2. Academic Validation
  3. Discovery of thienothiazolocarboxamide analogues as novel anti-tubercular agent

Discovery of thienothiazolocarboxamide analogues as novel anti-tubercular agent

  • Bioorg Med Chem. 2020 Dec 1;28(23):115797. doi: 10.1016/j.bmc.2020.115797.
Guanghai Jin 1,  Young Mi Kim 1,  Aram Lee 1,  Junghwan Choi 1,  Sunhee Kang 1,  Mooyoung Seo 1,  Jeong Jea Seo 1,  Sumi Lee 1,  Juhee Kang 1,  Jaeseung Kim 1,  Sinyoung Park 2,  Minjeong Woo 3,  Virgínia Carla de Almeida Falcão 3,  Honggun Lee 4,  Jinyeong Heo 4,  David Shum 4,  Kaapjoo Park 1,  Vincent Delorme 3,  Inhee Choi 5
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
  • 2 Animal Facility and Lab Support, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
  • 3 Tuberculosis Research Lab, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
  • 4 Screening Development Platform, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
  • 5 Medicinal Chemistry, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. Electronic address: [email protected].
PMID: 33075682 DOI: 10.1016/j.bmc.2020.115797
Abstract

In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of Mycobacterium tuberculosis H37Rv, using a dual phenotypic assay. Compounds were assessed against bacteria replicating in broth medium, as well as inside macrophages, and thienothiazolocarboxamide (TTCA) scaffold was identified as hit in both assays, with submicromolar inhibitory concentrations. Derivatives of TTCA were further synthesized and evaluated for their inhibitory effects on M.tuberculosis H37Rv. In the present study we report the structure-activity relationship of these TTCA derivatives. Compounds 28, 32 and 42 displayed good anti-tubercular activities, as well as favorable ADME and PK properties. Compound 42 exhibited excellent oral bioavailability in mice with high distribution to lungs, within 1 h. It was found to be efficacious in a dose dependent manner in a murine model of M. tuberculosis Infection. Hence, compound 42 is now under evaluation as a potential lead candidate for treatment of tuberculosis.

Keywords

In vivo efficacy; Pharmacokinetics (PK); Structure-activity relationship (SAR); Structure-property relationship (SPR); Thienothiazolocarboxamide (TTCA); Tuberculosis (TB).

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