|
In vitro anti protozoal activity against Trypanosoma cruzi strain Tulahuen CL2 was determined
|
Trypanosoma cruzi
|
450.0
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.
|
The compound was tested in vitro for antitrypanosomal activity against Trypanosoma cruzi epimastigotes at a dose of 25 uM
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : 1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs: structure-activity relationships.
Year : 1999
Volume : 42
Issue : 11
First Page : 1941
Last Page : 1950
Authors : Cerecetto H, Di Maio R, González M, Risso M, Saenz P, Seoane G, Denicola A, Peluffo G, Quijano C, Olea-Azar C.
Abstract : The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of Trypanosoma cruzi. For the most effective drugs, derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.
|
In vitro anti-protozoal parasite activity against Trypanosoma cruzi TC-1
|
trypanasoma cruzi
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,4-Dihydroxy-2,3-dioxatricyclo[8.4.0.0(4,9)]tetradecane and derivatives with in vitro activity against Plasmodium falciparum, Trypanasoma b brucei, Trypanasoma cruzi, and Leishmaniasis infantum.
Year : 2003
Volume : 13
Issue : 12
First Page : 2013
Last Page : 2015
Authors : Howarth J, Wilson D.
Abstract : 1,4-Dihydroxy-2,3-dioxatricyclo[8.4.0.0(4,9)]tetradecane and derivatives have been synthesised and their in vitro activity against Plasmodium falciparum (malaria) Ghana, Trypanasoma b brucei (sleeping sickness) TB-1, and Trypanasoma cruzi (Chagas' disease) TC-1, and Leishmaniasis infantum (leishmaniasis) L1 parasite strains has been assessed.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 1 mg/mL after incubation for 24 hr
|
Trypanosoma cruzi
|
17.39
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 1 mg/mL after incubation for 48 hr
|
Trypanosoma cruzi
|
20.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 1 mg/mL after incubation for 72 hr
|
Trypanosoma cruzi
|
19.64
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 1 mg/mL after incubation for 98 hr
|
Trypanosoma cruzi
|
13.24
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 10 mg/mL after incubation for 24 hr
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 10 mg/mL after incubation for 48 hr
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 10 mg/mL after incubation for 72 hr
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 10 mg/mL after incubation for 98 hr
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 100 mg/mL after incubation for 24 hr
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 100 mg/mL after incubation for 48 hr
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 100 mg/mL after incubation for 72 hr
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Percent of growth inhibition of Trypanosoma cruzi (Y strain) epimastigote forms at compound concentration of 100 mg/mL after incubation for 98 hr
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antitrypanosomal activity of novel Nifurtimox analogues.
Year : 2005
Volume : 15
Issue : 5
First Page : 1417
Last Page : 1421
Authors : Pozas R, Carballo J, Castro C, Rubio J.
Abstract : Eight novel analogues of Nifurtimox, 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide, containing alpha-beta unsaturated amides, were synthesized and evaluated for their in vitro activity against Trypanosoma cruzi epimastigotes. Four derivatives bearing a nitro group at the 5-position of the furan ring were the most active in inhibiting culture growth and provoking cell death, showing trypanocidal activity more than threefold the potency of Nifurtimox, our positive control. Two derivatives lacking a nitro group were less potent than the positive control. Active nitro derivatives very efficiently caused epimastigote death, which suggests a nitro reduction mechanism of action.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen CL2 by microdilution method
|
Trypanosoma cruzi
|
390.0
nM
|
|
Journal : J. Nat. Prod.
Title : Triterpenoids from Brazilian Ilex species and their in vitro antitrypanosomal activity.
Year : 2004
Volume : 67
Issue : 10
First Page : 1697
Last Page : 1700
Authors : Taketa AT, Gnoatto SC, Gosmann G, Pires VS, Schenkel EP, Guillaume D.
Abstract : From the leaves of Ilex affinis and Ilex buxifolia, two adulterant species of "erva mate" (Ilex paraguariensis), three new triterpenoid glycosides were isolated. Affinoside 1 (3beta-O-[beta-D-glucopyranosyl-(1-->3)-[2-O-acetyl-(1-->2]]-alpha-L-arabinopyranosyl pomolic acid 28-O-beta-D-glucopyranosyl ester, 1) was isolated from I. affinis, while buxifolioside I (28-O-beta-D-glucopyranosyl ester of (20S)-3alpha,19alpha-dihydroxyurs-12-ene-23,28-dioic acid, 7) and buxifolioside II (28-O-beta-D-glucopyranosyl ester of (20S)-3beta,19alpha-dihydroxyurs-12-en-24,28-dioic acid, 8) were isolated from I. buxifolia. Along with these new compounds, ilexoside II (2), ursolic acid (3), 28-nor-ursolic acid (4), 3beta-O-acetylursolic acid (5), and uvaol (6) were also isolated. The observed results confirm the structural specificity of the I. paraguariensis triterpenoids and reinforce a previous proposal to detect mate adulteration by triterpenoid analysis. In addition, the in vitro antitrypanosomal activity of some Ilex triterpenoids is also reported.
|
Antitrypanosomal activity against Trypanosoma cruzi
|
Trypanosoma cruzi
|
3.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antileishmanial constituents of the Panamanian endophytic fungus Edenia sp.
Year : 2008
Volume : 71
Issue : 12
First Page : 2011
Last Page : 2014
Authors : Martínez-Luis S, Della-Togna G, Coley PD, Kursar TA, Gerwick WH, Cubilla-Rios L.
Abstract : Bioassay-directed fractionation of extracts from the fermentation broth and mycelium of the fungus Edenia sp. led tothe isolation of five antileishmanial compounds, preussomerin EG1 (1), palmarumycin CP2 (2), palmarumycin CP17 (3), palmarumycin CP18 (4), and CJ-12,371 (5). Compounds 3 and 4 are new natural products, and this is only the second report of compound 1. The structures of compounds 1-5 were established by spectroscopic analyses (HRMS and NMR). All metabolites caused significant inhibition of the growth of Leishmania donoVani in the amastigote form, with IC50 values of 0.12, 3.93, 1.34, 0.62, and 8.40 microM, respectively. Compounds 1-5 were inactive when tested against Plasmodium falciparum or Trypanasoma cruzi at a concentration of 10 microg/mL, indicating that they have selective activity against Leishmania parasites. Compounds 1-5 showed weak cytotoxicity to Vero cells (IC50 of 9, 162, 174, 152, and 150 microM, respectively); however, the therapeutic window of these compounds is quite significant with 75, 41, 130, 245, and 18 times (respectively) more antileishmanial activity than cytotoxicity.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen C4 in african green monkey Vero cells after 120 hrs
|
Trypanosoma cruzi
|
520.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, cytotoxicity, and anti-Trypanosoma cruzi activity of new chalcones.
Year : 2008
Volume : 51
Issue : 19
First Page : 6230
Last Page : 6234
Authors : Aponte JC, Verástegui M, Málaga E, Zimic M, Quiliano M, Vaisberg AJ, Gilman RH, Hammond GB.
