title: Design, synthesis, and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercular agents.
abstract: Tuberculosis remains a global public health problem in recent years. To develop novel type of potential antitubercular agents, twelve novel dihydroartemisinin-fluoroquinolone (DHA-FQ) conjugates (three types of molecules) were gradually designed and conveniently synthesized. All the newly synthesized conjugates were well characterized and evaluated against different Mycobacterium tuberculosis strains in vitro. The screening results showed that five DHA-FQ conjugates were active toward M. tuberculosis H37Rv, and compound 3a exhibited the strongest inhibitory activity (MIC=0.0625 μg/mL), which was comparable to the positive control Moxifloxacin and even stronger than Ofloxacin. Conjugates 2a and 3a also displayed comparable activities against various clinically isolated sensitive and resistant M. tuberculosis strains (MIC=0.125-16 μg/mL) to Moxifloxacin. All target compounds possessed selective anti-M. tuberculosis ability. Preliminary structure-activity relationship demonstrated that short linker between DHA and FQ was favorable for strong antitubercular activity. This study provides a new clue for the development of novel antitubercular lead molecules.
authors.affiliation: Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
authors.forename: Fu-Wei
authors.initials: FW
authors.lastname: Zhou
authors.affiliation: Chongqing Pharmaceutical Research Institute Co., Ltd., Chongqing 400061, China.
authors.forename: Huang-Shu
authors.initials: HS
authors.lastname: Lei
authors.affiliation: Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China. Electronic address: hxfanl@swu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: Schlumberger Technology Corporation, 110 Schlumberger Drive, Sugar Land, TX 77478, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
authors.forename: Xin-Mei
authors.initials: XM
authors.lastname: Peng
authors.affiliation: College of Pharmaceutical Science, Southwest University, Chongqing 400715, China.
authors.forename: Xing-Ran
authors.initials: XR
authors.lastname: Xu
authors.affiliation: College of Pharmaceutical Science, Southwest University, Chongqing 400715, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
authors.forename: Cheng-He
authors.initials: CH
authors.lastname: Zhou
authors.affiliation: Chongqing Pharmaceutical Research Institute Co., Ltd., Chongqing 400061, China.
authors.forename: Yan-Ye
authors.initials: YY
authors.lastname: Zou
authors.affiliation: Chongqing Pharmaceutical Research Institute Co., Ltd., Chongqing 400061, China.
authors.forename: Cai-Ping
authors.initials: CP
authors.lastname: Liu
authors.affiliation: Chongqing Pharmaceutical Research Institute Co., Ltd., Chongqing 400061, China.
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: He
authors.affiliation: Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China. Electronic address: hxydc@swu.edu.cn.
authors.forename: Da-Cheng
authors.initials: DC
authors.lastname: Yang
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D024841:Fluoroquinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D037621:Artemisinins; D024841:Fluoroquinolones; C039060:artenimol
keywords: Antibacterial activity; Antitubercular activity; Artemisinin; Dihydroartemisinin; Fluoroquinolone