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Molecular modeling studies and synthesis of fused heterocyclic compounds with potential inhibitory activities of menthionine synthase catalysed reaction

Hosam Elshihawy, Mohamed Hammad

Methionine synthase catalyses the transfer of a methyl group from 5- methyltetrahydrofolate to homocysteine, producing methionine and tetrahydrofolate. This enzyme has been linked to the pathogenesis of anemias, neurodegenerative disorders and cancer. The development of potent and specific inhibitors of methionine synthase could therefore be used to explore the enzyme as a target for pharmacological intervention and elucidate its role in these disorders. Benzimidazole derivatives have been shown to inhibit methionine synthase by competing with the substrate 5- methyltetrahydrofolate. The aim of this article was to design and synthesize a novel series of substituted benzimidazole derivatives and assesses their inhibitory activity against purified rat liver methionine synthase. Cobalamin-dependent methionine synthase was isolated and purified from rat liver. The inhibitors were assessed using an in vitro, colourimetric enzyme assay, kinetic analysis of the most potent compound (S)-1-(5-nitro- 1H-benzimidazole-2-yl)ethanamine using Lineweaver-Burk plots revealed characteristics of mixed inhibition with Ki value of 450 ìM and percentage inhibition 64%. The results of this study have led to the identification of this lead compound with good inhibitory activity that can inform the design of the next generation inhibitors of methionine synthase.