITat 1.2 variant 221 after 72 hrs
|
Trypanosoma brucei brucei
|
190.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isoflavonoids and other compounds from Psorothamnus arborescens with antiprotozoal activities.
Year : 2006
Volume : 69
Issue : 1
First Page : 43
Last Page : 49
Authors : Salem MM, Werbovetz KA.
Abstract : Bioactivity-guided fractionation of the root extract of Psorothamnus arborescens yielded the new isoflavone 5,7,3',4'-tetrahydroxy-2'-(3,3-dimethylallyl)isoflavone (1a) and the new 2-arylbenzofuran 2-(2'-hydroxy-4',5'-methylenedioxyphenyl)-6-methoxybenzofuran-3-carbaldehyde (2), together with seven known compounds, including three isoflavones, fremontin (3a), glycyrrhisoflavone (4a), and calycosin (5), two pterocarpans, maackiain (6) and 4-hydroxymaackiain (7), one triterpene, oleanolic acid (8), and one chalcone, isoliquiritigenin (9). In addition, the structure of the isoflavone fremontin was revised using spectroscopic and chemical methods and was assigned the new structure 3a. The isoflavone 1a and the chalcone 9 displayed leishmanicidal activity with IC50 values of 13.0 and 20.7 microM, respectively, against Leishmania donovani axenic amastigotes. Calycosin (5) exhibited selective toxicity against Trypanosoma brucei brucei (IC50 12.7 microM) compared to L. donovani amastigotes and Vero cells (IC50 100 and 159 microM, respectively). These results prompted us to test a small group of structurally related isoflavones for their antitrypanosomal activities. Genistein and 7,3',4'-trihydroxyisoflavone displayed promising activity (IC50 values 4.2 and 7.1 microM, respectively) and selectivity (IC50 versus Vero cells: 32.9 and 135 microM, respectively). These studies suggest that the isoflavone skeleton deserves further investigation as a template for novel antileishmanial and trypanocidal compounds.
|
Antiparasitic activity against Trypanosoma brucei rhodesiense
|
Trypanosoma brucei rhodesiense
|
0.13
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : New potent imidazoisoquinolinone derivatives as anti-Trypanosoma cruzi agents: biological evaluation and structure-activity relationships.
Year : 2009
Volume : 17
Issue : 4
First Page : 1437
Last Page : 1444
Authors : Bollini M, Casal JJ, Alvarez DE, Boiani L, González M, Cerecetto H, Bruno AM.
Abstract : A series of novel benzoimidazo and N-aryl-5-oxo-imidazo[1,2-b]isoquinoline-10-carbothioamides was developed. All the compounds were evaluated for their in vitro action against the epimastigote form of Trypanosoma cruzi. Four of them showed higher activity than Nifurtimox. Their unspecific cytotoxicity was evaluated using HeLa and L6 cells, being non-toxic at concentrations at least 15 and 200 times higher than that of T. cruzi IC(50.) To gain insight into the mechanism of action, their DNA binding properties and reactivity with glutathione were studied, and QSAR study was performed.
|
Inhibition of HIV1 RT
|
Human immunodeficiency virus 1
|
18.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Evaluation of natural products as inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase.
Year : 1991
Volume : 54
Issue : 1
First Page : 143
Last Page : 154
Authors : Tan GT, Pezzuto JM, Kinghorn AD, Hughes SH.
Abstract : Inhibition of human immunodeficiency virus reverse transcriptase is currently considered a useful approach in the prophylaxis and intervention of acquired immunodeficiency syndrome (AIDS), and natural products have not been extensively explored as inhibitors of this enzyme. We currently report that the reverse transcriptase assay developed for the detection of the enzyme in virions involving polyadenylic acid.oligodeoxythymidylic acid (poly rA.oligo dT) and radiolabeled thymidine 5'-triphosphate (TTP), can be applied as a simple method for screening the human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) inhibitory potential of natural products. As reported herein, 156 pure natural products have been examined in this system. Benzophenanthridine alkaloids such as faragaronine chloride [1] and nitidine chloride, which are known inhibitors of avian myeloblastosis virus reverse transcriptase, demonstrated potent activity in the HIV-1 RT system, and 1 (IC50 10 micrograms/ml) was adopted as a positive-control substance. Additional inhibitors found were columbamine iodide [2] and other protoberberine alkaloids, the isoquinoline alkaloid O-methylpsychotrine sulfate [3], and the iridoid fulvoplumierin [4]. A number of indolizidine, pyrrolizidine, quinolizidine, indole, and other alkaloids, as well as compounds of many other structural classes, were tested and found to be inactive. A total of 100 plant extracts have also been evaluated, and 15 of these extracts showed significant inhibitory activity. Because tannins and other polyphenolic compounds are potent reverse transcriptase inhibitors, methods were evaluated for the removal of these from plant extracts prior to testing. Polyphenolic compounds were found to be responsible for the activity demonstrated by the majority of plant extracts. After appropriate tannin removal procedures were established, the bioassay system was shown to be generally applicable to both pure natural products and plant extracts. The method also proved useful in directing an isolation procedure with Plumeria rubra to yield fulvoplumierin [4] as an active compound (IC50 45 micrograms/ml).
|
Antitrypanosomal activity against Trypanosoma brucei brucei GUTat3.1 after 72 hrs by alamar blue assay
|
Trypanosoma brucei brucei
|
1.58
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : New lycorine-type alkaloid from Lycoris traubii and evaluation of antitrypanosomal and antimalarial activities of lycorine derivatives.
