Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Abstract

BackgroundTuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration.Methodology/Principal FindingsOur approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)thiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism.Conclusions/SignificanceThese findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents.

Thiolactomycin-based β-Ketoacyl-AcpM Synthase A (KasA) Inhibitors

“…Moreover, as observed for the smaller acyl substituents at C3 (compounds 5 and 6), a keto group with larger substituents (compounds 7-11) resulted in improved binding affinities with both the free enzyme and the acyl mimic. In addition, compounds with larger, more hydrophobic groups were generally found to have higher affinity for wild-type and C171Q KasA enzymes, in agreement with previous studies in which lipophilicity was identified as a key feature of KAS inhibitor design (7)(8)(9). For example, ethyl-chlorophenyl analog compound 12 had K d and K i values of 128 and Ͼ 400 M, respectively, whereas butyl-chlorophenyl analog compounds 15 had K d and K i values of 68 and 77 M, respectively.…”

Composing Compound Libraries for Hit Discovery – Rationality-Driven Preselection or Random Choice by Structural Diversity?

“…In strategy A, we took advantage of the high homology between PqsD and the β-ketoacyl-acyl carrier protein synthase III. Hence, seven described FabH inhibitors were selected as starting points for the development of PqsD inhibitors (Figure 2A) [20][21][22][23][24][25]. After synthesis of additional derivatives compounds A1-A12 were tested for in vitro activity.…”

Synthesis of aminothiazoles: polymer-supported approaches

“…2-Aminothiazole moieties are useful structural motifs in medicinal chemistry as they have been reported to possess antitumor, 2 antiviral, 3,4 antibacterial, [5][6][7] anti-prion, 8 psychotropic, anti-allergic, 10 anti-hypertensive, 11 anti-inammatory, 12,13 antifungal, 14 antitubercular, 15 anti-HIV, 16 pesticidal, 17 antiprotozoal, 18 antipyretic, 19 antioxidative, 20 and analgesic 21 activities. Aminothiazoles acts as ligands of estrogen receptors 22 and represent a novel class of adenosine receptor antagonists; 23 its other analogues are used as fungicides, inhibiting the in vivo growth of Xanthomonas, and as an ingredient of herbicides or as schistosomicidal and anthelmintic drugs.…”