Abstract : Synthesis of a cytotoxic dihydrochalcone, first isolated from a traditional Amazonian medicinal plant Iryanthera juruensis Warb (Myristicaceae), followed by a comprehensive SAR analysis of saturated and unsaturated chalcone synthetic intermediates, led to the identification of analogues with selective and significant in vitro anti- Trypanosoma cruzi activity. Further SAR studies were undertaken with the synthesis of 21 new chalcones containing two allyloxy moieties that resulted in the discovery of 2',4'-diallyloxy-6'-methoxy chalcones with improved selectivity against this parasite at concentrations below 25 microM, four of which exhibited a selectivity index greater than 12.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen infected in mouse 3T3 cells assessed as beta-galactosidase activity after 7 days by chagas bioassay
|
Trypanosoma cruzi
|
3.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Almiramides A-C: discovery and development of a new class of leishmaniasis lead compounds.
Year : 2010
Volume : 53
Issue : 10
First Page : 4187
Last Page : 4197
Authors : Sanchez LM, Lopez D, Vesely BA, Della Togna G, Gerwick WH, Kyle DE, Linington RG.
Abstract : Leishmaniasis is a debilitating disease caused by protozoan parasites of the genus Leishmania, which affects an estimated 12 million people worldwide. The discovery of new lead compounds for leishmaniasis is therefore a pressing concern for global health programs. The organic extract of a Panamanian collection of the marine cyanobacterium Lyngbya majuscula showed strong in vitro activity in two complementary screens against the tropical parasite Leishmania donovani, the causative agent of visceral leishmaniasis. Chromatographic separation of this complex mixture led to the isolation of the highly N-methylated linear lipopeptides, almiramides A-C (1-3). Comparison with the biological activities of a number of related metabolites and semisynthetic derivatives revealed key features required for activity and afforded one new compound (11) with superior in vitro activity. Subsequent synthesis of a library of simplified analogues led to the discovery of several compounds with improved therapeutic indices to the natural products.
|
Antitrypanosomal activity against Trypanosoma cruzi Sylvio-X10/7 infected in BESM cells measured after 88 hrs postinfection by HTS assay
|
Trypanosoma cruzi
|
700.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Image-based high-throughput drug screening targeting the intracellular stage of Trypanosoma cruzi, the agent of Chagas' disease.
Year : 2010
Volume : 54
Issue : 8
First Page : 3326
Last Page : 3334
Authors : Engel JC, Ang KK, Chen S, Arkin MR, McKerrow JH, Doyle PS.
Abstract : Chagas' disease, caused by infection with the parasite Trypanosoma cruzi, is the major cause of heart failure in Latin America. Classic clinical manifestations result from the infection of heart muscle cells leading to progressive cardiomyopathy. To ameliorate disease, chemotherapy must eradicate the parasite. Current drugs are ineffective and toxic, and new therapy is a critical need. To expedite drug screening for this neglected disease, we have developed and validated a cell-based, high-throughput assay that can be used with a variety of untransfected T. cruzi isolates and host cells and that simultaneously measures efficacy against the intracellular amastigote stage and toxicity to host cells. T. cruzi-infected muscle cells were incubated in 96-well plates with test compounds. Assay plates were automatically imaged and analyzed based on size differences between the DAPI (4',6-diamidino-2-phenylindole)-stained host cell nuclei and parasite kinetoplasts. A reduction in the ratio of T. cruzi per host cell provided a quantitative measure of parasite growth inhibition, while a decrease in count of the host nuclei indicated compound toxicity. The assay was used to screen a library of clinically approved drugs and identified 55 compounds with activity against T. cruzi. The flexible assay design allows the use of various parasite strains, including clinical isolates with different biological characteristics (e.g., tissue tropism and drug sensitivity), and a broad range of host cells and may even be adapted to screen for inhibitors against other intracellular pathogens. This high-throughput assay will have an important impact in antiparasitic drug discovery.
|
Antimicrobial activity against Trypanosoma brucei gambiense
|
Trypanosoma brucei gambiense
|
260.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis.
Year : 2010
Volume : 54
Issue : 7
First Page : 2893
Last Page : 2900
Authors : Sokolova AY, Wyllie S, Patterson S, Oza SL, Read KD, Fairlamb AH.
Abstract : The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (approximately 27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.
|
Antitrypanosomal activity against Trypanosoma cruzi clone Cl-Brener infected in african green monkey Vero cells assessed as growth inhibition after 3 days by luciferase reporter gene assay
|
Trypanosoma cruzi
|
240.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Trypanocidal activity of aziridinyl nitrobenzamide prodrugs.
Year : 2010
Volume : 54
Issue : 10
First Page : 4246
Last Page : 4252
Authors : Bot C, Hall BS, Bashir N, Taylor MC, Helsby NA, Wilkinson SR.
Abstract : The trypanocidal agents nifurtimox and benznidazole both function as prodrugs and must undergo enzyme-mediated activation, a reaction catalyzed by type I nitroreductase (NTR). In the search for new parasitic therapies, we have utilized this finding to investigate whether aziridinyl nitrobenzamide derivatives have activity against bloodstream-form Trypanosoma brucei and Trypanosoma cruzi amastigotes, parasite stages that replicate in the mammalian host. For T. cruzi drug screening, we generated trypanosomes that expressed the luciferase reporter gene and optimized a mammalian infection model in a 96-well plate format. A subset of compounds having a 5-(aziridin-1-yl)-2,4-dinitrobenzyl structure was shown to be metabolized by purified T. brucei NTR and when screened against both parasite life cycle stages displayed significant growth-inhibitory properties: the most potent compounds generated 50% inhibitory concentrations of <1 μM. The trypanocidal activity was shown to be NTR specific, since parasites overexpressing this enzyme were hypersensitive to the aziridinyl dinitrobenzyl agents. We conclude that members of the aziridinyl nitrobenzamide class of nitroheterocycles provide new lead structures that have the potential to treat trypanosomal infections.
|
DNDI: Inhibition of Chagas Disease parasite Trypanosoma cruzi (Tulahuen LacZ, Clone C4), in vitro.
|
Trypanosoma cruzi
|
230.0
nM
|
|
Title : Optimisation of fenarimol series for the treatment of Chagas disease
Authors : DNDi lead Optimization consortium (Epichem, Murdoch University, CDCO)
Abstract : As part of a hit generation effort to discover new T. cruzi inhibitors, a diversity set of agrochemicals was screened in vitro in a whole cell parasite assay against a T. cruzi strain (Tulahuen) belonging to T. cruzi group VI (TcVI) [1] and transfected with the Lac-Z gene. [2] The plant fungicides fenarimol [DNDI1246778] and pyrifenox [DNDI1255613], used in the control of powdery mildew and fungus on fruits and vegetables, demonstrated good activity in the assay with IC50's of 350 nM and 290 nM, respectively. With simple aromatic components and modular synthesis, fenarimol was an ideal starting point for structure-activity-relationship (SAR) investigations aimed at improving activity against T. cruzi and developing compounds suitable for in vivo characterisation.
|
Antitrypanosomal activity against tetracycline-induced blood-stream Trypanosoma brucei brucei overexpressing type 1 nitroreductase after 3 days by alamar blue assay
|
Trypanosoma brucei brucei
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based aliphatic and aromatic amines as anti-chagasic agents.