Year : 2008
Volume : 16
Issue : 24
First Page : 10182
Last Page : 10189
Authors : Toriizuka Y, Kinoshita E, Kogure N, Kitajima M, Ishiyama A, Otoguro K, Yamada H, Omura S, Takayama H.
Abstract : A new lycorine derivative LT1 (4) was isolated from the aerial part and bulbs of Lycoris traubii Hayward (Amaryllidaceae). Its structure including absolute configuration was established by spectroscopic analysis and semi-synthesis to be 1-O-(3'S)-hydroxybutanoyllycorine. Some lycorine ester derivatives including LT1 were examined for their inhibitory activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and against Plasmodium falciparum, the causative agent of malaria. Among them, 2-O-acetyllycorine (6) showed the most potent activity against parasitic T. b. brucei, and LT1 (4), 1-O-(3'R)-hydroxybutanoyllycorine (8), 1,2-di-O-butanoyllycorine (11), and 1-O-propanoyllycorine (12) showed significant activity against P. falciparum in an in vitro experiment.
|
Cytotoxicity against human MRC5 cells after 7 days by MTT assay
|
Homo sapiens
|
100.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : New lycorine-type alkaloid from Lycoris traubii and evaluation of antitrypanosomal and antimalarial activities of lycorine derivatives.
Year : 2008
Volume : 16
Issue : 24
First Page : 10182
Last Page : 10189
Authors : Toriizuka Y, Kinoshita E, Kogure N, Kitajima M, Ishiyama A, Otoguro K, Yamada H, Omura S, Takayama H.
Abstract : A new lycorine derivative LT1 (4) was isolated from the aerial part and bulbs of Lycoris traubii Hayward (Amaryllidaceae). Its structure including absolute configuration was established by spectroscopic analysis and semi-synthesis to be 1-O-(3'S)-hydroxybutanoyllycorine. Some lycorine ester derivatives including LT1 were examined for their inhibitory activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and against Plasmodium falciparum, the causative agent of malaria. Among them, 2-O-acetyllycorine (6) showed the most potent activity against parasitic T. b. brucei, and LT1 (4), 1-O-(3'R)-hydroxybutanoyllycorine (8), 1,2-di-O-butanoyllycorine (11), and 1-O-propanoyllycorine (12) showed significant activity against P. falciparum in an in vitro experiment.
|
Inhibition of Dengue virus sEnvelope glycoprotein binding to immobilized heparin
|
Dengue virus
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : The medicinal chemistry of dengue fever.
Year : 2009
Volume : 52
Issue : 24
First Page : 7911
Last Page : 7926
Authors : Stevens AJ, Gahan ME, Mahalingam S, Keller PA.
|
Inhibition of human full length SIRT1 expressed in DE3 cells by fluorimetric assay
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Identification and characterization of novel sirtuin inhibitor scaffolds.
Year : 2009
Volume : 17
Issue : 19
First Page : 7031
Last Page : 7041
Authors : Sanders BD, Jackson B, Brent M, Taylor AM, Dang W, Berger SL, Schreiber SL, Howitz K, Marmorstein R.
Abstract : The sirtuin proteins are broadly conserved NAD(+)-dependent deacetylases that are implicated in diverse biological processes including DNA recombination and repair, transcriptional silencing, longevity, apoptosis, axonal protection, insulin signaling, and fat mobilization. Because of these associations, the identification of small molecule sirtuin modulators has been of significant interest. Here we report on high throughput screening against the yeast sirtuin, Hst2, leading to the identification of four unique inhibitor scaffolds that also inhibit the human sirtuins, SIRT1-3, and are able to inhibit telomeric silencing of yeast Sir2 in vivo. The identified inhibitor scaffolds range in potency from IC(50) values of 6.5-130 microM against Hst2. Each of the inhibitor scaffolds binds reversibly to the enzyme, and kinetic analysis reveals that each of the inhibitors is non-competitive with respect to both acetyl-lysine and NAD(+) binding. Limited SAR analysis of the scaffolds also identifies which functional groups may be important for inhibition. These sirtuin inhibitors are low molecular weight and well-suited for lead molecule optimization, making them useful chemical probes to study the mechanism and biological roles of sirtuins and potential starting points for optimization into therapeutics.
|
Inhibition of human recombinant C-terminal FLAG-tagged autotaxin expressed in baculovirus-infected Sf9 cells assessed as FS-3 hydrolysis at 10 uM relative to control
|
Homo sapiens
|
27.0
%
|
|
Journal : J. Med. Chem.
Title : Pharmacophore development and application toward the identification of novel, small-molecule autotaxin inhibitors.
Year : 2010
Volume : 53
Issue : 8
First Page : 3095
Last Page : 3105
Authors : North EJ, Howard AL, Wanjala IW, Pham TC, Baker DL, Parrill AL.
