Evolution of a thienopyrimidine antitubercular relying on medicinal chemistry and metabolomics insights

Abstract

The metabolic instability of an antitubercular small molecule CD117 was addressed through iterative alteration of a key sulfide substituent and interrogation of the effect on growth inhibition of cultured Mycobacterium tuberculosis. This process was informed by studies of the intramycobacterial metabolism of CD117 and its inactive carboxylic acid derivative. Isoxazole 4e and thiazole 4m demonstrated significant gains in mouse liver microsomal stability with slight losses in whole-cell activity. This work illustrates the challenges of antitubercular hit evolution, requiring a balance of chemical and biological insights.

Antimycobacterial Metabolism: Illuminating Mycobacterium tuberculosis Biology and Drug Discovery

“…, signaling a detoxification pathway) [20]. Driven by the need to identify novel antitubercular agents, research laboratories are adopting metabolomics as a platform technology to evolve antibacterial chemical tools and drug discovery hit and lead compounds [21]. In this review, we will describe such efforts, grouping metabolic transformations in an early effort to generalize the types of chemical reactions of which M. tuberculosis is capable, and propose a new workflow for antitubercular chemical tools and drug discovery that involves understanding drug metabolism and biotransformations occurring within M. tuberculosis.…”

“…While the compound was stable in Middlebrook 7H9 medium, its poor mouse liver microsomal stability (t 1/2 < 1 min) was attributed to rapid hydrolysis of the ethyl ester to afford the corresponding carboxylic acid (independently synthesized as JSF-2000; MIC > 200 μg/mL) as the major metabolite [21]. Metabolic instability of the ethyl ester was also responsible for a lack of antitubercular activity in ex vivo studies with mice.…”

“…Li et al employed metabolomics to probe the CD117 intramycobacterial metabolism and test this hypothesis [21]. M. tuberculosis was exposed to 1x, 5x and 10x the MIC of CD117 or equimolar amounts of the carboxylic acid JSF-2000 [21, 45].…”

Synthesis of Thienopyrimidine Derivatives Starting From Thiophene Ring and Pyrimidine Ring

“….12 in a two-or a three-step procedure, respectively, as depicted in the following Scheme, starting from compound (30). The starting materials methyl 3-amino-5-(3-methoxyphenyl)-thiophene-2-carboxylate (30) was synthesized using the multi-step procedure well described in the literature.…”

“…The starting materials methyl 3-amino-5-(3-methoxyphenyl)-thiophene-2-carboxylate (30) was synthesized using the multi-step procedure well described in the literature. 13 The condensation of molecule (30) with N,N-dimethylformamide dimethyl acetal (DMF-DMA) gave methyl 3-dimethylaminomethylideneamino-5-(3-methoxy-phenyl)thiophene-2-carboxylate (31) in very good yield 14 which were used directly in the next step without purification to afford compound (32). The condensation of 6-(3-methoxyphenyl)-4H-thieno [3,2-d] [1,3]oxazin-4-one (33) with 3-methoxybenzyl amine as an alternative route to produce (32) was failed.…”