Year : 2011
Volume : 54
Issue : 23
First Page : 8214
Last Page : 8223
Authors : Papadopoulou MV, Trunz BB, Bloomer WD, McKenzie C, Wilkinson SR, Prasittichai C, Brun R, Kaiser M, Torreele E.
Abstract : A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for antitrypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, 18 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC(50) ranging from 40 nM to 1.97 μM), without concomitant toxicity toward the host cells (L6 cells), having selectivity indices (SI) 44-1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream-form (BSF) T. b. rhodesiense trypomastigotes (IC(50) at nM levels and SI 220-993). An NADH-dependent nitroreductase (TbNTR) plays a role in the antiparasitic activity because BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei brucei Lister 427 clone 221a overexpressing tet-inducible NTR in absence of tetracycline after 3 days
|
Trypanosoma brucei brucei
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents.
Year : 2012
Volume : 55
Issue : 11
First Page : 5554
Last Page : 5565
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Chatelain E, Kaiser M, Wilkinson SR, McKenzie C, Ioset JR.
Abstract : A series of novel 3-nitro-1H-1,2,4-triazole-based (and in some cases 2-nitro-1H-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against Trypanosoma cruzi intracellular amastigotes (IC(50) ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66-2782). Twenty-three of these active compounds were more potent (up to 58-fold) than the reference drug benznidazole, tested in parallel. In addition, nine nitrotriazoles which were moderately active (0.5 μM ≤ IC(50) < 6.0 μM) against Trypanosoma brucei rhodesiense trypomastigotes were 5-31-fold more active against bloodstream-form Trypanosoma brucei brucei trypomastigotes engineered to overexpress reduced nicotinamide adenine dinucleotide dependent nitroreductase. Finally, three nitrotriazoles displayed a moderate activity against the axenic form of Leishmania donovani . Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent antitrypanosomal agents.
|
Antitrypanosomal activity against Trypanosoma brucei bloodstream form overexpressing nitroreductase assessed as growth inhibition after 3 days by Alamar blue assay
|
Trypanosoma brucei
|
260.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and evaluation of potential prodrugs of DFMO for reductive activation.
Year : 2012
Volume : 22
Issue : 21
First Page : 6583
Last Page : 6586
Authors : Yang Y, Voak A, Wilkinson SR, Hu L.
Abstract : A series of potential DFMO prodrugs was designed through the incorporation of 4-nitrobenzyl ester or carbamate groups for potential activation by trypanosomal nitroreductase. It was found that only modification of N(ε)-amino group of DFMO by 4-nitro-2-fluorobenzyloxycarbonyl resulted in significant trypanocidal activity and could serve as a lead for further investigation.
|
Antimicrobial activity against amastigote stage of Trypanosoma cruzi CL Brener infected in mouse NCTC-929 cells assessed as growth inhibition after 7 days by beta-galactosidase reporter gene assay
|
Trypanosoma cruzi strain CL Brener
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents.
Year : 2014
Volume : 24
Issue : 4
First Page : 1209
Last Page : 1213
Authors : Fonseca-Berzal C, Rojas Ruiz FA, Escario JA, Kouznetsov VV, Gómez-Barrio A.
Abstract : In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3, SI12 and SIBZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI=12.73). These results, supported by the in silico prediction of a good oral bioavailability and a suitable risk profile, propose the 4-amino-7-chloroquinoline scaffold as a potential template for designing trypanocidal prototypes.
|
Cytotoxicity against mouse NCTC-929 cells at 256 uM after 48 hrs by resazurin staining-based fluorescence assay
|
Mus musculus
|
26.83
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents.
Year : 2014
Volume : 24
Issue : 4
First Page : 1209
Last Page : 1213
Authors : Fonseca-Berzal C, Rojas Ruiz FA, Escario JA, Kouznetsov VV, Gómez-Barrio A.
Abstract : In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy)quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3, SI12 and SIBZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI=12.73). These results, supported by the in silico prediction of a good oral bioavailability and a suitable risk profile, propose the 4-amino-7-chloroquinoline scaffold as a potential template for designing trypanocidal prototypes.
|
Antiparasitic activity against epimastigote stage of Trypanosoma cruzi assessed as growth inhibition at 50 uM
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : MedChemComm
Title : Recent applications of multicomponent reactions in medicinal chemistry
Year : 2012
Volume : 3
Issue : 10
First Page : 1189
Last Page : 1218
Authors : Slobbe P, Ruijter E, Orru RVA
|
Antitrypanosomal activity against Trypanosoma cruzi infected in albino CF1 mouse assessed as reduction in number of parasites in blood at 104 mg/kg/day, intramuscular treatment started on day 10 of infection up to day 14
|
Trypanosoma cruzi
|
99.0
%
|
|
Journal : J. Med. Chem.
Title : In search of anti-Trypanosoma cruzi drugs: new leads from a mouse model.
Year : 1977
Volume : 20
Issue : 6
First Page : 741
Last Page : 744
Authors : Kinnamon KE, Steck EA, Hanson WL, Chapman WL.
Abstract : Nine of 25 carefully selected compounds (from a stock of more than 200 000 chemical species amassed principally as a result of testing against other parasitic diseases) were found to have significant suppressive activity against the parasites in the blood of a Trypanosoma cruzi mouse model. Eight of these compounds evaluated in this model had suppressive activity equal to or greater than the reference compound, nifurtimox. For the first time, suppressive activity against T. cruzi is reported for a 7-aminoquinoline, a phosphonium salt, and TAC pamoate; The biological model is believed to be able to serve as a means of identifying other new "leads* in seeking drugs broadly effective against T=ruzi infections in man.
|
Antitrypanosomal activity against Trypanosoma cruzi infected in albino CF1 mouse assessed as reduction in number of parasites in blood at 52 mg/kg/day, intramuscular treatment started on day 10 of infection up to day 14
|
Trypanosoma cruzi
|
92.0
%
|
|
Journal : J. Med. Chem.
Title : In search of anti-Trypanosoma cruzi drugs: new leads from a mouse model.
Year : 1977
Volume : 20
Issue : 6
First Page : 741
Last Page : 744
Authors : Kinnamon KE, Steck EA, Hanson WL, Chapman WL.
Abstract : Nine of 25 carefully selected compounds (from a stock of more than 200 000 chemical species amassed principally as a result of testing against other parasitic diseases) were found to have significant suppressive activity against the parasites in the blood of a Trypanosoma cruzi mouse model. Eight of these compounds evaluated in this model had suppressive activity equal to or greater than the reference compound, nifurtimox. For the first time, suppressive activity against T. cruzi is reported for a 7-aminoquinoline, a phosphonium salt, and TAC pamoate; The biological model is believed to be able to serve as a means of identifying other new "leads* in seeking drugs broadly effective against T=ruzi infections in man.
|
Antitrypanosomal activity against Trypanosoma cruzi infected in albino CF1 mouse assessed as reduction in number of parasites in blood at 13 mg/kg/day, intramuscular treatment started on day 10 of infection up to day 14
|
Trypanosoma cruzi
|
57.0
%
|
|
Journal : J. Med. Chem.
Title : In search of anti-Trypanosoma cruzi drugs: new leads from a mouse model.
Year : 1977
Volume : 20
Issue : 6
First Page : 741
Last Page : 744
Authors : Kinnamon KE, Steck EA, Hanson WL, Chapman WL.