Abstract : Autotaxin (ATX) is a secreted glycoprotein with lysophospholipase D (LPLD) activity that generates the bioactive lipid lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been linked to the promotion and progression of cancer as well as cardiovascular disease and obesity. Despite the fact that ATX inhibitors have the potential to be useful chemotherapeutics for multiple indications, few examples of potent ATX inhibitors are described in the current literature. Here we describe the development of pharmacophore models for the inhibition of ATX by nonlipids and apply these tools to the discovery of additional ATX inhibitors using the NCI open chemical repository database. From this database of > 250,000 compounds, 168 candidate inhibitors were identified. Of these candidates, 106 were available for testing and 33 were identified as active (those that inhibited ATX activity by > or =50% at a single 10 microM concentration), a 31% hit rate. Five of these compounds had IC(50) < 1.5 microM and the most potent compound possessed a K(i) of 271 nM.
|
Inhibition of Trypanosoma brucei rhodesiense recombinant rhodesain at 100 uM
|
Trypanosoma brucei rhodesiense
|
32.0
%
|
|
Journal : J. Med. Chem.
Title : On-bead screening of a combinatorial fumaric acid derived peptide library yields antiplasmodial cysteine protease inhibitors with unusual peptide sequences.
Year : 2009
Volume : 52
Issue : 18
First Page : 5662
Last Page : 5672
Authors : Machon U, Büchold C, Stempka M, Schirmeister T, Gelhaus C, Leippe M, Gut J, Rosenthal PJ, Kisker C, Leyh M, Schmuck C.
Abstract : A new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. As target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (Plasmodium falciparum) and African sleeping sickness (Trypanosoma brucei rhodesiense). The best inhibitors with unusual amino acid sequences not reported before for this type of enzyme were also fully analyzed in detail in solution. K(i) values in the lower micromolar and even nanomolar region were found. Some inhibitors are even active against plasmodia and show good selectivity relative to other enzymes. Also the mechanism of action was studied and could be shown to be irreversible inhibition.
|
Antitrypanosomal activity against Trypanosoma brucei brucei
|
Trypanosoma brucei brucei
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : On-bead screening of a combinatorial fumaric acid derived peptide library yields antiplasmodial cysteine protease inhibitors with unusual peptide sequences.
Year : 2009
Volume : 52
Issue : 18
First Page : 5662
Last Page : 5672
Authors : Machon U, Büchold C, Stempka M, Schirmeister T, Gelhaus C, Leippe M, Gut J, Rosenthal PJ, Kisker C, Leyh M, Schmuck C.
Abstract : A new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. As target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (Plasmodium falciparum) and African sleeping sickness (Trypanosoma brucei rhodesiense). The best inhibitors with unusual amino acid sequences not reported before for this type of enzyme were also fully analyzed in detail in solution. K(i) values in the lower micromolar and even nanomolar region were found. Some inhibitors are even active against plasmodia and show good selectivity relative to other enzymes. Also the mechanism of action was studied and could be shown to be irreversible inhibition.
|
Inhibition of Schistosoma mansoni recombinant NAD+ glycohydrolase expressed in Pichia pastoris at up to 100 uM by continuous fluorometric method
|
Schistosoma mansoni
|
10.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Identification by high-throughput screening of inhibitors of Schistosoma mansoni NAD(+) catabolizing enzyme.
Year : 2010
Volume : 18
Issue : 22
First Page : 7900
Last Page : 7910
Authors : Kuhn I, Kellenberger E, Said-Hassane F, Villa P, Rognan D, Lobstein A, Haiech J, Hibert M, Schuber F, Muller-Steffner H.
Abstract : Schistosomiasis is a major tropical parasitic disease. For its treatment, praziquantel remains the only effective drug available and the dependence on this sole chemotherapy emphasizes the urgent need for new drugs to control this neglected disease. In this context, the newly characterized Schistosoma mansoni NAD(+) catabolizing enzyme (SmNACE) represents a potentially attractive drug target. This potent NAD(+)glycohydrolase, which is localized to the outer surface (tegument) of the adult parasite, is presumably involved in the parasite survival by manipulating the host's immune regulatory pathways. In an effort to identify SmNACE inhibitors, we have developed a sensitive and robust fluorometric high-throughput screening assay. The implementation of this assay to the screening of a highly diverse academic chemical library of 14,300 molecules yielded, after secondary assays and generation of dose-response curves, the identification of two natural product inhibitors, cyanidin and delphinidin. These confirmed hits inhibit SmNACE with IC(50) values in the low micromolar range. To rationalize the structure-activity relationship, several related flavonoids were tested, thereby leading to the identification of 15 additional natural product inhibitors. A selection of representative flavonoid inhibitors indicated that although they also inhibit the homologous human CD38, a selectivity in favor of SmNACE could be reached. Docking studies indicated that these inhibitors mimic the binding mode of the enzyme substrate NAD(+) and suggested the pharmacophoric features required for SmNACE active site recognition.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei s427 after 72 hrs by MTT assay
|
Trypanosoma brucei
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and antitrypanosomal evaluation of derivatives of N-benzyl-1,2-dihydroquinolin-6-ols: Effect of core substitutions and salt formation.
Year : 2011
Volume : 19
Issue : 1
First Page : 513
Last Page : 523
Authors : Reid CS, Patrick DA, He S, Fotie J, Premalatha K, Tidwell RR, Wang MZ, Liu Q, Gershkovich P, Wasan KM, Wenzler T, Brun R, Werbovetz KA.
