Generation and exploration of new classes of antitubercular agents: The optimization of oxazolines, oxazoles, thiazolines, thiazoles to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds

Abstract

Tuberculosis (TB) is a devastating disease resulting in a death every 20 seconds. Thus, new drugs are urgently needed. Herein we report ten classes of compounds—oxazoline, oxazole, thiazoline, thiazole, pyrazole, pyridine, isoxazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-c]pyrimidine—which have good (micromolar) to excellent (sub-micromolar) antitubercular potency. The 5,6-fused heteroaromatic compounds were the most potent with MIC’s as low as <0.195 μM (9 and 11). Overall, the imidazo[1,2-a]pyridine class was determined to be most promising, with potency similar to isoniazid and PA-824 against replicating Mtb H37Rv, clinically relevant drug sensitive, multi- and extensively resistant Mtb strains as well as having good in vitro metabolic stability.

Respiratory Flexibility in Response to Inhibition of Cytochrome c Oxidase in Mycobacterium tuberculosis

“…We previously established that the majority of clinical strains of M. tuberculosis tested were susceptible to full growth inhibition by the imidazo[1,2-␣]pyridines (4,7,8) but found that the laboratory-adapted strains H37Rv, CDC1551, and Erdman overcame this growth inhibition, despite the ability of these respiratory inhibitors to block the transfer of electrons to resazurin (Tables 1 and 2, compound 2; Fig. 1).…”

Ruthenium (II) complexes containing 2-mercaptothiazolinates as ligands and evaluation of their antimicrobial activity

“…Noteworthy is the route for the synthesis of racemic cysteine introduced by Degussa AG, in which the key intermediate is the 2,2-dimethyl-3-thiazoline [35]. Thiazolines are also important due to their activity against several life threatening infections or diseases, including antimicrobial [36], anti-inflammatory [37], anticancer [38], anti-oxidant [39] and antimycobacterium [40] activities.…”

Scaffold-switching: An exploration of 5,6-fused bicyclic heteroaromatics systems to afford antituberculosis activity akin to the imidazo[1,2-a]pyridine-3-carboxylates

“…4 Through an intensive structure activity relationship (SAR) campaign we improved the Mtb potency of the oxazolines to sub-micromolar MIC’s and expanded the chemical space to include various other heterocyclic scaffolds (oxazole, thiazole, imidazole, and pyridine). 5 Further SAR effort complimented by a screening agreement with Dow AgroSciences (DAS) iteratively led to the exploration of fused heterocyclic scaffolds which resulted in the discovery of a “hit” 5,6-fused bicyclic imidazo[1,2- a ]pyridine. 6-8 We have since reported on the advent and advancement of various imidazo[1,2- a ]pyridine-3-carboxamides ( 1-3 ), imidazo[1,2- a ]pyrimidine-3-carboxamide ( 5, 6 ) and a benzyl 2,5,7-trimethylimidazo[1,2- c ]pyrimidine-3-carboxylate ( 7 ) with excellent in vitro potency against replicating (H 37 Rv), as well as multi- (MDR) and extensively drug (XDR) resistant Mtb strains (Fig.…”