Abstract : Nine of 25 carefully selected compounds (from a stock of more than 200 000 chemical species amassed principally as a result of testing against other parasitic diseases) were found to have significant suppressive activity against the parasites in the blood of a Trypanosoma cruzi mouse model. Eight of these compounds evaluated in this model had suppressive activity equal to or greater than the reference compound, nifurtimox. For the first time, suppressive activity against T. cruzi is reported for a 7-aminoquinoline, a phosphonium salt, and TAC pamoate; The biological model is believed to be able to serve as a means of identifying other new "leads* in seeking drugs broadly effective against T=ruzi infections in man.
|
Antitrypanosomal activity against Trypanosoma cruzi Sylvio X-10 amastigotes infected in African green monkey Vero cells assessed as eradication of amastigotes after 72 hrs by Giemsa staining-based assay
|
Trypanosoma cruzi
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of antitrypanosomatid agents: identification of nonmutagenic drug candidates with in vivo activity.
Year : 2014
Volume : 57
Issue : 10
First Page : 3984
Last Page : 3999
Authors : Álvarez G, Varela J, Márquez P, Gabay M, Arias Rivas CE, Cuchilla K, Echeverría GA, Piro OE, Chorilli M, Leal SM, Escobar P, Serna E, Torres S, Yaluff G, Vera de Bilbao NI, González M, Cerecetto H.
Abstract : Chagas disease, caused by Trypanosoma cruzi parasite, was described thousands of years ago. Currently, it affects millions of people, mostly in Latin America, and there are not suitable drugs for treating it. As an attempt to find appropriate drugs to deal with this problem, we report here on the design, synthesis, and characterization of 82 new compounds. Trypanosomicidal behavior in vitro showed more than 20 outstanding derivatives with anti-Trypanosoma cruzi activity. Furthermore, we studied the nonspecific toxicity against mammalian cells determining their selectivity and also performed mutagenicity studies. Proof of concept, in vivo studies, was conducted with two of the most promising derivatives (77 and 80). They were identified as candidates because they have (i) very simple and cost-effective syntheses; (ii) activity against different stages and strains of the parasite showing excellent in vivo behavior during the acute phase of Chagas disease; and (iii) neither nonspecific toxicity nor mutagenic activity.
|
Trypanocidal activity against bloodstream forms of Trypanosoma brucei brucei Lister 427 clone 221a overexpressing type I nitroreductase assessed as inhibition of proliferation after 3 days by resazurin assay in presence of tetracycline
|
Trypanosoma brucei brucei
|
130.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides as potential antitrypanosomal agents.
Year : 2014
Volume : 87
First Page : 79
Last Page : 88
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Wilkinson SR, Kaiser M.
Abstract : We have previously shown that 3-nitro-1H-1,2,4-triazole-based arylamides and arylsulfonamides demonstrate significant activity in vitro against Trypanosoma cruzi, the causative parasite of Chagas disease. More importantly, several such analogs displayed significant antichagasic activity in vivo, superior to that of benznidazole, the current clinical standard. We now report the synthesis and in vitro evaluation of a small series of novel nitro(triazole/imidazole)-based heteroarylamides/sulfonamides (including 3-nitrotriazole-, 2- and 4-nitroimidazole-based compounds) as potential antitrypanosomal agents. All nitrotriazoles displayed significant growth inhibitory properties against T. cruzi with the most potent generating IC50 values of <1 μM and up to >1400-fold selectivity toward the parasite. The 2-nitroimidazole-based derivatives were moderately active against T. cruzi and displayed selectivity <50, while the 4-nitroimidazoles were mostly inactive. Several 3-nitrotriazole-based analogs showed activity against Trypanosoma brucei rhodesiense but none of the tested compounds displayed activity toward Leishmania donovani. From the detailed SARs presented here, we identified the 3-nitrotriazole-based chlorinated thiophene/benzothiophene sulfonamides/amides as being the most active antichagasic compounds, displaying up to 14-fold higher potency against T. cruzi than the reference compound benznidazole.
|
Trypanocidal activity against nifurtimox-sensitive Trypanosoma cruzi Tulahuen CL2 infected in human MRC5 SV2 cells assessed as parasite growth inhibition after 168 hrs by beta-galactosidase assay
|
Trypanosoma cruzi
|
700.0
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 trypomastigote form of Trypanosoma cruzi infected in african green monkey Vero cells assessed as cell viability after 5 to 7 days by MTT assay
|
Trypanosoma cruzi
|
42.62
%
|
|
Journal : Bioorg. Med. Chem.
Title : 2-Phenylaminonaphthoquinones and related compounds: synthesis, trypanocidal and cytotoxic activities.
Year : 2014
Volume : 22
Issue : 17
First Page : 4609
Last Page : 4620
Authors : Sieveking I, Thomas P, Estévez JC, Quiñones N, Cuéllar MA, Villena J, Espinosa-Bustos C, Fierro A, Tapia RA, Maya JD, López-Muñoz R, Cassels BK, Estévez RJ, Salas CO.
Abstract : A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds.
|
Antiparasitic activity against blood stream form of Trypanosoma brucei brucei overexpressing type-1 nitroreductase after 3 days by Alamar blue assay in presence of tetracycline
|
Trypanosoma brucei brucei
|
430.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation.
Year : 2015
Volume : 23
Issue : 19
First Page : 6467
Last Page : 6476
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, O'Shea IP, Wilkinson SR, Kaiser M, Chatelain E, Ioset JR.
Abstract : 3-Nitro-1H-1,2,4-triazole- and 2-nitro-1H-imidazole-based amides with an aryloxy-phenyl core were synthesized and evaluated as antitrypanosomal agents. All 3-nitrotriazole-based derivatives were extremely potent anti-Trypanosoma cruzi agents at sub nM concentrations and exhibited a high degree of selectivity for the parasite. The 2-nitroimidazole analogs were only moderately active against T. cruzi amastigotes and exhibited low selectivity. Both types of compound were active against Leishmania donovani axenic amastigotes with excellent selectivity for the parasite, whereas three 2-nitroimidazole-based analogs were also moderately active against infected macrophages. However, no compound demonstrated selective activity against Trypanosoma brucei rhodesiense. The most potent in vitro anti-T. cruzi compounds were tested in an acute murine model and reduced the parasites to an undetectable level after five days of treatment at 13 mg/kg/day. Such compounds are potential inhibitors of T. cruzi CYP51 and, being excellent substrates for the type I nitroreductase (NTR) which is specific to trypanosomatids, work as prodrugs and constitute a new generation of effective and more affordable antitrypanosomal agents.
|
Antimicrobial activity against bloodstream forms of Trypanosoma brucei brucei overexpressing type I nitroreductase assessed as reduction in cell viability after 3 days by alamar blue assay in presence of tetracycline
|
Trypanosoma brucei brucei
|
430.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 3-Nitrotriazole-based piperazides as potent antitrypanosomal agents.
Year : 2015
Volume : 103
First Page : 325
Last Page : 334
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, O'Shea IP, Wilkinson SR, Kaiser M.
