Vincent Remusat

Lowering of 5-nitroimidazole's mutagenicity: Towards optimal antiparasitic pharmacophore

To improve the antiparasitic pharmacophore, 20 5-nitroimidazoles bearing an arylsulfonylmethyl group were prepared from commercial imidazoles. The antiparasitic activity of these molecules was assessed against Trichomonas vaginalis, the in vitro cytotoxicity was evaluated on human monocytes and the mutagenicity was determined by the Salmonella mutagenicity assay. All IC(50) on T. vaginalis were below the one of metronidazole. The determination of the specificity indexes (SIs), defined as the ratios of the cytotoxic activity and the antitrichomonas activity, indicated that 11 derivatives had a SI over the one of metronidazole. Molecules, bearing an additional methyl group on the 2-position, showed a lower mutagenicity than metronidazole. Moreover, three derivatives were characterized by a low mutagenicity and an efficient antitrichomonas activity.

Discovery of a new antileishmanial hit in 8-nitroquinoline series.

A series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward Leishmania donovani promastigotes. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an IC(50) value of 6.6 μM and CC(50) values ≥ 100 μM, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference (amphotericin B, miltefosine and pentamidine). Compound 21 also appears as an efficient in vitro antileishmanial molecule against both Leishmania infantum promastigotes and the intracellular L. donovani amastigotes (respective IC(50) = 7.6 and 6.5 μM). Moreover, hit quinoline 21 does not show neither significant antiplasmodial nor antitoxoplasmic in vitro activity and though, presents a selective antileishmanial activity. Finally, a structure-activity relationships study enabled to define precisely the antileishmanial pharmacophore based on this nitroquinoline scaffold: 2-hydroxy-8-nitroquinoline.

Targeting the human malaria parasite Plasmodium falciparum: in vitro identification of a new antiplasmodial hit in 4-phenoxy-2-trichloromethylquinazoline series.

From the promising results we previously obtained in quinazoline series and to complete the evaluation of the in vitro antiplasmodial activity of original 2-trichloromethylquinazolines, we synthesized new quinazolines possessing a variously substituted phenoxy group at position 4 through a simple and efficient two-step-synthesis approach. The studies of their activity toward the multi-resistant W2 Plasmodium falciparum strain and of their cytotoxicity on the human hepatocyte HepG2 cell line highlighted a hit compound (molecule 7) displaying a W2 IC(50) value of 1.1 μM and a HepG2 CC(50) value of 50 μM, comparable to chloroquine and doxycycline. Structure-activity- and toxicity relationships indicate that the trichloromethyl group plays a key role in the antiplasmodial activity of such chemical scaffold and also that the phenoxy group substitution as a direct influence on the molecules selectivity. Moreover, molecule 7 displays significant specific activity against the Plasmodium genus in comparison with Toxoplasma and does not show any mutagenic property at the Ames test.

Targeting the human parasite Leishmania donovani: Discovery of a new promising anti-infectious pharmacophore in 3-nitroimidazo[1,2-a]pyridine series

We report herein the discovery of antileishmanial molecules based on the imidazo[1,2-a]pyridine ring. In vitro screenings of imidazopyridines belonging to our chemical library, toward the promastigotes stage of Leishmania donovani, J774A.1 murine and HepG2 human cells, permitted to identify three selective hit-compounds (12, 20 and 28). New derivatives were then synthesized to allow structure-activity and -toxicity relationships analyses, enabling to characterize a lead-compound (44) displaying both a high potency (IC50=1.8 μM) and a good selectivity index, in comparison with three antileishmanial reference drug-compounds (amphotericin B, miltefosine and pentamidine). Moreover, lead-compound 44 also exhibits good in vitro activity against the intracellular amastigote stage of L. donovani. Thus, the 6-halo-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine scaffold appears as a new promising selective antileishmanial pharmacophore, especially when substituted at position 8 by a bromine atom.

Rapid Synthesis of New 5‐Nitroimidazoles as Potential Antibacterial Drugs via VNS Procedure

Abstract Original 4‐arylsulfonylmethyl‐5‐nitroimidazoles were prepared by reacting four chloromethylaryl sulfones with 5‐nitroimidazole derivatives via a vicarious nucleophilic substitution (VNS) of hydrogen reaction.

New series of monoamidoxime derivatives displaying versatile antiparasitic activity.

Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R(1), R(2) or R(3) substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 μM), whereas a polysubstituted group (36-37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 μM). Modulating chemical substituents in R(2) and R(3) only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.

Synthesis of 3-Alkenyl-1-azaanthraquinones via Diels-Alder and Electron Transfer Reactions

A convenient route to 3-alkenyl-1-azaanthraquinones via a hetero Diels-Alder reaction between an azadiene and naphthoquinone, a free radical chlorination and an electron transfer reaction is reported.