title: Design, synthesis, and enzyme kinetics of novel benzimidazole and quinoxaline derivatives as methionine synthase inhibitors.
abstract: Methionine synthase catalyzes the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine, producing methionine and tetrahydrofolate. Benzimidazole and deazatetrahydrofolates derivatives have been shown to inhibit methionine synthase by competing with the substrate 5-methyltetrahydrofolate. In this study, a novel series of substituted benzimidazoles and quinoxalines were designed and assessed for inhibitory activity against purified rat liver methionine synthase using a radiometric enzyme assay. Compounds 3g, 3j, and 5c showed the highest activity against methionine synthase (IC₅₀: 20 μM, 18 μM, 9 μM, respectively). Kinetic analysis of these compounds using Lineweaver-Burk plots revealed characteristics of mixed inhibition for 3g and 5c; and uncompetitive inhibition for 3j. Docking study into a homology model of the rat methionine synthase gave insights into the molecular determinants of the activity of this class of compounds. The identification of these drug-like inhibitors could lead the design of the next generation modulators of methionine synthase.
authors.affiliation: Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
authors.forename: Hosam
authors.initials: H
authors.lastname: Elshihawy
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Helal
authors.affiliation: Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Said
authors.affiliation: Eli & Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, 1425 San Pablo Street, BCC 505, Los Angeles, CA 90033, USA. Electronic address: mhammad@usc.edu.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Hammad
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D008958:Models, Molecular; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001562:Benzimidazoles; D005656:Fungal Proteins; D011810:Quinoxalines; D008715:Methionine; C031000:benzimidazole; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
keywords: 5-Methyltetrahydrofolate; Benzimidazole; Cancer; Methionine synthase; Quinoxaline