Design, synthesis and antifungal activity of isosteric analogues of benzoheterocyclic N-myristoyltransferase inhibitors

• Published in: European journal of medicinal chemistry Vol. 45; no. 9; pp. 3531 - 3540
• Main Authors: Sheng, Chunquan, Xu, Hui, Wang, Wenya, Cao, Yongbing, Dong, Guoqiang, Wang, Shengzheng, Che, Xiaoying, Ji, Haitao, Miao, Zhenyuan, Yao, Jianzhong, Zhang, Wannian
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.09.2010; Elsevier
• Subjects: Acyltransferases - antagonists & inhibitors; Acyltransferases - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal activity; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Benzoxazole; Benzoxazoles - chemical synthesis; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Biological and medical sciences; Candida albicans - drug effects; Candida albicans - enzymology; Catalytic Domain; Chemistry, Medicinal; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Indole; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; N-Myristoyltransferase inhibitors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; Antifungal activity; Indole; Benzoxazole; N-Myristoyltransferase inhibitors; MYRISTOYLATION; MOLECULAR DOCKING; MYRISTIC ACID; POTENT; CANDIDA-ALBICANS; DIPEPTIDE AMIDES; SELECTIVE INHIBITORS; AGENTS; BENZOFURANS; DERIVATIVES; Acyltransferases; Benzoxazole derivatives; Enzyme; Transferases; Aminoether; In vitro; Modeling; Pyridine derivatives; Glycylpeptide N-tetradecanoyltransferase; Antifungal agent; Structure activity relation; Molecular model; Inhibitor; Fluorine Organic compounds; Indole derivatives; Chemical synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.03.007

N-myristoyltransferase (NMT) has been a promising new target for the design of novel antifungal agents with new mode of action. A series of benzoxazole and indole derivatives were designed and synthesized as isosteric analogues of benzoheterocyclic NMT Inhibitors. In vitro antifungal assay indicated that the benzoxazole derivatives were far more potent than the indoles. Molecular docking studies revealed that the hydrogen bonding interaction between the benzoheterocyclic core and NMT might be essential in the orientation of the inhibitor to a proper position. The antifungal activity of benzoxazole derivative 8f was comparable or superior to that of fluconazole, which can serve as a good starting point for further studies of structural diversity of the benzoheterocyclic NMT inhibitors. [Display omitted] A series of benzoxazole and indole derivatives were designed and synthesized as isosteric analogues of benzoheterocyclic NMT Inhibitors. The binding mode was investigated by molecular docking.