title: Synthesis and biological evaluation of novel phosphoramidate derivatives of coumarin as chitin synthase inhibitors and antifungal agents.
abstract: A series of novel phosphoramidate derivatives of coumarin have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their chitin synthase inhibition activity and antimicrobial activity in vitro. The bioactive assay manifested that most of the target compounds exhibited good efficacy against CHS and a variety of clinically important fungal pathogens. In particular, compound 7t with IC50 of 0.08 mM against CHS displayed stronger efficiency than the reference Polyoxin B with IC50 of 0.16 mM. In addition, the apparent Ki values of compound 7t was 0.096 mM while the Km of Chitin synthase prepared from Candida tropicalis was 3.86 mM for UDP-N-acetylglucosamine, and the result of the Ki showed that the compounds was a non-competitive inhibitor of the CHS. As far as the antifungal activity is concerned, compounds 7o, 7r and 7t were highly active against Aspergillus flavus with MIC values in the range of 1 μg/mL to 2 μg/Ml while the results of antibacterial screening showed that these compounds have negligible actions to the tested bacteria. These results indicated that the design of these compounds as antifungal agents was rational.
authors.affiliation: School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China. Electronic address: jiqing@swu.edu.cn.
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Ji
authors.affiliation: School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Citrus Research Institute, Southwest University, Chongqing 400712, PR China.
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Ge
authors.affiliation: School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
authors.forename: Kaizhi
authors.initials: K
authors.lastname: Chen
authors.affiliation: School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
authors.forename: Hualong
authors.initials: H
authors.lastname: Wu
authors.affiliation: School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
authors.forename: Lvjiang
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Unit for Analytical Probe and Protein Biotechnology, Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Unit for Analytical Probe and Protein Biotechnology, Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liao
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001231:Aspergillus flavus / Q000187:drug effects; D001232:Aspergillus fumigatus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D041022:Candida tropicalis / Q000187:drug effects* / Q000201:enzymology; D002687:Chitin Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000935:Antifungal Agents; D003374:Coumarins; D004791:Enzyme Inhibitors; D010756:Phosphoric Acids; C011067:phosphoramidic acid; C030123:coumarin; D002687:Chitin Synthase
keywords: Antifungal agents; Chitin synthase inhibitor; Coumarin; Phosphoramidate