Synthèse et réactivité en série hétérocyclique

Abstract

A number of new chalcones containing in their structure a (benz)imidazole nucleus were prepared using a simple aldol-condensation reaction. Addition of hydrazine derivatives to the prepared chalcones led to the formation of a series of new hybrid heterocyclic compounds: imidazole-2-pyrazoline-aryl and imidazole-pyrazole-aryl, via an addition-cyclization reaction. Thus, the addition of hydrazine derivatives such as: semicarbazide, thiosemicarbazide, N2H4.H2O/AcOH) and ArN2H3 to (benz)imidazolic chalcones allowed us to access (Nsubstituted) 2-pyrazolines, while the addition of hydrazine monohydrate led to (NH) 2- pyrazolines. The yields are good or excellent in most cases (50-92%). Some imidazole-pyrazole-aryl derivatives (9 compounds) were also synthesized in relatively low yields (10-37%), they were obtained following a two steps one-pot reaction: The reaction of 2-acetyl-1-methyl-1H-imidazole with benzoyl chloride derivatives (or naphtoyle chloride) in the presence of LiHMDS, followed by the addition of hydrazine monohydrate Several chalcones (9 compounds) were screened for their anti-proliferative activity against two human cancer cell lines: AGS gastric cancer, A549 lung cells, and a non-cancerous human cell line MRC- 5 (lung), in concentration ranges up to 100 µM. The analysis of the (SAR) of the tested compounds shows the importance of the structural arrangement in the antiproliferative activity. In fact, compounds carrying a (benz)imidazole ring in the  position of the carbonyl group (Series 1) have greater toxicity than where the (benz)imidazole ring is directly linked to the carbonyl group (Series 2). Likewise, some chalcones were evaluated for their antibacterial activity against 5 strains (one Gram (+) and four Gram (-)), and the SAR analysis shows that only the compounds of Series 1 exhibited an inhibitory power. Some chalcone were tested for their antioxidant activity using Four complementary methods: DPPH•, ABTS•+, superoxide O2•-, and CUPRAC, but no antioxidant activity was observed for the tested chalcones. On the other hand, some derivatives of 2-pyrazoline, divided into two series: (NH) 2-pyrazolines (7 compounds) and (N-substituted) 2-pyrazolines (5 compounds), and using the same assessment methods, displayed antioxidant activity. The comparative study of the antioxidant power of the two series showed that the (NH) 2-pyrazoline had remarkable antioxidant power clearly higher than that of the (N-substituted) 2-pyrazolines. Likewise, some 2-pyrazoline derivatives have been evaluated for their anti-proliferative activity against the cancer cell lines AGS, A549, and their studied selectivity compared to noncancerous lung cells (MCR5) in concentration ranges up to 100 µM. No activity was observed for all the compounds tested. All the compounds prepared were identified by the usual spectroscopic methods (IR, 1H and 13C NMR) and additional analyses were also carried out (elemental analysis and / or mass spectrometry).