Inhibition of cobalamin‐dependent methionine synthase by substituted benzo‐fused heterocycles

Abstract

The cobalamin–dependent cytosolic enzyme, methionine synthase (EC.2.1.1.13), catalyzes the remethylation of homocysteine to methionine using 5‐methyltetrahydrofolate as the methyl donor. The products of this remethylation – methionine and tetrahydrofolate – participate in the active methionine and folate pathways. Impaired methionine synthase activity has been implicated in the pathogenesis of anaemias, cancer and neurological disorders. Although the need for potent and specific inhibitors of methionine synthase has been recognized, there is a lack of such agents. In this study, we designed, synthesized and evaluated the inhibitory activity of a series of substituted benzimidazoles and small benzothiadiazoles. Kinetic analysis revealed that the benzimidazoles act as competitive inhibitors of the rat liver methionine synthase, whilst the most active benzothiadiazole (IC50 = 80 µm) exhibited characteristics of uncompetitive inhibition. A model of the methyltetrahydrofolate‐binding site of the rat liver methionine synthase was constructed; docking experiments were designed to elucidate, in greater detail, the binding mode and reveal structural requirements for the design of inhibitors of methionine synthase. Our results indicate that the potency of the tested compounds is related to a planar region of the inhibitor that can be positioned in the centre of the active site, the presence of a nitro functional group and two or three probable hydrogen‐bonding interactions.

Methionine synthase supports tumor tetrahydrofolate pools

“…Side effects could potentially be mitigated by rescue therapy, perhaps with leucovorin, as is common for other anti-folates. To our knowledge, no clinically approved antifolate therapies are known to directly inhibit MTR, though some low potency, folate-like small molecule inhibitors have been reported [50][51][52]. We look forward to the advancement of such compounds into in vivo tools so that the therapeutic potential of MTR inhibition can be more rigorously evaluated.…”

Metal-Free, Rapid, and Highly Chemoselective Reduction of Aromatic Nitro Compounds at Room Temperature

“…Obtained as a brown solid (39.6 mg, 99%). mp 155−164 °C (reported 53 54 2-Methyl-6-Benzoxazolamine (2ab). Purified by column chromatography using hexane/EtOAc = 3:1 as eluent.…”

Metabolite Profiling: A Tool for the Biochemical Characterisation of Mycobacterium sp.

“…This led to the discovery of metronidazole, which targets DNA in anaerobe bacteria without antagonistic effects in combination with isoniazid or rifampicin [49]. Other studies identified methionine synthesis, important for nucleotide and protein synthesis, as a viable target, as human cells do not synthesize this amino acid [50,51]. The permeability of the cell wall can be influenced by a diverse range of compounds.…”