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

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 (EC50 = 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 (T1/2 > 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 (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

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.

International audienceTo 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 (EC50 = 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 (T1/2 > 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 (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

Synthesis, pharmacomodulation and biological evaluation of new quinazoline derivatives as potential antiparasitic and anticancer agents

Ce travail est consacré à la synthèse, pharmacomodulation et évaluation de nouveaux dérivés de quinazoline à visées antiparasitaire et anticancéreuse sous irradiation micro-ondes. Dans un premier chapitre, nous indiquons les principales méthodes d’accès au noyau quinazoline, les propriétés pharmacologiques associées aux principes actifs comportant ce motif et nous présentons les données bibliographiques actualisées sur la réaction de SRN1. Lors du second chapitre, la synthèse et la réactivité avec les anions nitronates et sulfinates de la 2-chlorométhyl-3-méthylquinazolin-4(3H)-one sont successivement décrites. Une étude mécanistique permet de démontrer le mécanisme radicalaire en chaîne SRN1 concernant la réaction avec les anions nitronates et un mécanisme de type SN2 avec les anions sulfinates. Par la suite, nous nous sommes intéressés à la préparation de nouvelles quinazolines, sous irradiation micro-ondes, en étudiant les réactions de SNAr puis de couplage de Suzuki-Miyaura en série 4-chloroquinazoline. A partir de ces résultats, nous avons développé la réaction régiosélective de Suzuki-Miyaura, sur la 4,7-dichloro-2-(2-méthylprop-1-ényl)-6-nitroquinazoline, et préparé toute une série de 4,7-diarylquinazolines hautement fonctionnalisées. Enfin, l’évaluation biologique des produits issus des réactions de SNAr a révélé des activités antipaludiques, anti-Leishmania et inhibitrices d’EGFR1 prometteuses, détaillées dans le dernier chapitre.This work focuses on the synthesis of new bioactive quinazoline derivatives under microwave irradiation. In the first chapter, we indicate the main methods for preparing the quinazoline ring, the pharmacological properties associated to the quinazoline-derivated drug compounds and we present the SRN1 reaction updated bibliography. In the second chapter, the synthesis and reactivity of 2-chloromethyl-3-methylquinazolin-4(3H)-one with nitronate and sulfinate anions are successively described. A mechanistic study permits to demonstrate the SRN1 radical chain mechanism for the reaction with nitronate anions and a SN2 one for sulfinate anions. Afterwards, we prepared new original quinazolines, under microwave irradiation, by studying SNAr and Suzuki-Miyaura coupling reactions in 4-chloroquinazoline series. From these results, we have developed a regioselective Suzuki-Miyaura reaction on the 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline and prepared a new series of highly functionalized 4,7-diarylquinazolines. Finally, the biological evaluation of the products prepared by SNAr, showed interesting antiplasmodial and anti-leishmania activities along with EGFR1 inhibition properties

Regioselective Suzuki-Miyaura Reaction: Application to the Microwave-promoted Synthesis of 4,7-Diarylquinazolines

International audienceNew diarylquinazolines displaying pharmaceutical potential were synthesized in high yields from 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline by using microwave-promoted regioselective Suzuki-Miyaura cross-coupling reactions

Efficient access to 2,6,8-trisubstituted 4-aminoquinazolines via microwave-assisted one-pot chemoselective tri-Suzuki-Miyaura or SNAr/bis-Suzuki-Miyaura reactions in water

International audienceAn efficient sequential one-pot strategy for synthesizing polyfunctionalized quinazoline derivatives is presented. After selective amination of 4 at C-4 position, 2,6,8-trisubstituted 4-aminoquinazoline derivatives are prepared through one-pot chemoselective sequential tri-Suzuki-Miyaura or SNAr/bis-Suzuki-Miyaura reactions under microwave irradiation in an aqueous medium. This approach used with a variety of boronic acids affords the polysubstituted quinazoline derivatives in good to excellent yields in only a few steps and in environmentally benign solvent water

One-Pot Chemoselective Bis(Suzuki-Miyaura Cross-Coupling): Efficient Access to 3,9-Bis[(hetero)aryl]-4H-pyrido[1,2-a]pyrimidin-4-one Derivatives Under Microwave Irradiation

International audienceA one-pot chemoselective bis(SuzukiMiyaura cross-coupling) reaction under microwave irradiation is reported for the 4H-pyrido[1,2-a]pyrimidin-4-one series. First, we ascertained an initial coupling reaction that was selectively carried out at the C-3 position of (7,9-dichloro-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4). Next, we developed an extremely efficient one-pot chemoselective bis(SuzukiMiyaura cross-coupling) reaction, allowing us to substitute successively at the 3- and then at the 9-position of compound 4 with various boronic acids

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

Rapid synthesis of new 2-methyl-7-nitro-5-substituted-2,3-dihydroimidazo[5,1-b]oxazole as potential antibacterial drugs through one-pot cyclization and Suzuki-Miyaura coupling

WOS:000432219600010Original 2-methyl-7-nitro-5-substituted-2,3-dihydroimidazo[5,1-b]oxazoles were prepared by reacting 1-(2,5-dibromo-4-nitro-1H-imidazol-1-yl)propan-2-ol and various arylboronic acids through one-pot cyclization and Suzuki-Miyaura reactions under microwave irradiation. [GRAPHICS]

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