Abstract : Analogs of the trypanocidal lead compound 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were prepared to extend the structure-activity relationship in this series of molecules, improve the in vivo antitrypanosomal activity of the lead, and determine whether ester prodrugs are needed to overcome the instability of the dihydroquinolin-6-ols. Two of the most active compounds identified in this study were 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxy)benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride. These stable solids possessed low nanomolar IC(50) values against Trypanosoma brucei rhodesiense STIB900 in vitro and provided cures in an early treatment acute mouse model of African trypanosomiasis when given ip at 50mg/kg/day for four consecutive days.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense STIB900 after 70 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and antitrypanosomal evaluation of derivatives of N-benzyl-1,2-dihydroquinolin-6-ols: Effect of core substitutions and salt formation.
Year : 2011
Volume : 19
Issue : 1
First Page : 513
Last Page : 523
Authors : Reid CS, Patrick DA, He S, Fotie J, Premalatha K, Tidwell RR, Wang MZ, Liu Q, Gershkovich P, Wasan KM, Wenzler T, Brun R, Werbovetz KA.
Abstract : Analogs of the trypanocidal lead compound 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were prepared to extend the structure-activity relationship in this series of molecules, improve the in vivo antitrypanosomal activity of the lead, and determine whether ester prodrugs are needed to overcome the instability of the dihydroquinolin-6-ols. Two of the most active compounds identified in this study were 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxy)benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride. These stable solids possessed low nanomolar IC(50) values against Trypanosoma brucei rhodesiense STIB900 in vitro and provided cures in an early treatment acute mouse model of African trypanosomiasis when given ip at 50mg/kg/day for four consecutive days.
|
Antitrypanosomal activity against bloodstream-form Trypanosoma brucei brucei 427 after 72 hrs
|
Trypanosoma brucei brucei
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationship of Trypanosoma brucei leucyl-tRNA synthetase inhibitors as antitrypanosomal agents.
Year : 2011
Volume : 54
Issue : 5
First Page : 1276
Last Page : 1287
Authors : Ding D, Meng Q, Gao G, Zhao Y, Wang Q, Nare B, Jacobs R, Rock F, Alley MR, Plattner JJ, Chen G, Li D, Zhou H.
Abstract : African trypanosomiasis, caused by the proto zoal pathogen Trypanosoma brucei (T. brucei), is one of the most neglected tropical diseases that are in great need of new drugs. We report the design and synthesis of T. brucei leucyl-tRNA synthetase (TbLeuRS) inhibitors and their structure--activity relationship. Benzoxaborole was used as the core structure and C(6) was modified to achieve improved affinity based on docking results that showed further binding space at this position. Indeed, compounds with C(7) substitutions showed diminished activity due to clash with the eukaryote specific I4ae helix while substitutions at C(6) gave enhanced affinity. TbLeuRS inhibitors with IC(50) as low as 1.6 μM were discovered, and the structure-activity relationship was discussed. The most potent enzyme inhibitors also showed excellent T. brucei parasite growth inhibition activity. This is the first time that TbLeuRS inhibitors are reported, and this study suggests that leucyl-tRNA synthetase (LeuRS) could be a potential target for antiparasitic drug development.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei brucei
|
Trypanosoma brucei brucei
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent antiprotozoal activity of a novel semi-synthetic berberine derivative.
Year : 2011
Volume : 21
Issue : 9
First Page : 2606
Last Page : 2610
Authors : Bahar M, Deng Y, Zhu X, He S, Pandharkar T, Drew ME, Navarro-Vázquez A, Anklin C, Gil RR, Doskotch RW, Werbovetz KA, Kinghorn AD.
Abstract : Treatment of diseases such as African sleeping sickness and leishmaniasis often depends on relatively expensive or toxic drugs, and resistance to current chemotherapeutics is an issue in treating these diseases and malaria. In this study, a new semi-synthetic berberine analogue, 5,6-didehydro-8,8-diethyl-13-oxodihydroberberine chloride (1), showed nanomolar level potency against in vitro models of leishmaniasis, malaria, and trypanosomiasis as well as activity in an in vivo visceral leishmaniasis model. Since the synthetic starting material, berberine hemisulfate, is inexpensive, 8,8-dialkyl-substituted analogues of berberine may lead to a new class of affordable antiprotozoal compounds.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei rhodesiense EATRO3 after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
185.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Diamine and aminoalcohol derivatives active against Trypanosoma brucei.
Year : 2012
Volume : 22
Issue : 1
First Page : 440
Last Page : 443
Authors : Olmo ED, Diaz-González R, Escarcena R, Carvalho L, Bustos LA, Navarro M, Feliciano AS.
Abstract : Twenty compounds selected as representative members of three series of long-chain 1,2-diamines, 2-amino-1-alkanols and 1-amino-2-alkanols structurally related to dihydrosphingosin, were synthesized and tested in vitro for their ability to inhibit the sleeping sickness parasites Trypanosoma bruceirhodesiense and Trypanosoma brucei gambiense. Eight compounds showed EC(50) values in the submicromolar range, with selectivity indexes up to 39 related to the respective cytotoxicity values for Vero cells. The parasite phenotype detected after treatment with the most potent compounds showed irreversible cell morphology alterations of the flagellar pocket that lead to inhibition of cell growth and parasite death.
|
Inhibition of human SIRT1 using Fluor-de-Lys as substrate at 50 uM
|
Homo sapiens
|
53.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel acridinedione derivatives: design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies.
