Synthèse, caractérisation et évaluation biologique de nouveaux dérivés poly-hétérocycliques à base d’imidazole

Abstract

Some 2-halo-(1-methyl-1H-imidazole) derivatives were prepared by selective halogenation reaction (bromination, chlorination and iodination). The addition of -bromoacetophenone to 2-bromo(chloro)-1-methyl-1H-imidazole allowed us to access to corresponding imidazolium salts in satisfactory yields (47-64%). The reactivity of 2-halogeno-N-phenyl-1-methyl-1Himidazolium bromide with activated methylene compounds of diverse structures has been studied. A series of original heterocyclic products composed of a core 1-methyl-1H-imidazole associated at 2-position to highly functionalized heterocyclic compounds such as 4H-pyran, chromene, benzo (pyrido) chromenes, 1,4-dihydropyridine, pyridine, quinazoline, pyrrolidines and other pyrazolines have been prepared. It will be noted that upon addition of methyl ketone derivatives, 1-methylimidazole-pyridine hybrid compounds obtained are accompanied by the formation of corresponding 2,6- dicyanoaniline derivatives in low yields. The adaptation of the operating conditions enabled us to selectively direct the reaction towards the formation of new 2,6-dicyanoaniline derivatives in good yields for aliphatic methyl ketone derivatives (62-70%), and in 45 % of yield for acetophenone. These compounds are also fluorescent. Some series of hybrid compounds such as (1-methyl-1H-imidazol-2-yl)-4H-pyran, - pyridine, -1,4-dihydropyridine and -quinazoline have been subjected to an in vitro assessment of their antimicrobial, and antioxydante (DPPH) activities, and also for their hepatotoxicity towards liver cells HepG2 in a gradient concentration from 1M to 300M, and a structureactivity relationship (SAR) has been demonstrated. A "valorization" of (1-methyl-1H-imidazol-2-yl)-4-pyran hybrid derivatives was undertaken and resulted in the preparation of some original series of highly and diversely functionalized Tacrine analogues (Tacrine is a drug used in the treatment of Alzheimer's disease) as pyranotacrines. These novel racemic Tacrine analogues are siginificantly less hepatotoxic than Tacrine, retaining potent, and selective EeAChE inhibition with IC50 values in the M range, with a remarkable antioxydant effect. Yields are good in most cases. All prepared compounds were identified by the usual spectroscopic methods (IR, 1H NMR and 13C NMR), and for some of them additional analyzes were carried out (elemental analysis and / or X-ray diffraction).