8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

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 mu M 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 mu M) 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 mu M), slightly lower than the one of miltefosine (IC50 = 4.3 mu M). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 mu M) 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 mu M). 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 (NTRI), 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

La maladie d Alzheimer (la voie amyloïde : les sécrétases, cibles thérapeutiques potentielles)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Synthesis of New Potentially Bioactive Bicyclic 2-Pyridones

Three convenient methods of reduction of the nitro group of 5-nitroimidazoles and 5-nitrothiazole that bear a diethylmethylene malonate group in an ortho-like position with respect to the nitro group and cyclization of the resulting amino derivatives are reported. These reactions afforded the target bicyclic 2-pyridones in good to excellent yields

Designing New 5-Nitroimidazoles: Towards Safer Anti-infectious Agents

International audience5-Nitroimidazoles are drugs having both antiprotozoal and antibacterial activity, but show mutagenicity and development of resistance observed particularly with metronidazole. For the development of new potentially safer derivatives, we investigated new strategies of synthesis: such as Vicarious Nucleophilic Substitution of hydrogen (VNS), palladium-catalyzed cross-coupling reactions (Suzuki-Miyaura, Sonogashira…) and electron transfer reactions (Unimolecular Radical Nucleophilic Substitution (SRN1), TDAE methodology) applied in 5-nitroimidazole series

Synthèse et réactivité de nouvelles pyridones polycycliques à visée thérapeutique

L objectif consiste en la synthèse de nouvelles pyridones bi- ou tricycliques à visée thérapeutique, en faisant appel à deux stratégies de synthèse. La première fait intervenir une réaction VNS conduisant à des 4- et 5-nitroimidazoles portant en position b du nitro, un groupement PhSO2CH2. En série 5-nitroimidazole, le carbanion stabilisé en [alpha] du groupement phénylsulfonyle réagit avec divers électrophiles pour conduire par SN2 ou SRN1 aux sulfones correspondantes. Avec le cétomalonate de diéthyle, une réaction inédite conduit directement au 5-nitroimidazole portant un groupement méthylène malonate de diéthyle. La seconde stratégie pour la préparation des diesters éthyléniques utilise une réaction SRN1 entre divers nitrohétérocycles avec un groupement CH2Cl en position b et l anion du nitromalonate de diéthyle suivie de l élimination de HNO2. La réduction du groupe nitro suivie d une cyclisation donnent les pyridones attendues, lesquelles font l objet d une fonctionnalisation ultérieure.AIX-MARSEILLE3-BU Sc.St Jérô (130552102) / SudocSudocFranceF

Unexpected palladium catalyzed O-arylation occurring in 4-(4-fluoro-3-nitrophenyl)-1,2-dimethyl-5-nitro-1H-imidazole series

International audienceWe describe herein a new unexpected palladium-catalyzed O-arylation reaction in fluorinated nitro(o-nitrophenyl)imidazole series involving arylboronic acids under Suzuki-Miyaura cross-coupling reaction conditions. (C) 2012 Elsevier Ltd. All rights reserved

Efficient and Original Microwave-Assisted Suzuki-Miyaura Cross-Coupling Reaction in the 4H-Pyrido[1,2-a]pyrimidin-4-one Series

International audienceAn efficient synthesis of new series of various 3-aryl, 3-heteroaryl, and 3-styryl-4H-pyrido[1,2-a]pyrimidin-4-ones by palladium-catalyzed Suzuki-Miyaura cross-coupling reactions using microwave irradiation is described. The coupling process is tolerant of electron-poor, electron-rich, and bulky boronic acid derivatives, and leads to the desired products in good yields

Long distance-S(RN)1 in nitroimidazole series favored by temperature

International audienceNew reductive alkylating agents in 4- and 5-nitroimidazole series produce exclusively O-alkylation with nitronate anions under classical S(RN)1 conditions at room temperature. Electron-transfer C-alkylation is observed under microwave irradiation or under conventional heating. Furthermore, X-ray spectroscopy shows that the dihedral angles between the phenyl and imidazole rings for the two series are different, which could greatly influence reactivity in 4- and 5-nitroimidazole series. (C) 2011 Elsevier Ltd. All rights reserved

One-pot preparation of 2-(alkyl)arylbenzoselenazoles from the corresponding N-(acetyl)benzoyl-2-iodoanilines via a microwave-assisted methodology

International audienceWe report here the first example of a one-pot synthesis of 2-(alkyl)arylbenzoselenazoles from N-(acetyl)benzoyl-2-iodoanilines. The reaction was carried out in the presence of Woollins' reagent under microwave irradiation and resulted in moderate to good yields