title: Design, synthesis, and structure-activity relationship studies of novel thienopyrrolidone derivatives with strong antifungal activity against Aspergillus fumigates.
abstract: In order to further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (I), two series of novel azoles featuring thieno[2,3-c]pyrrolidone and thieno[3,2-c]pyrrolidone nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SARs of antifungal triazoles. Most of target compounds exhibited excellent activity against Candida and Cryptococcus spp., with MIC values in the range of 0.0625 μg/ml to 0.0156 μg/ml. The thieno[3,2-c]pyrrolidone unit was more suited for improving activity against Aspergillus spp. The most potent compound, 18a, was selected for further development due to its significant in vitro activity against Aspergillus spp. (MIC = 0.25 μg/ml), as well as its high metabolic stability in human liver microsomes.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 555 Zuchong Zhi Road, Shanghai 201203, China.
authors: Xufeng
authors: X
authors: Cao
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 555 Zuchong Zhi Road, Shanghai 201203, China.
authors: Yuanyuan
authors: Y
authors: Xu
authors: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors: Yongbing
authors: Y
authors: Cao
authors: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors: Ruilian
authors: R
authors: Wang
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchong Zhi Road, Shanghai 201203, China.
authors: Ran
authors: R
authors: Zhou
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 555 Zuchong Zhi Road, Shanghai 201203, China.
authors: Wenjing
authors: W
authors: Chu
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 555 Zuchong Zhi Road, Shanghai 201203, China. Electronic address: ysyang@simm.ac.cn.
authors: Yushe
authors: Y
authors: Yang
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D011758:Pyrroles; C521801:thienopyrrole
keywords: Antifungal activity; Azoles; CYP51; Molecular docking; Synthesis