Synthesis of Potent Inhibitors of β-Ketoacyl-Acyl Carrier Protein Synthase III as Potential Antimicrobial Agents

摘要

Mycobacterium tuberculosis FabH, an essential enzyme in the mycolic acid biosynthetic pathway, is an attractive target for novel anti-tubercolosis agents. Structure-based design and synthesis of 1-(4-carboxybutyl)-4-(4-(substituted benzyloxy)phenyl)-1H-pyrrole-2-carboxylic acid derivatives >7a–h, a subset of eight potential FabH inhibitors, is described in this paper. The Vilsmeier-Haack reaction was employed as a key step. The structures of all the newly synthesized compounds were identified by IR, ¹H-NMR, ¹³C-NMR, ESI-MS and HRMS. The alamarBlue™ microassay was employed to evaluate the compounds >7a–h against Mycobacterium tuberculosis H37Rv. The results demonstrate that the compound >7d possesses good in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (Minimum Inhibitory Concentration value [MIC], 12.5 µg/mL).These compounds may prove useful in the discovery and development of new anti-tuberculosis drugs.