Year : 2012
Volume : 22
Issue : 9
First Page : 3256
Last Page : 3260
Authors : Alvala M, Bhatnagar S, Ravi A, Jeankumar VU, Manjashetty TH, Yogeeswari P, Sriram D.
Abstract : A new scaffold N-(9-(ortho/meta/para-(benzyloxy)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl) isonicotinamide (H1-3) was discovered as a hSIRT1 inhibitor through virtual screening of in-house database. Based on these hits, a library of compounds were designed, synthesized and tested for in vitro hSIRT1 activity. The most potent compound 4d in the series showed a significant inhibition of SIRT1 activity. Further antitumor studies of compound 4d, showed a dose dependent increase in acetylation of p53K382 and decrease in SIRT1 with an IC(50) of 0.25 μM in MDA-MB231 breast cancer cell lines. Individual 3D-QSAR analysis using Schrödinger showed distribution of hydrophobic and non polar positive co-efficient at ortho position essential for bioactivity based on 4d.
|
Inhibition of Sirt1 expressed in human U2OS cells assessed as acetylation of p53 at 10 uM
|
Homo sapiens
|
79.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential anticancer agents.
Year : 2012
Volume : 22
Issue : 15
First Page : 5063
Last Page : 5066
Authors : Mulakayala N, Kandagatla B, Ismail, Rapolu RK, Rao P, Mulakayala C, Kumar CS, Iqbal J, Oruganti S.
Abstract : A convenient and practical methodology for the synthesis of 2-aryl quinazolin-4(3H)-ones by the condensation of o-aminobenzamides with aromatic aldehydes under mild conditions using catalytic InCl(3) with good yields and high selectivities. This method has been extended for the synthesis of 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones which have potential applications in medicinal chemistry. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.
|
Inhibition of full length recombinant human SIRT1 expressed in Escherichia coli BL21 (DE3) PLysS using Fluor-de-Lys as substrate at 10 uM by fluorimetric assay
|
Homo sapiens
|
82.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Ethylenediamine diacetate (EDDA) mediated synthesis of aurones under ultrasound: their evaluation as inhibitors of SIRT1.
Year : 2012
Volume : 22
Issue : 19
First Page : 6160
Last Page : 6165
Authors : Manjulatha K, Srinivas S, Mulakayala N, Rambabu D, Prabhakar M, Arunasree KM, Alvala M, Basaveswara Rao MV, Pal M.
Abstract : An improved synthesis of functionalized aurones has been accomplished via the reaction of benzofuran-3(2H)-one with a range of benzaldehydes in the presence of a mild base EDDA under ultrasound. A number of aurones were synthesized (within 5-30min) and the molecular structure of a representative compound determined by single crystal X-ray diffraction study confirmed Z-geometry of the C-C double bond present within the molecule. Some of the compounds synthesized have shown SIRT1 inhibiting as well as anti proliferative properties against two cancer cell lines in vitro. Compound 3a [(Z)-2-(5-bromo-2-hydroxybenzylidene) benzofuran-3(2H)-one] was identified as a potent inhibitor of SIRT1 (IC(50)=1μM) which showed a dose dependent increase in the acetylation of p53 resulting in induction of apoptosis.
|
Inhibition of recombinant SIRT1 using ZMAL substrate after 4 hrs by homogeneous fluorescence assay
|
None
|
300.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Inhibitors of the NAD(+)-Dependent Protein Desuccinylase and Demalonylase Sirt5.
Year : 2012
Volume : 3
Issue : 12
First Page : 1050
Last Page : 1053
Authors : Maurer B, Rumpf T, Scharfe M, Stolfa DA, Schmitt ML, He W, Verdin E, Sippl W, Jung M.
Abstract : NAD(+)-dependent histone deacetylases (sirtuins) play important roles in epigenetic regulation but also through nonhistone substrates for other key cellular events and have been linked to the pathogenesis of cancer, neurodegeneration, and metabolic diseases. The subtype Sirt5 has been shown recently to act as a desuccinylating and demalonylating enzyme. We have established an assay for biochemical testing of Sirt5 using a small labeled succinylated lysine derivative. We present a comparative study on the profiling of several established sirtuin inhibitors on Sirt1-3 as well as Sirt5 and also present initial results on a screening for new compounds that block Sirt5. Thiobarbiturates were identified as new Sirt5 inhibitors in the low micromolar range, which are selective over Sirt3 that can be found in the same cell compartment as Sirt5.
|
Inhibition of Homo sapiens (human) recombinant PTP1B at 10 uM relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : Med Chem Res
Title : Identification of ZINC02765569: a potent inhibitor of PTP1B by vHTS
Year : 2013
Volume : 22
Issue : 1
First Page : 28
Last Page : 34
Authors : Joshi P, Deora GS, Rathore V, Tanwar O, Rawat AK, Srivastava AK, Jain D
|
Inhibition of Homo sapiens (human) recombinant PTP1B assessed as decrease in free phosphate release at 10 uM by malachite staining relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : Med Chem Res
Title : Molecular modeling and synthesis of ZINC02765569 derivatives as protein tyrosine phosphatase 1B inhibitors: lead optimization study
Year : 2013
Volume : 22
Issue : 4
First Page : 1618
Last Page : 1623
Authors : Joshi P, Deora GS, Rathore V, Rawat AK, Srivastava AK, Jain D
|
Inhibition of human Sirt5 desuccinylation activity using SKEYFS-succinylLys-QK as substrate at 100 uM after 60 mins by glutamate dehydrpgenase-coupled assay
|
Homo sapiens
|
20.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of the human deacylase Sirtuin 5 by the indole GW5074.
