"Design, synthesis and biological evaluation of novel spiro-quinazolinone derivatives as chitin synthase inhibitors and antifungal agents"
作者全名:"Du, Chuanbiao; Yang, Xinlong; Long, Yan; Lang, Xueqing; Liu, Lige; Xu, Yajie; Wu, Hu; Chu, Yiwen; Hu, Xiaolei; Deng, Junfeng; Ji, Qinggang"
作者地址:"[Du, Chuanbiao; Yang, Xinlong; Long, Yan; Liu, Lige; Xu, Yajie; Wu, Hu; Ji, Qinggang] Southwest Univ, Sch Chem & Chem Engn, Chongqing 400715, Peoples R China; [Chu, Yiwen; Deng, Junfeng] Chengdu Univ, Sch Pharm, Sichuan Ind Inst Antibiot, Antibiot Res & Reevaluat Key Lab Sichuan Prov, Chengdu 610106, Peoples R China; [Lang, Xueqing; Hu, Xiaolei] Chongqing Med Univ, Dept Lab Med, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China"
通信作者:"Ji, QG (通讯作者),Southwest Univ, Sch Chem & Chem Engn, Chongqing 400715, Peoples R China.; Deng, JF (通讯作者),Chengdu Univ, Sch Pharm, Sichuan Ind Inst Antibiot, Antibiot Res & Reevaluat Key Lab Sichuan Prov, Chengdu 610106, Peoples R China.; Hu, XL (通讯作者),Chongqing Med Univ, Dept Lab Med, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China."
来源:EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ESI学科分类:CHEMISTRY
WOS号:WOS:000999641000001
JCR分区:Q1
影响因子:6.7
年份:2023
卷号:255
期号:
开始页:
结束页:
文献类型:Article
关键词:Spiro[thiophen-quinazoline]-one; Chitin synthase inhibitors; Drug -resistant fungi; Drug combination
摘要:"A series of spiro-quinazolinone scaffolds were constructed based on the bioactivity of quinazolinone and the inherent feature of spirocycle to design novel chitin synthase inhibitors that possess mode of action different from that of the currently used antifungal agents. Among them, the spiro[thiophen-quinazolin]-one derivatives containing a, 13-unsaturated carbonyl fragments had shown inhibitory activities against chitin synthase and antifungal activities. The enzymatic experiments showed that among the sixteen compounds, compounds 12d, 12g, 12j, 12l and 12m exhibited inhibitions against chitin synthase with IC50 values of 116.7 +/- 19.6 mu M, 106.7 +/- 14.2 mu M, 102.3 +/- 9.6 mu M, 122.7 +/- 22.2 mu M and 136.8 +/- 12.4 mu M, respectively, which were comparable to that of polyoxin B (IC50 = 93.5 +/- 11.1 mu M). The assays of enzymatic Kinetic parameters showed that compound 12g was a non-competitive inhibitor of chitin synthase. The antifungal assays showed that compounds 12d, 12g, 12j, 12l and 12m exhibited a broad-spectrum of antifungal activity against the four strains tested in vitro. In which, compounds 12g and 12j had stronger antifungal activity against four tested strains than that of polyoxin B and similar to that of fluconazole, while compounds 12d, 12l and 12m showed antifungal activity comparable to that of polyoxin B against four tested strains. Meanwhile, compounds 12d, 12g, 12j, 12l and 12m exhibited good antifungal activity against fluconazole-resistant and micafungin-resistant fungi variants with MIC values ranging from 4 to 32 mu g/mL while the MIC values of reference drugs were above 256 mu g/mL. Furthermore, the results of drug-combination experiments showed that compounds 12d, 12g, 12j, 12l and 12m had synergistic or additive effects with fluconazole or polyoxin B. The results of sorbitol protection experiment and the experiment of antifungal activity against micafungin-resistant fungi further demonstrated that these compounds target chitin synthase. The result of cytotoxicity assay showed that compound 12g had low toxicity toward human lung cancer A549 cells and the ADME analysis in silico displayed that compound 12g possessed promising pharmacokinetic properties. The molecular docking indicated that compound 12g formed multiple hydrogen bond interactions binding to chitin synthase, which might be conductive to increasing the binding affinity and inhibiting the activity of chitin synthase. The above results indicated that the designed compounds were chitin synthase inhibitors with selectivity and broad-spectrum antifungal activity and could be act as the lead compounds against drugresistant fungi."
基金机构:"Key project of Innovation Research 2035 Pilot Plan of Southwest University, China [SWU-XDZD22007]; Open Project of Antibiotics Research and Re -profiling Key Lab of Sichuan Province, China [ARRLKF22-02]"
基金资助正文:"This work was supported by Key project of Innovation Research 2035 Pilot Plan of Southwest University, China (SWU-XDZD22007) ; Open Project of Antibiotics Research and Re -profiling Key Lab of Sichuan Province, China (ARRLKF22-02) ."