Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility

被引:0
作者
Zhong, Xijun [1 ]
Wu, Jizhou [1 ]
Du, Na [1 ]
Zhou, Sheng [2 ]
Ma, Chao [1 ,3 ]
Xue, Tiezheng [2 ]
Wei, Meng [1 ]
Gong, Jiaqi [1 ]
Wang, Bin [4 ]
Liu, Mingliang [1 ]
Wang, Apeng [1 ]
Lv, Kai [1 ]
Lu, Yu [4 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, Beijing 100050, Peoples R China
[2] Hebei Med Univ, Shijiazhuang 050017, Peoples R China
[3] MindRank AI Ltd, Hangzhou 310000, Peoples R China
[4] Med Univ, Beijing Chest Hosp, Beijing TB & Thorac Tumor Res Inst, Capital Coll Pharm,Beijing Key Lab Drug Resistance, Beijing 100149, Peoples R China
基金
北京市自然科学基金;
关键词
Nitrobenzothiazinones; Antimycobacterial activity; Water solubility; Synthesis; MYCOBACTERIUM-TUBERCULOSIS; DPRE1;
D O I
10.1016/j.ejmech.2024.116829
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents targeting DprE1. Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H(37)Rv and MDR-MTB strains (MIC: <0.029-0.095 mu M), low toxicity and acceptable oral PK profiles, as well as significantly improved water solubility (1200 and > 2000 mu g/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery.
引用
收藏
页数:9
相关论文
共 27 条
[1]  
[Anonymous], PHASE 2A STUDY PBTZ1
[2]  
[Anonymous], SINGLE ASCENDING DOS
[3]   DprE1 Is a Vulnerable Tuberculosis Drug Target Due to Its Cell Wall Localization [J].
Brecik, Miroslav ;
Centarova, Ivana ;
Mukherjee, Raju ;
Kolly, Gaelle S. ;
Huszar, Stanislav ;
Bobovska, Adela ;
Kilacskova, Emoeke ;
Mokosova, Veronika ;
Svetlikova, Zuzana ;
Sarkan, Michal ;
Neres, Joao ;
Kordulakova, Jana ;
Cole, Stewart T. ;
Mikusova, Katarina .
ACS CHEMICAL BIOLOGY, 2015, 10 (07) :1631-1636
[4]   Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents [J].
Fan, Dongguang ;
Wang, Bin ;
Stelitano, Giovanni ;
Savkova, Karin ;
Shi, Rui ;
Huszar, Stanislav ;
Han, Quanquan ;
Mikusova, Katarina ;
Chiarelli, Laurent R. ;
Lu, Yu ;
Qiao, Chunhua .
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (19) :14526-14539
[5]   Tuberculosis Drug Discovery: Challenges and New Horizons [J].
Fernandes, Guilherme F. S. ;
Thompson, Andrew M. ;
Castagnolo, Daniele ;
Denny, William A. ;
Dos Santos, Jean L. .
JOURNAL OF MEDICINAL CHEMISTRY, 2022, 65 (11) :7489-7531
[6]   hERG toxicity assessment: Useful guidelines for drug design [J].
Garrido, Amanda ;
Lepailleur, Alban ;
Mignani, Serge M. ;
Dallemagne, Patrick ;
Rochais, Christophe .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2020, 195
[7]   New agents for the treatment of drug-resistant Mycobacterium tuberculosis [J].
Hoagland, Daniel T. ;
Liu, Jiuyu ;
Lee, Robin B. ;
Lee, Richard E. .
ADVANCED DRUG DELIVERY REVIEWS, 2016, 102 :55-72
[8]   Identification of novel benzothiopyranone compounds against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones [J].
Li, Peng ;
Wang, Bin ;
Zhang, Xinwei ;
Batt, Sarah M. ;
Besra, Gurdyal S. ;
Zhang, Tingting ;
Ma, Chen ;
Zhang, Dongfeng ;
Lin, Ziyun ;
Li, Gang ;
Huang, Haihong ;
Lu, Yu .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 160 :157-170
[9]   Improving solubility of poorly water-soluble drugs by protein-based strategy: A review [J].
Liu, Xiaowen ;
Zhao, Limin ;
Wu, Baojian ;
Chen, Fener .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 2023, 634
[10]   Clofazimine Analogs with Efficacy against Experimental Tuberculosis and Reduced Potential for Accumulation [J].
Lu, Yu ;
Zheng, Meiqin ;
Wang, Bin ;
Fu, Lei ;
Zhao, Weijie ;
Li, Peng ;
Xu, Jian ;
Zhu, Hui ;
Jin, Haixia ;
Yin, Dali ;
Huang, Haihong ;
Upton, Anna M. ;
Ma, Zhenkun .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2011, 55 (11) :5185-5193