Year : 2013
Volume : 23
Issue : 1
First Page : 143
Last Page : 146
Authors : Suenkel B, Fischer F, Steegborn C.
Abstract : Sirtuins are NAD(+) consuming protein deacylases involved in many cellular processes from DNA-repair to metabolism. Their contribution to age-related and metabolic diseases makes them attractive pharmaceutical targets. Few pharmacological inhibitors have been reported yet for human Sirt5 since substrates and assays for reliable testing of its activity were unavailable until recently, and most modulators of other Sirtuins were not tested against Sirt5 and therefore have only partially characterized isoform selectivities. We used here improved substrates and assays for testing of known Sirtuin inhibitors for their effects on two activities of human Sirt5, the generic Sirtuin activity deacetylation and the more pronounced Sirt5 activity desuccinylation. Our tests show that most of the compounds have no significant effect on either Sirt5 activity. The indole GW5074, however, was found to be a potent inhibitor for Sirt5's desuccinylation activity, identifying a first pharmacological scaffold for development into Sirt5-specific inhibitors. Interestingly, the compound showed weaker effects in Sirt5 deacetylation assays and also varying potencies against different peptide sequences, indicating a substrate-specific effect of GW5074.
|
Inhibition of human GST-tagged SIRT1 expressed in Escherichia coli BL21(DE3) assessed as inhibition of ZMAL conversion to ZML after 4 hrs by fluorescence assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.
Year : 2013
Volume : 56
Issue : 9
First Page : 3666
Last Page : 3679
Authors : Disch JS, Evindar G, Chiu CH, Blum CA, Dai H, Jin L, Schuman E, Lind KE, Belyanskaya SL, Deng J, Coppo F, Aquilani L, Graybill TL, Cuozzo JW, Lavu S, Mao C, Vlasuk GP, Perni RB.
Abstract : The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.
|
Antitrypanosomal activity against Trypanosoma brucei brucei blood-stream forms
|
Trypanosoma brucei brucei
|
130.0
nM
|
|
Journal : J. Nat. Prod.
Title : 8,8-dialkyldihydroberberines with potent antiprotozoal activity.
Year : 2013
Volume : 76
Issue : 3
First Page : 311
Last Page : 315
Authors : Endeshaw M, Zhu X, He S, Pandharkar T, Cason E, Mahasenan KV, Agarwal H, Li C, Munde M, Wilson WD, Bahar M, Doskotch RW, Kinghorn AD, Kaiser M, Brun R, Drew ME, Werbovetz KA.
Abstract : Semisynthetic 8,8-dialkyldihydroberberines (8,8-DDBs) were found to possess mid- to low-nanomolar potency against Plasmodium falciparum blood-stage parasites, Leishmania donovani intracellular amastigotes, and Trypanosoma brucei brucei bloodstream forms. For example, 8,8-diethyldihydroberberine chloride (5b) exhibited in vitro IC50 values of 77, 100, and 5.3 nM against these three parasites, respectively. In turn, two 8,8-dialkylcanadines, obtained by reduction of the corresponding 8,8-DDBs, were much less potent against these parasites in vitro. While the natural product berberine is a weak DNA binder, the 8,8-DDBs displayed no affinity for DNA, as assessed by changes in the melting temperature of poly(dA·dT) DNA. Selected 8,8-DDBs showed efficacy in mouse models of visceral leishmaniasis and African trypanosomiasis, with 8,8-dimethyldihydroberberine chloride (5a) reducing liver parasitemia by 46% in L. donovani-infected BALB/c mice when given at an intraperitoneal dose of 10 mg/kg/day for five days. The 8,8-DDBs may thus serve as leads for discovering new antimalarial, antileishmanial, and antitrypanosomal drug candidates.
|
Antitrypanosomal activity against Trypanosoma brucei brucei Lister 427 bloodstream form assessed as parasite LDH activity by three-fold serial dilution method
|
Trypanosoma brucei brucei
|
0.11
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Antiparasitic hybrids of Cinchona alkaloids and bile acids.
Year : 2013
Volume : 66
First Page : 355
Last Page : 363
Authors : Leverrier A, Bero J, Frédérich M, Quetin-Leclercq J, Palermo J.
Abstract : A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC₅₀ values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC₅₀ ≤ 6 μg/ml), particularly those containing a nor-chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC₅₀ values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7.
|
Cytotoxicity against human MRC5 cells
|
Homo sapiens
|
100.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.
