Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents

Qinggang Ji; Dan Yang; Xin Wang; Chunyan Chen; Qiao Deng; Zhiqiang Ge; Lvjiang Yuan; Xiaolan Yang; Fei Liao

doi:10.1016/j.bmc.2014.04.042

Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents

Bioorg Med Chem. 2014 Jul 1;22(13):3405-13. doi: 10.1016/j.bmc.2014.04.042. Epub 2014 Apr 30.

Authors

Qinggang Ji¹, Dan Yang², Xin Wang³, Chunyan Chen³, Qiao Deng², Zhiqiang Ge², Lvjiang Yuan², Xiaolan Yang³, Fei Liao⁴

Affiliations

¹ School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China. Electronic address: [email protected].
² School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.
³ 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.
⁴ 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: [email protected].

PMID: 24856180
DOI: 10.1016/j.bmc.2014.04.042

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.

Keywords: Antifungal activity; Chitin synthase; Chitin synthase inhibitor; Quinazoline-2,4-dione.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Aspergillus flavus / drug effects
Candida albicans / drug effects
Chitin Synthase / antagonists & inhibitors*
Chitin Synthase / metabolism
Cryptococcus neoformans / drug effects
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Microbial Sensitivity Tests
Molecular Structure
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

Antifungal Agents
Enzyme Inhibitors
Quinazolines
2,4(1H,3H)-quinazolinedione
Chitin Synthase