Abstract : Novel linear 3-nitro-1H-1,2,4-triazole-based piperazides were synthesized and evaluated as antitrypanosomal agents. In addition, some bisarylpiperazine-ethanones which were formed as by-products were also screened for antiparasitic activity. Most 3-nitrotriazole-based derivatives were potent and selective against Trypanosoma cruzi parasites, but only one displayed these desired properties against Trypanosoma brucei rhodesiense. Moreover, two 3-nitrotriazole-based chlorophenylpiperazides were moderately and selectively active against Leishmania donovani. Although the bisarylpiperazine-ethanones were active or moderately active against T. cruzi, none of them demonstrated an acceptable selectivity. In general, 3-nitrotriazole-based piperazides were less toxic to host L6 cells than the previously evaluated 3-nitrotriazole-based piperazines and seven of 13 were 1.54- to 31.2-fold more potent antichagasic agents than the reference drug benznidazole. Selected compounds showed good ADMET characteristics. One potent in vitro antichagasic compound (3) was tested in an acute murine model and demonstrated antichagasic activity after a 10-day treatment of 15 mg/kg/day. However, neither compound 3 nor benznidazole showed a statistically significant P value compared to control due to high variability in parasite burden among the untreated animals. Working as prodrugs, 3-nitrotriazole-based piperazides were excellent substrates of trypanosomal type I nitroreductases and constitute a novel class of potentially effective and more affordable antitrypanosomal agents.
|
Trypanocidal activity against Trypanosoma cruzi Tulahuen 2 epimastigotes at 25 uM after 5 days
|
Trypanosoma cruzi
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of quinoxaline di-N-oxide derivatives with in vitro trypanocidal activity.
Year : 2016
Volume : 26
Issue : 3
First Page : 903
Last Page : 906
Authors : Pérez-Silanes S, Torres E, Arbillaga L, Varela J, Cerecetto H, González M, Azqueta A, Moreno-Viguri E.
Abstract : We report the synthesis and in vitro activity against Trypanosoma cruzi epimastigotes of 15 novel quinoxaline derivatives. Ten of the derivatives presented IC50 values lower than the reference drugs Nfx and Bzn; four of them standed out with IC50 values lower than 1.5 μM. Moreover, unspecific cytotoxicity and genotoxicity studies are also reported. Compound 14 showed a SI higher than 24, whereas compound 10 was the only one that was negative in the genotoxicity screening.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei brucei overexpressing type I nitroreductase assessed as inhibition of parasite growth after 3 days by resazurin assay in presence of tetracycline
|
Trypanosoma brucei brucei
|
869.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Antitrypanosomal activity of 5-nitro-2-aminothiazole-based compounds.
Year : 2016
Volume : 117
First Page : 179
Last Page : 186
Authors : Papadopoulou MV, Bloomer WD, Rosenzweig HS, Wilkinson SR, Szular J, Kaiser M.
Abstract : A small series of 5-nitro-2-aminothiazole-based amides containing arylpiperazine-, biphenyl- or aryloxyphenyl groups in their core were synthesized and evaluated as antitrypanosomatid agents. All tested compounds were active or moderately active against Trypanosoma cruzi amastigotes in infected L6 cells and Trypanosoma brucei brucei, four of eleven compounds were moderately active against Leishmania donovani axenic parasites while none were deemed active against T. brucei rhodesiense. For the most active/moderately active compounds a moderate selectivity against each parasite was observed. There was good correlation between lipophilicity (clogP value) and antileishmanial activity or toxicity against L6 cells. Similarly, good correlation existed between clogP values and IC50 values against T. cruzi in structurally related subgroups of compounds. Three compounds were more potent as antichagasic agents than benznidazole but were not activated by the type I nitrorectusase (NTR).
|
Antitrypanosomal activity against amastigote stage of Trypanosoma cruzi Y infected in human U2OS cells after 96 hrs by Draq5 staining-based high content screening assay
|
Trypanosoma cruzi
|
340.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and antitrypanosomal activity of some nitrofurazone 1,2,4-triazolic bioisosteric analogues.
Year : 2016
Volume : 121
First Page : 553
Last Page : 560
Authors : Silva FT, Franco CH, Favaro DC, Freitas-Junior LH, Moraes CB, Ferreira EI.
Abstract : Chagas disease, caused by Trypanosoma cruzi, is a parasitosis that predominates in Latin America. It is estimated that 25 million people are under the risk of infection and, in 2008, more than 10 thousand deaths were registered. The only two drugs available in the therapeutics, nifurtimox and benznidazole, showed to be more effective in the acute phase of the disease. However, there is no standard treatment protocol effective for the chronic phase. Nitrofurazone (NF), an antimicrobial drug, has activity against T. cruzi, although being toxic. Considering the need for new antichagasic drugs, the existence of promising new therapeutic targets, as 14α-sterol demethylase and cruzain, and employing the bioisosterism and molecular hybridization approaches, four novel compounds were synthesized, characterized by melting point range, elemental analysis, IR and NMR spectroscopy. The compounds were tested against T. cruzi amastigotes in infected U2OS cells. All compounds showed selectivity towards T. cruzi and showed trypanomicidal activity in low micromolar range. The compound 3 showed potency similar to benznidazole, but lower efficacy. These results highlight the importance of the 1,2,4-triazole, thiosemicarbazonic and nitro group moieties for designing new efficient compounds, potentially for the chronic phase of Chagas disease.
|
Anti-parasitic activity against Leishmania amazonensis promastigotes after 44 hrs by CellTiter-Blue assay
|
Leishmania amazonensis
|
800.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids.
Year : 2017
Volume : 27
Issue : 4
First Page : 755
Last Page : 758
Authors : Hackler A, Patrick SL, Kahney EW, Flaherty DP, Sharlow ER, Morris JC, Golden JE.
Abstract : A sulfonamidebenzamide series was assessed for anti-kinetoplastid parasite activity based on structural similarity to the antiparasitic drug, nifurtimox. Through structure-activity optimization, derivatives with limited mammalian cell toxicity and increased potency toward African trypanosomes and Leishmania promastigotes were developed. Compound 22 had the best potency against the trypanosome (EC50=0.010μM) while several compounds showed ∼10-fold less potency against Leishmania promastigotes without impacting mammalian cells (EC50>25μM). While the chemotype originated from an unrelated optimization program aimed at selectively activating an apoptotic pathway in mammalian cancer cells, our preliminary results suggest that a distinct mechanism of action from that observed in mammalian cells is responsible for the promising activity observed in parasites.
|
Antitrypanosomal activity against Trypanosoma cruzi Silvio X10/7 intracellular forms
|
Trypanosoma cruzi
|
900.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification and preliminary structure-activity relationship studies of novel pyridyl sulfonamides as potential Chagas disease therapeutic agents.
Year : 2018
Volume : 28
Issue : 11
First Page : 2018
Last Page : 2022
Authors : Peres RB, Ullah AI, de Almeida Fiuza LF, Silva PB, Batista MM, Corcoran O, Reddy TRK, de Nazaré Correia Soeiro M.
