Discovery of thienothiazolocarboxamide analogues as novel anti-tubercular agent - Institut Pasteur de Corée
Article Dans Une Revue Bioorganic and Medicinal Chemistry Année : 2020

Discovery of thienothiazolocarboxamide analogues as novel anti-tubercular agent

Résumé

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.
Fichier principal
Vignette du fichier
S0968089620306271.pdf (683.46 Ko) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03493703 , version 1 (17-10-2022)

Licence

Identifiants

Citer

Guanghai Jin, Young Mi Kim, Aram Lee, Junghwan Choi, Sunhee Kang, et al.. Discovery of thienothiazolocarboxamide analogues as novel anti-tubercular agent. Bioorganic and Medicinal Chemistry, 2020, 28 (23), pp.115797. ⟨10.1016/j.bmc.2020.115797⟩. ⟨hal-03493703⟩

Collections

RIIP RIIP_COREE
32 Consultations
32 Téléchargements

Altmetric

Partager

More