Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains.
Following up the SAR study of triazolothiadiazoles for their antitubercular activities targeting Mt SD in our previous study, on the principle of scaffold hopping, the C3 and C6 positions of triazolothiadiazine were examined systematically to define a preliminary structure-activity relationship (SAR) with respect to biological activity. This study herein highlights the potential of two highly potent advanced leads 6c-3, 6g-3 and several other compounds with comparable potencies as promising new candidates for the treatment of TB (6c-3, MIC-H37Rv=0.25μg/mL; MIC-MDRTB=2.0μg/mL; MIC-RDRTB=0.25μg/mL; Mt SD-IC50=86.39μg/mL; and 6g-3, MIC-H37Rv=1.0μg/mL; MIC-MDRTB=4.0μg/mL; MIC-RDRTB=2.0μg/mL; Mt SD-IC50=73.57μg/mL). Compounds 6c-3 and 6g-3 possessed a para-nitro phenyl at the 6 position showed low Vero and HepG2 cells toxicity, turning out to be two excellent lead candidates for preclinical trials. In addition, in vitro Mt SD inhibitory assay indicates that Mt SD is at least one of the targets for their antitubercular activity. Thus, they may turn out to be promising multidrug-resistance-reversing agents.
School of Pharmacy, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Linghe District, Jinzhou 121001, China.
Ziqiang
Z
Li
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
Xiaoguang
X
Bai
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
Qi
Q
Deng
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
Guoning
G
Zhang
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
Lei
L
Zhou
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
Yishuang
Y
Liu
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China. Electronic address: imbjxwang@163.com.
Juxian
J
Wang
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China. Electronic address: wyc9999@gmail.com.
Yucheng
Y
Wang
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D002522:Chlorocebus aethiops; D024881:Drug Resistance, Bacterial; D018432:Drug Resistance, Multiple; D056945:Hep G2 Cells; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D014709:Vero Cells
C000625530:3-(3-fluoropyridin-4-yl)-6-(4-nitrophenyl)-7H-(1,2,4)triazolo(3,4-b)(1,3,4)thiadiazine; C000625529:3-(4-bromophenyl)-6-(4-nitrophenyl)-7H-(1,2,4)triazolo(3,4-b)(1,3,4)thiadiazine; D000995:Antitubercular Agents; D013829:Thiadiazines; D014230:Triazoles; D007538:Isoniazid; D012293:Rifampin
3,6-Disubstituted triazolothiadiazine; Antitubercular agent; SAR; Shikimate dehydrogenase