title: Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents.
abstract: A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed, synthesized, and characterized by (1)H NMR, (13)C NMR and MS spectral data. Their inhibition against chitin synthase (CHS) and antifungal activities were evaluated in vitro. Results showed compounds 5b, 5c, 5e, 5f, 5j, 5k, 5l, and 5o had strong inhibitory potency against CHS. Compound 5c, which has the highest potency among these compounds, had a half-inhibition concentration (IC50) of 0.08mmol/L, while polyoxin B as positive drug had IC50 of 0.18mmol/L. These IC50 values of compounds 5i, 5m, 5n, and 5s were greater than 0.75mmol/L, which revealed that those compounds had weak inhibition activity against CHS. Moreover, most of these compounds exhibited moderate to excellent antifungal activities. In detail, to Candida albicans, the activities of compound 5g and 5k were 8-fold stronger than that of fluconazole and 4-fold stronger than that of polyoxin B; to Aspergillus flavus, the activities of 5g, 5l and 5o were16-fold stronger than that of fluconazole and 8-fold stronger than that of polyoxin B; to Cryptococcus neoformans, the minimum-inhibition-concentration (MIC) values of compounds 5c, 5d, 5e and 5l were comparable to those of fluconazole and polyoxin B. The antifungal activities of these compounds were positively correlated to their IC50 values against CHS. Furthermore, these compounds had negligible actions to bacteria. Therefore, these compounds were promising selective antifungal agents.
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: Dan
authors.initials: D
authors.lastname: Yang
authors.affiliation: Unit for Analytical Probe and Protein Biotechnology, Key Laboratory of Clinical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Unit for Analytical Probe and Protein Biotechnology, Key Laboratory of Clinical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Deng
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: 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, Key Laboratory of Clinical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, 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, Key Laboratory of Clinical Laboratory Diagnostics of the Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China. Electronic address: liaofeish@yeah.net.
authors.forename: Fei
authors.initials: F
authors.lastname: Liao
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001231:Aspergillus flavus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002687:Chitin Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; C081989:2,4(1H,3H)-quinazolinedione; D002687:Chitin Synthase
keywords: Antifungal activity; Chitin synthase; Chitin synthase inhibitor; Quinazoline-2,4-dione