Year : 2014
Volume : 24
Issue : 2
First Page : 442
Last Page : 446
Authors : Aoyagi Y, Fujiwara K, Yamazaki A, Sugawara N, Yano R, Fukaya H, Hitotsuyanagi Y, Takeya K, Ishiyama A, Iwatsuki M, Otoguro K, Yamada H, Ōmura S.
Abstract : A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.
|
Antitrypanosomal activity against Trypanosoma brucei brucei GUTat 3.1 after 72 hrs by AlamarBlue assay
|
Trypanosoma brucei brucei
|
1.58
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.
Year : 2014
Volume : 24
Issue : 2
First Page : 442
Last Page : 446
Authors : Aoyagi Y, Fujiwara K, Yamazaki A, Sugawara N, Yano R, Fukaya H, Hitotsuyanagi Y, Takeya K, Ishiyama A, Iwatsuki M, Otoguro K, Yamada H, Ōmura S.
Abstract : A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.
|
Inhibition of human recombinant PTP1B using phosphopeptide as substrate at 10 uM after 30 mins by malachite green assay relative to control
|
Homo sapiens
|
60.0
%
|
|
Journal : MedChemComm
Title : Identification of novel urea derivatives as PTP1B inhibitors: synthesis, biological evaluation and structureactivity relationships
Year : 2013
Volume : 4
Issue : 10
First Page : 1382
Last Page : 1387
Authors : Gupta S, Varshney K, Srivastava R, Rahuja N, Rawat AK, Srivastava AK, Saxena AK
|
Antitrypanosomal activity against Trypanosoma brucei brucei 427 after 72 hrs by alamar blue assay
|
Trypanosoma brucei brucei
|
5.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel pyrrolobenzoxaboroles: design, synthesis, and biological evaluation against Trypanosoma brucei.
Year : 2014
Volume : 81
First Page : 59
Last Page : 75
Authors : Wu P, Zhang J, Meng Q, Nare B, Jacobs RT, Zhou H.
Abstract : Human African trypanosomiasis is a fatal parasitic infection caused by the protozoan Trypanosoma brucei. The development of novel antitrypanosomal agents is urgently needed. Here we report the synthesis and structure-activity relationship of a new class of benzoxaboroles as antitrypanosomal agents. These compounds showed antiparasitic IC50 values ranging from 4.02 to 0.03 μg/mL and satisfactory cytotoxicity profile. Three of the lead compounds were demonstrated to cure the parasitic infection in a murine acute infection model. The structure-activity relationship of the pyrrolobenzoxaboroles are also discussed.
|
Inhibition of recombinant human N-terminal GST-tagged full length SIRT1 expressed in Escherichia coli BL21(DE3) using ZMAL as substrate after 4 hrs by homogeneous fluorescent deacetylase assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : MedChemComm
Title : Targeting epigenetic modifiers: Inhibitors of histone methyltransferases
Year : 2010
Volume : 1
Issue : 2
First Page : 114
Last Page : 124
Authors : Bissinger E, Heinke R, Sippl W, Jung M
|
Antitrypanocidal activity against suramin-sensitive Trypanosoma brucei brucei Squib427 assessed as reduction in parasite growth after 72 hrs
|
Trypanosoma brucei brucei
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds.
Year : 2014
Volume : 22
Issue : 19
First Page : 5241
Last Page : 5248
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Dirié B, Lyssens S, Michiels J, Cos P, Lewi PJ, Vanham G, Maes L, Van der Veken P, Augustyns K.
Abstract : The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure-activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.
|
Antitrypanocidal activity against suramin-sensitive Trypanosoma brucei rhodesiense STIB-900 assessed as reduction in parasite growth after 72 hrs
|
Trypanosoma brucei rhodesiense
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds.
Year : 2014
Volume : 22
Issue : 19
First Page : 5241
Last Page : 5248
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Dirié B, Lyssens S, Michiels J, Cos P, Lewi PJ, Vanham G, Maes L, Van der Veken P, Augustyns K.
Abstract : The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure-activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.
|
Trypanocidal activity against suramin-sensitive Trypanosoma brucei brucei Squib427 infected in Swiss mouse assessed as reduction in parasitemia at 10 mg/kg first dose through orally and next four dosed administered intraperitoneally for 4 days
|
Trypanosoma brucei brucei
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds.
Year : 2014
Volume : 22
Issue : 19
First Page : 5241
Last Page : 5248
Authors : Venkatraj M, Ariën KK, Heeres J, Joossens J, Dirié B, Lyssens S, Michiels J, Cos P, Lewi PJ, Vanham G, Maes L, Van der Veken P, Augustyns K.
Abstract : The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure-activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.
|
Antitrypanosomal activity against Trypanosoma brucei brucei NYSM bloodstream forms incubated for 46 hrs by alamar blue assay
|
Trypanosoma brucei brucei
|
310.0
nM
|
|
Journal : J. Nat. Prod.
Title : Antitrypanosomal quinoline alkaloids from the roots of Waltheria indica.
Year : 2014
Volume : 77
Issue : 10
First Page : 2304
Last Page : 2311
Authors : Cretton S, Breant L, Pourrez L, Ambuehl C, Marcourt L, Ebrahimi SN, Hamburger M, Perozzo R, Karimou S, Kaiser M, Cuendet M, Christen P.