Abstract : Chagas disease is a neglected pathology responsible for about 12,000 deaths every year across Latin America. Although six million people are infected by the Trypanosoma cruzi, current therapeutic options are limited, highlighting the need for new drugs. Here we report the preliminary structure activity relationships of a small library of 17 novel pyridyl sulfonamide derivatives. Analogues 4 and 15 displayed significant potency against intracellular amastigotes with EC50 of 5.4 µM and 8.6 µM. In cytotoxicity assays using mice fibroblast L929 cell lines, both compounds indicated low toxicity with decent selectivity indices (SI) >36 and >23 respectively. Hence these compounds represent good starting points for further lead optimization.
|
Antitrypanosomal activity against Trypanosoma cruzi clone CL B5 amastigotes harboring lacZ infected in mouse NCTC-929 cells after 7 days by beta-galactosidase reporter gene assay
|
Trypanosoma cruzi
|
500.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel Imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxides as antiproliferative trypanosoma cruzi drugs: Computational screening from neural network, synthesis and in vivo biological properties.
Year : 2017
Volume : 136
First Page : 223
Last Page : 234
Authors : Guerra A, Gonzalez-Naranjo P, Campillo NE, Varela J, Lavaggi ML, Merlino A, Cerecetto H, González M, Gomez-Barrio A, Escario JA, Fonseca-Berzal C, Yaluf G, Paniagua-Solis J, Páez JA.
Abstract : A new family of imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxide with antiproliferative Trypanosoma cruzi properties was identified from a neural network model published by our group. The synthesis and evaluation of this new class of trypanocidal agents are described. These compounds inhibit the growth of Trypanosoma cruzi, comparable with benznidazole or nifurtimox. In vitro assays were performed to study their effects on the growth of the epimastigote form of the Tulahuen 2 strain, as well as the epimastigote and amastigote forms of CL clone B5 of Trypanosoma cruzi. To verify selectivity towards parasite cells, the non-specific cytotoxicity of the most relevant compounds was studied in mammalian cells, i.e. J774 murine macrophages and NCTC clone 929 fibroblasts. Furthermore, these compounds were assayed regarding the inhibition of cruzipain. In vivo studies revealed that one of the compounds, 19, showed interesting trypanocidal activity, and could be a very promising candidate for the treatment of Chagas disease.
|
Antitrypanosomal activity against beta-galactosidase expressing nifurtimox-sensitive Trypanosoma cruzi Tulahuen CL2 infected in human MRC5 SV2 cells assessed as decrease in parasite burden after 168 hrs by spectrophotometric method
|
Trypanosoma cruzi
|
700.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel triazine dimers with potent antitrypanosomal activity.
Year : 2018
Volume : 143
First Page : 306
Last Page : 319
Authors : Venkatraj M, Salado IG, Heeres J, Joossens J, Lewi PJ, Caljon G, Maes L, Van der Veken P, Augustyns K.
Abstract : Human African trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease transmitted by the bite of the 'Glossina' insect, commonly known as the tsetse fly. This disease affects mostly poor populations living in remote rural areas of Africa. Untreated, it is usually fatal. Currently, safe and effective treatments against this disease are lacking. Phenotypic screening of triazine non-nucleoside HIV-1 reverse transcriptase inhibitors (monomers) resulted in potent and selective antitrypanosomal compounds. This serendipitous discovery and the presence of dimers in many compounds active against these neglected tropical diseases prompted us to investigate antitrypanosomal activity of triazine dimers. Optimization of the triazine dimers resulted in 3,3'-(((ethane-1,2-diylbis(azanediyl))bis(4-(mesityloxy)-1,3,5-triazine-6,2-diyl))bis(azanediyl))dibenzonitrile (compound 38), a compound with very potent in vitro and moderate in vivo antitrypanosomal activity.
|
Antitrypanosomal activity against Trypanosoma cruzi Colombiana Tc1 trypamastigotes infected in monkey LLC-MK2 cells assessed as inhibition of parasite viability by measuring motility at 1 uM after 20 hrs by light microscopic method relative to control
|
Trypanosoma cruzi
|
7.3
%
|
|
Journal : Eur J Med Chem
Title : Investigating the structure-activity relationships of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds.
Year : 2018
Volume : 144
First Page : 29
Last Page : 40
Authors : Palace-Berl F, Pasqualoto KFM, Zingales B, Moraes CB, Bury M, Franco CH, da Silva Neto AL, Murayama JS, Nunes SL, Silva MN, Tavares LC.
Abstract : Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T. cruzi strains. Here we show that these compounds are also active against a BZD- and NFX-resistant strain. Herein, multivariate approaches (hierarchical cluster analysis and principal component analysis) were applied to a set of thirty-six formerly characterized compounds. Based on the findings from exploratory data analysis, novel compounds were designed and synthesized. These compounds showed two-to three-fold higher trypanocidal activity against epimastigote forms than the previous set and were 25-30-fold more active than BZD. Their activity was also evaluated against intracellular amastigotes by high content screening (HCS). The most active compounds (BSF-38 to BSF-40) showed a selective index (SI') greater than 200, in contrast to the SI' values of reference drugs (NFX, 16.45; BZD, > 3), and a 70-fold greater activity than BZD. These findings indicate that nitrofuran compounds designed based on the activity against epimastigote forms show promising trypanocidal activity against intracellular amastigotes, which correspond to the predominant parasite stage in the chronic phase of Chagas disease.
|
Antitrypanosomal activity against Trypanosoma cruzi Sylvio X10/7 intracellular amastigotes forms assessed as reduction in number of amastigotes per host cell measured every 24 hrs for 96 hrs by time-kill assay
|
Trypanosoma cruzi
|
900.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of Pyrazolo[3,4-e][1,4]thiazepin based CYP51 inhibitors as potential Chagas disease therapeutic alternative: In vitro and in vivo evaluation, binding mode prediction and SAR exploration.
Year : 2018
Volume : 149
First Page : 257
Last Page : 268
Authors : Ferreira de Almeida Fiuza L, Peres RB, Simões-Silva MR, da Silva PB, Batista DDGJ, da Silva CF, Nefertiti Silva da Gama A, Krishna Reddy TR, Soeiro MNC.
Abstract : American trypanosomiasis or Chagas disease (CD) is a vector borne pathology caused by the parasite Trypanosoma cruzi (T. cruzi), which remains a serious global health problem. The current available treatment for CD is limited to two nitroderivatives with limited efficacy and several side effects. The rational design of ergosterol synthetic route inhibitors (e.g. CYP51 inhibitors) represents a promising strategy for fungi and trypanosomatids, exhibiting excellent anti-T.cruzi activity in pre-clinical assays. In the present work, we evaluate through different approaches (molecular docking, structure activity relationships, CYP51 inhibitory assay, and phenotypic screenings in vitro and in vivo) the potency and selectivity of a novel CYP51 inhibitor (compound 1) and its analogues against T.cruzi infection. Regarding anti-parasitic effect, compound 1 was active in vitro with EC50 3.86 and 4.00 μM upon intracellular (Tulahuen strain) and bloodstream forms (Y strain), respectively. In vivo assays showed that compound 1 reduced in 43% the parasitemia peak but, unfortunately failed to promote animal survival. In order to promote an enhancement at the potency and pharmacological properties, 17 new analogues were purchased and screened in vitro. Our findings demonstrated that five compounds were active against intracellular forms, highlighting compounds 1e and 1f, with EC50 2.20 and 2.70 μM, respectively, and selectivity indices (SI) = 50 and 36, respectively. Against bloodstream trypomastigotes, compound 1f reached an EC50 value of 20.62 μM, in a similar range to Benznidazole, but with low SI (3). Although improved the solubility of compound 1, the analogue 1f did not enhance the potency in vitro neither promote better in vivo efficacy against mouse model of acute T.cruzi infection arguing for the synthesis of novel pyrazolo[3,4-e][1,4]thiazepin derivatives aiming to contribute for alternative therapies for CD.
|
Antitrypanosomal activity against nifurtimox-sensitive Trypanosoma cruzi Tulahuen CL2 infected in human MRC5 SV2 cells assessed as reduction in parasite burden after 168 hrs by CPRG and Nonidet based spectrophotometric analysis
|
Trypanosoma cruzi
|
900.0
nM
|
|
Journal : Eur J Med Chem
Title : Optimization of the pharmacokinetic properties of potent anti-trypanosomal triazine derivatives.
