title: Synthesis of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents.
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.
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Wu
authors.initials: W
authors.lastname: Zhong
authors.forename: Rui-Juan
authors.initials: RJ
authors.lastname: Li
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D009171:Mycolic Acids / Q000378:metabolism; D010078:Oxazines; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014966:Xanthenes
chemical_list: D000995:Antitubercular Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D009171:Mycolic Acids; D010078:Oxazines; D011758:Pyrroles; D014966:Xanthenes; C005843:resazurin; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; C530127:FabH protein, Mycobacterium tuberculosis