New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

International Journal of Molecular Sciences

卷:22

Lucreția Udrescu¹  Marius Mioc²  Roxana Racoviceanu²  Codruța Șoica²  Adrian Voicu³  Adrian Militaru⁴  Mihai Udrescu⁴  Jason Cummings⁵  Gregory Robertson⁵  Diane J. Ordway⁵  Richard A. Slayden⁵  Anastasiya Petrova⁶  Oxana Kazakova⁶ 

[1] Department I-Drug Analysis, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timişoara, 2 Eftimie Murgu Sq., 300041 Timişoara, Romania;

[2] Department II-Pharmaceutical Chemistry, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timişoara, 2 Eftimie Murgu Sq., 300041 Timişoara, Romania;

[3] Department III-Informatics and Medical Biostatistics, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy Timişoara, 2 Eftimie Murgu Sq., 300041 Timişoara, Romania;

[4] Department of Computer and Information Technology, University Politehnica of Timişoara, 2 Vasile Pârvan Blvd., 300223 Timişoara, Romania;

[5] Department of Microbiology, Immunology & Pathology, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523, USA;

[6] Ufa Institute of Chemistry, The Ufa Federal Research Centre, The Russian Academy of Sciences, 71, Pr. Oktyabrya, 450054 Ufa, Russia;

关键词: triterpenoids;    lupane;    betulin;    azepane;    M. tuberculosis;    resistant MTB strains;   

DOI  :  10.3390/ijms222212542

来源: DOAJ

【 摘 要 】

Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.

【 授权许可】

Unknown