Year : 2018
Volume : 151
First Page : 18
Last Page : 26
Authors : Salado IG, Baán A, Verdeyen T, Matheeussen A, Caljon G, Van der Veken P, Kiekens F, Maes L, Augustyns K.
Abstract : Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of sub-saharan Africa. There is a high unmet medical need since the approved drugs are poorly efficacious, show considerable toxicity and are not easy to administer. This work describes the optimization of the pharmacokinetic properties of a previously published family of triazine lead compounds. One compound (35 (UAMC-03011)) with potent anti-trypanosomal activity and no cytotoxicity was selected for further study because of its good microsomal stability and high selectivity for Trypanosoma brucei over a panel including Trypanosoma cruzi, L.eishmania infantum, and Plasmodium falciparum. In vivo pharmacokinetic parameters were determined and the compound was studied in an acute in vivo mouse disease model. One of the important learnings of this study was that the rate of trypanocidal activity is an important parameter during the lead optimization process.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen amastigote forms infected in rat H9c2 cells assessed as reduction in amastigote number per cell after 72 hrs by DRAQ5 DNA dye based confocal microscopic analysis
|
Trypanosoma cruzi
|
400.0
nM
|
|
Journal : Bioorg Med Chem
Title : Quinoxaline derivatives as potential antitrypanosomal and antileishmanial agents.
Year : 2018
Volume : 26
Issue : 14
First Page : 4065
Last Page : 4072
Authors : Cogo J, Cantizani J, Cotillo I, Sangi DP, Corrêa AG, Ueda-Nakamura T, Filho BPD, Martín JJ, Nakamura CV.
Abstract : Continuous efforts have been made to discover new drugs for the treatment of Chagas' disease, human African trypanosomiasis, and leishmaniasis. We have previously reported the synthesis and antileishmanial and antitrypanosomal (Y strain) properties of 2,3-disubstituted quinoxalines. Considering their promising antiparasitic potential, the present study was conducted to expand our search and take advantage of high-throughput assays to investigate the effects of quinoxaline derivatives against Leishmania donovani, Trypanosoma brucei, and Trypanosoma cruzi (Tulahuen strain). These compounds were active against the kinetoplastid parasites that were evaluated. The 2-chloro-3-methylsulfoxylsulfonyl and 2-chloro-3-methylsulfinyl quinoxalines were the most potent, and some of these derivatives were even more active than the reference drugs. Although the 2,3-diaryl-substituted quinoxalines were not active against all of the parasites, they were active against T. brucei and intracellular amastigotes of T. cruzi, without interfering with mammalian cell viability. These compounds presented encouraging results that will guide our future studies on in vivo bioassays towards the mode of action.
|
Substrate activity at recombinant type-1 nitroreductase in bloodstream form of Trypanosoma brucei brucei S427 assessed as inhibition of parasite growth after 72 hrs
|
Trypanosoma brucei brucei
|
600.0
nM
|
|
Journal : Eur J Med Chem
Title : 8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases.
Year : 2018
Volume : 157
First Page : 115
Last Page : 126
Authors : Fersing C, Boudot C, Pedron J, Hutter S, Primas N, Castera-Ducros C, Bourgeade-Delmas S, Sournia-Saquet A, Moreau A, Cohen A, Stigliani JL, Pratviel G, Crozet MD, Wyllie S, Fairlamb A, Valentin A, Rathelot P, Azas N, Courtioux B, Verhaeghe P, Vanelle P.
Abstract : Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.
|
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
|
33.42
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
6.0
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
15.43
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
14.26
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
12.66
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
4.12
%
|
|
|
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
|
5.99
%
|
|
|
Antitrypanosomal activity against blood stream form of Trypanosoma brucei brucei S427 trypomastigotes overexpressing NTR assessed as inhibition of parasite growth
|
Trypanosoma brucei brucei
|
600.0
nM
|
|
Journal : ACS Med Chem Lett
Title : New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi.
Year : 2020
Volume : 11
Issue : 4
First Page : 464
Last Page : 472
Authors : Pedron J, Boudot C, Brossas JY, Pinault E, Bourgeade-Delmas S, Sournia-Saquet A, Boutet-Robinet E, Destere A, Tronnet A, Bergé J, Bonduelle C, Deraeve C, Pratviel G, Stigliani JL, Paris L, Mazier D, Corvaisier S, Since M, Malzert-Fréon A, Wyllie S, Milne R, Fairlamb AH, Valentin A, Courtioux B, Verhaeghe P.
Abstract : An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.
|
Antitrypanosomal activity against Trypanosoma cruzi MHOM/BR/78/Silvio cloneX10/7A epimastigotes measured after 4 days by resazurin dye based fluorescence assay
|
Trypanosoma cruzi
|
300.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Nongenotoxic 3-Nitroimidazo[1,2-<i>a</i>]pyridines Are NTR1 Substrates That Display Potent <i>in Vitro</i> Antileishmanial Activity.
Year : 2019
Volume : 10
Issue : 1
First Page : 34
Last Page : 39
Authors : Fersing C, Basmaciyan L, Boudot C, Pedron J, Hutter S, Cohen A, Castera-Ducros C, Primas N, Laget M, Casanova M, Bourgeade-Delmas S, Piednoel M, Sournia-Saquet A, Belle Mbou V, Courtioux B, Boutet-Robinet É, Since M, Milne R, Wyllie S, Fairlamb AH, Valentin A, Rathelot P, Verhaeghe P, Vanelle P, Azas N.
Abstract : Twenty nine original 3-nitroimidazo[1,2-<i>a</i>]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. <i>In vitro</i> evaluation highlighted compound <b>5</b> as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC<sub>50</sub> > 100 μM) alongside good antileishmanial activities (IC<sub>50</sub> = 1-2.1 μM) against <i>L. donovani</i>, <i>L. infantum</i>, and <i>L. major</i>; and good antitrypanosomal activities (IC<sub>50</sub> = 1.3-2.2 μM) against <i>T. brucei brucei</i> and <i>T. cruzi</i>, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC<sub>50</sub> = 0.6 to 13.3 μM). Molecule <b>5</b>, presenting a low reduction potential (<i>E</i>° = -0.63 V), was shown to be selectively bioactivated by the <i>L. donovani</i> type 1 nitroreductase (NTR1). Importantly, molecule <b>5</b> was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule <b>5</b> showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making <b>5</b> a good candidate for further <i>in vivo</i> studies.
|
Growth inhibiting activity of Naegleria gruberi in vitro
|
Naegleria gruberi
|
11.1
%
|
|
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.
|
Antitrypanosomal activity against bloodstream form Trypanosoma brucei brucei 427 infected in 449_Grx-roGFP2 cells assessed as cell viability after 48 hrs by propidium iodide staining based flow cytometric analysis
|
Trypanosoma brucei brucei
|
57.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel distamycin analogues that block the cell cycle of African trypanosomes with high selectivity and potency.
