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Synthesis of Potent Inhibitors of β-Ketoacyl-Acyl Carrier Protein Synthase III as Potential Antimicrobial Agents
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
* Author to whom correspondence should be addressed.
Received: 26 December 2011; in revised form: 11 April 2012 / Accepted: 16 April 2012 / Published: 25 April 2012
Abstract: 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.
Keywords: tuberculosis; Mycobacterium tuberculosis FabH; structure based design; synthesis; alamarBlue™ microassay
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MDPI and ACS Style
Liu, Y.; Zhong, W.; Li, R.-J.; Li, S. Synthesis of Potent Inhibitors of β-Ketoacyl-Acyl Carrier Protein Synthase III as Potential Antimicrobial Agents. Molecules 2012, 17, 4770-4781.
Liu Y, Zhong W, Li R-J, Li S. Synthesis of Potent Inhibitors of β-Ketoacyl-Acyl Carrier Protein Synthase III as Potential Antimicrobial Agents. Molecules. 2012; 17(5):4770-4781.
Liu, Yan; Zhong, Wu; Li, Rui-Juan; Li, Song. 2012. "Synthesis of Potent Inhibitors of β-Ketoacyl-Acyl Carrier Protein Synthase III as Potential Antimicrobial Agents." Molecules 17, no. 5: 4770-4781.