2. Academic Validation
  3. Identification of Pyrazolo[1,5- a]pyridine-3-carboxamide Diaryl Derivatives as Drug Resistant Antituberculosis Agents

Identification of Pyrazolo[1,5- a]pyridine-3-carboxamide Diaryl Derivatives as Drug Resistant Antituberculosis Agents

  • ACS Med Chem Lett. 2019 Feb 21;10(3):295-299. doi: 10.1021/acsmedchemlett.8b00410.
Xianglong Hu 1,  Baojie Wan 2,  Yang Liu 3,  Jiayi Shen 1,  Scott G Franzblau 2,  Tianyu Zhang 3,  Ke Ding 1,  Xiaoyun Lu 1
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190, Kai Yuan Avenue, Guangzhou 510530, China.
PMID: 30891129 DOI: 10.1021/acsmedchemlett.8b00410
Abstract

A series of pyrazolo[1,5-a]pyridine-3-carboxamide (PPA) derivatives bearing diaryl side chain was designed and synthesized as new antituberculosis agents, aiming to improve the efficacy toward drug resistant Mycobacterium tuberculosis (Mtb) strains. Most of the substituted diphenyl and heterodiaryl PPAs exhibited excellent in vitro potency against the drug susceptive H37Rv strain (MIC < 0.002-0.381 μg/mL) and drug resistant Mtb strains (INH-resistant (rINH), MIC < 0.002-0.465 μg/mL; RMP-resistant (rRMP), MIC < 0.002-0.004 μg/mL). Noticeably, some compounds also showed very low cytotoxicity against Vero cells. Further, compound 6j displayed good pharmacokinetic profiles with oral bioavailability (F) of 41% and significantly reduced the Bacterial burden in an autoluminescent H37Ra infected mouse model.

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