2. Academic Validation
  3. Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents

Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents

  • Bioorg Med Chem Lett. 2019 Sep 1;29(17):2511-2515. doi: 10.1016/j.bmcl.2019.06.055.
Xin Tao 1,  Chao Gao 2,  Zhi-Gang Huang 3,  Wei Luo 3,  Kun-Lin Liu 2,  Cui-Ting Peng 4,  Charles Z Ding 3,  Jian Li 3,  Shu-Hui Chen 3,  Luo-Ting Yu 5
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; Changzhou Yinsheng Pharmacy Co., Ltd., Weitang Chemical Industry Zone, Changzhou 213000, China.
  • 2 Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 WuXi AppTec. Co. Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 4 Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China.
  • 5 Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yuluot@scu.edu.cn.
PMID: 31353295 DOI: 10.1016/j.bmcl.2019.06.055
Abstract

New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation.

Keywords

Antitubercular agents; Nitroimidazoles; Physicochemical properties.

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