Abstract : Chemical investigation of the dichloromethane root extract of Waltheria indica led to the isolation and characterization of 10 quinoline alkaloids, namely, 8-deoxoantidesmone (1), waltheriones E-L (2-9), and antidesmone (10). Among these, compounds 2-9 have not yet been described in the literature. Their chemical structures were established by means of spectroscopic data interpretation including (1)H and (13)C NMR, HSQC, HMBC, COSY, and NOESY experiments and UV, IR, and HRESIMS. The absolute configurations of the compounds were established by comparison of experimental and TDDFT-calculated ECD spectra. In addition, the isolated constituents were evaluated for their in vitro antitrypanosomal activity. Compounds 4, 5, and 8 showed potent and selective growth inhibition toward Trypanosoma cruzi with IC50 values between 0.02 and 0.04 μM. Cytotoxicity for mouse skeletal L-6 cells was also determined for these compounds.
|
Antitrypanosomal activity against Trypanosoma brucei rhodesiense STIB900 bloodstream forms after 72 hrs by alamar blue assay
|
Trypanosoma brucei rhodesiense
|
7.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities.
Year : 2015
Volume : 25
Issue : 7
First Page : 1390
Last Page : 1393
Authors : Seebacher W, Wolkinger V, Faist J, Kaiser M, Brun R, Saf R, Bucar F, Gröblacher B, Brantner A, Merino V, Kalia Y, Scapozza L, Perozzo R, Weis R.
Abstract : Several bicyclic compounds, 3-azabicyclo[3.2.2]nonanes, have been prepared. The new compounds were tested for their activities against one strain of the causative organism of Malaria tropica, Plasmodium falciparum K1, which is resistant against chloroquine and pyrimethamine. In addition, their cytotoxicity and their activity against the pathogen of the East African form of sleeping sickness, Trypanosoma brucei rhodesiense, were investigated. Structure-activity relationships are discussed considering data of readily prepared compounds. For the first time, a distinct in vivo activity was observed against Plasmodium berghei in a mouse model. The active compound was further investigated.
|
Antitrypanosomal activity against Trypanosoma brucei brucei Lister 427 bloodstream forms by microtiter plate based assay
|
Trypanosoma brucei brucei
|
30.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities.
Year : 2015
Volume : 100
First Page : 10
Last Page : 17
Authors : Leverrier A, Bero J, Cabrera J, Frédérich M, Quetin-Leclercq J, Palermo JA.
Abstract : In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids were prepared from bile acids and a series of antiparasitic Cinchona alkaloids by the formation of a covalent C-C bond via a decarboxylative Barton-Zard reaction between the two entities. The bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (IC50: 0.48-5.39 μM) against Trypanosoma brucei. These hybrids were more active than their respective parent alkaloids (up to a 135 fold increase in activity), and displayed good selectivity indices. Aditionally, all these compounds inhibited the in vitro growth of a chloroquine-sensitive strain of Plasmodium falciparum (3D7: IC50: 36.1 nM to 8.72 μM), and the most active hybrids had IC50s comparable to that of artemisinin (IC50: 36 nM). Some structure-activity relationships among the group of 48 hybrids are discussed. The increase in antiparasitic activity may be explained by an improvement in bioavailability, since the more lipophilic derivatives showed the lowest IC50s.
|
Antiparasite activity against Trypanosoma brucei 427 assessed as growth inhibition incubated for 48 hrs by PrestoBlue based fluorescence assay
|
Trypanosoma brucei
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery.
Year : 2015
Volume : 58
Issue : 14
First Page : 5522
Last Page : 5537
Authors : Devine W, Woodring JL, Swaminathan U, Amata E, Patel G, Erath J, Roncal NE, Lee PJ, Leed SE, Rodriguez A, Mensa-Wilmot K, Sciotti RJ, Pollastri MP.
Abstract : Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
23.13
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
7.96
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
17.11
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
15.45
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
10.42
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
39.24
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
2.45
%
|
|
|
Inhibition of N-terminal His6-sumo-tagged full length Staphylococcus aureus ClpP expressed in Escherichia coli BL2 (DE3) at 10 uM pre-incubated for 10 mins before Suc-LY-AMC addition and measured after 1 hr by fluorescence based assay relative to control
|
Staphylococcus aureus
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo.
Year : 2020
Volume : 63
Issue : 6
First Page : 3104
Last Page : 3119
Authors : Ju Y, He L, Zhou Y, Yang T, Sun K, Song R, Yang Y, Li C, Sang Z, Bao R, Luo Y.
Abstract : Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.
|
Growth inhibiting activity of Naegleria gruberi in vitro
|
Naegleria gruberi
|
32.0
%
|
|
Title : Naegleria gruberi Pathogen Box compounds screening
Authors : Sarink, M; Mykytyn, A; Tielens, A; van Hellemond, J
Abstract : 400 compounds from the Pathogen box were screened for inhibitory activity against Naegleria gruberi strain NEG-M. N. gruberi was grown in modified PYNFH medium in 96-wells plates. Compounds were added in 10 uM concentrations in triplicate wells. Optical density was measured daily, after 6 days area under the curve was calculated and compared to 0.1 % DMSO control.
