Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: Novel antibacterial agents against Mycobacterium tuberculosis

Abstract

Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6 µg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.The emergence of multi-drug resistant (MDR-TB) and extensively-drug resistant (XDR-TB) strains of M. tuberculosis represents a severe threat to human health. Consequently, novel drugs are needed that are active against drug resistant bacteria and that also shorten the course of chemotherapy. In addition, novel agents are also required that are active against latent, nonreplicating populations of bacteria since M. tuberculosis can persist in this state for many years. 1-2 Since it seems likely that latent M. tuberculosis bacteria must respire in order to remain viable, compounds that target respiration are promising candidates for the development of drugs that are active against both replicating and non-replicating bacterial populations. Currently we are pursuing the hypothesis that menaquinone biosynthesis is essential for bacterial viability in vivo, and are actively engaged in identifying compounds that inhibit enzymes in this pathway.Menaquinone (vitamin K1) (Figure 1) is a polyisoprenylated naphthoquinone that shuttles electrons between membrane-bound protein complexes in the electron transport chain. In mammalian cells this function is performed by ubiquinone (Figure 1), and although

Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism

“…Initial investigations into potential inhibitors of this enzyme were conducted by Li et al 34 where a coupled assay was used to screen over 105 000 drug-like molecules with a large structural diversity. From this bank of molecules, 455 molecules showed at least 30% enzyme inhibition relative to control, of which four compounds with a benzoxazine scaffold were chosen for further investigation.…”

Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies

“…Coumarin derivatives show various biological and pharmacological activities 37,38 . In addition to numerous activities of coumarin derivatives, they were reported to inhibit carbonic anhydrase activity 31,32 42 , antihypertensive 43 , anti-inflammatory 44 and other biological activities of 1,4-oxazinones and benzoxazines were reported [45][46][47][48] . Beside various biological activities of 1,4-oxazinone and benzoxazine derivatives, anticonvulsant activities of benzoxazinones were reported in the literature 48 .…”

Antimycobacterial Activity of New 1,4-Benzoxazine-2-One Derivatives and Its 2-(Arylamino)-4-Oxobut-2-Enoate, Ring-Open Analogues

“…A few years ago, Li et al [1] identified several 1,4-benzoxazine-2-one derivatives, that target MenB (1,4-dihydroxy-2-naphtoyl-CoA synthase), endowed with high antibacterial activity against Mycobacterium tuberculosis H37Rv with MIC values of 0.6 μg/mL (4 μg/mL our data). By these assumptions, we designed and synthesized some analogous compounds in order to investigate the SAR and to discover new potent antimycobacterial derivatives.…”