Year : 2020
Volume : 189
First Page : 112043
Last Page : 112043
Authors : Franco J,Scarone L,Comini MA
Abstract : Polyamides-based compounds related to the Streptomycetal distamycin and netropsin are potent cytostatic molecules that bind to AT-rich regions of the minor groove of the DNA, hence interfering with DNA replication and transcription. Recently, derivatives belonging to this scaffold have been reported to halt the proliferation of deadly African trypanosomes by different and unrelated mechanisms. Here we describe the synthesis and preliminary characterization of the anti-trypanosomal mode of action of new potent and selective distamycin analogues. Two tri-heterocyclic derivatives containing a central N-methyl pyrrole ring (16 and 17) displayed high activity (EC < 20 nM) and selectivity (selectivity index >5000 with respect to mammalian macrophages) against the infective form of T. brucei. Both compounds caused cell cycle arrest by blocking the replication of the mitochondrial DNA but without affecting its integrity. This mode of action clearly differs from that reported for classical minor groove binder (MGB) drugs, which induce the degradation of the mitochondrial DNA. In line with this, in vitro assays suggest that 16 and 17 have a comparatively lower affinity for different template DNAs than the MGB drug diminazene. Therapeutic efficacy studies and stability assays suggest that the pharmacological properties of the hits should be optimized. The compounds can be rated as excellent scaffolds for the design of highly potent and selective anti-T. brucei agents.
|
Antiprotozoal activity against blood stream form of Trypanosoma brucei brucei assessed as growth inhibition expressing elevated level of type 1 nitroreductase incubated for 72 hrs followed by alamar blue addition further incubated for 16 hrs in presence of tetracycline
|
Trypanosoma brucei brucei
|
869.0
nM
|
|
Journal : Eur J Med Chem
Title : Nitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activity.
Year : 2016
Volume : 123
First Page : 895
Last Page : 904
Authors : Papadopoulou MV,Bloomer WD,Rosenzweig HS,Wilkinson SR,Szular J,Kaiser M
Abstract : 3-Nitro-1H-1,2,4-triazole-based acetamides bearing a biphenyl- or a phenoxyphenyl moiety have shown remarkable antichagasic activity both in vitro and in an acute murine model, as well as substantial in vitro antileishmanial activity but lacked activity against human African trypanosomiasis. We have shown now that by inserting a methylene group in the linkage to obtain the corresponding propanamides, both antichagasic and in particular anti-human African trypanosomiasis potency was increased. Therefore, IC50 values at low nM concentrations against both T. cruzi and T. b. rhodesiense, along with huge selectivity indices were obtained. Although several propanamides were active against Leishmania donovani, they were slightly less potent than their corresponding acetamides. There was a good correlation between lipophilicity (clogP value) and trypanocidal activity, for all new compounds. Type I nitroreductase, an enzyme absent from the human host, played a role in the activation of the new compounds, which may function as prodrugs. Antichagasic activity in vivo was also demonstrated with representative propanamides.
|
Antitrypanosomal activity against bloodstream form of Trypanosoma brucei brucei S427 trypomastigotes overexpressing NTR incubated for 72 hrs
|
Trypanosoma brucei brucei
|
600.0
nM
|
|
Journal : Eur J Med Chem
Title : 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.
Year : 2020
Volume : 202
First Page : 112558
Last Page : 112558
Authors : Fersing C,Boudot C,Castera-Ducros C,Pinault E,Hutter S,Paoli-Lombardo R,Primas N,Pedron J,Seguy L,Bourgeade-Delmas S,Sournia-Saquet A,Stigliani JL,Brossas JY,Paris L,Valentin A,Wyllie S,Fairlamb AH,Boutet-Robinet É,Corvaisier S,Since M,Malzert-Fréon A,Destere A,Mazier D,Rathelot P,Courtioux B,Azas N,Verhaeghe P,Vanelle P
Abstract : An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (-0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.
|
Antitrypanosomal activity against blood stream form of Trypanosoma brucei brucei S427 trypomastigotes overexpressing NTR1 assessed as inhibition of parasite growth
|
Trypanosoma brucei brucei
|
600.0
nM
|
|
Journal : Eur J Med Chem
Title : Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.
Year : 2020
Volume : 206
First Page : 112668
Last Page : 112668
Authors : Fersing C,Boudot C,Paoli-Lombardo R,Primas N,Pinault E,Hutter S,Castera-Ducros C,Kabri Y,Pedron J,Bourgeade-Delmas S,Sournia-Saquet A,Stigliani JL,Valentin A,Azqueta A,Muruzabal D,Destere A,Wyllie S,Fairlamb AH,Corvaisier S,Since M,Malzert-Fréon A,Di Giorgio C,Rathelot P,Azas N,Courtioux B,Vanelle P,Verhaeghe P
Abstract : To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.
|
Antileishmanial activity against Leishmania donovani LdBOB derived from MHOM/SD/62/1 S-CL2D promastigotes overexpressing NTR1 incubated for 72 hrs by resazurin dye based assay
|
Leishmania donovani
|
110.0
nM
|
|
|
Trypanocidal activity against Trypanosoma brucei brucei GUTat3.1 assessed as parasite growth inhibition incubated for 3 days by Celltiter-Glo luminescence assay
|
Trypanosoma brucei brucei
|
1.34
ug.mL-1
|
|
|
Trypanocidal activity against Trypanosoma brucei gambiense IL1922 assessed as parasite growth inhibition incubated for 3 days by Celltiter-Glo luminescence assay
|
Trypanosoma brucei gambiense
|
1.32
ug.mL-1
|
|
|
Trypanocidal activity against Trypanosoma brucei rhodesiense IL1501 assessed as parasite growth inhibition incubated for 3 days by Celltiter-Glo luminescence assay
|
Trypanosoma brucei rhodesiense
|
1.25
ug.mL-1
|
|
|
Trypanocidal activity against Trypanosoma brucei rhodesiense assessed as parasite growth inhibition incubated for 3 days by Celltiter-Glo luminescence assay
|
Trypanosoma brucei rhodesiense
|
0.42
ug.mL-1
|
|
|
Trypanocidal activity against Trypanosoma brucei congolense IL3000 assessed as parasite growth inhibition incubated for 3 days by Celltiter-Glo luminescence assay
|
Trypanosoma brucei rhodesiense
|
0.3
ug.mL-1
|
|
|
Trypanocidal activity against Trypanosoma evansi assessed as parasite growth inhibition incubated for 3 days by Celltiter-Glo luminescence assay
|
Trypanosoma evansi
|
0.75
ug.mL-1
|
|
