Anti-mycobacterial activity of 1,3-diaryltriazenes

• Published in: European journal of medicinal chemistry Vol. 77; pp. 193 - 203
• Main Authors: Cappoen, Davie, Vajs, Jure, Uythethofken, Cynthia, Virag, Andrej, Mathys, Vanessa, Kočevar, Marijan, Verschaeve, Luc, Gazvoda, Martin, Polanc, Slovenko, Huygen, Kris, Košmrlj, Janez
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 22.04.2014; Elsevier
• Subjects: 1,3-Diaryltriazene; Acute toxicity; Animals; Antibiotic lead; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Cell Line; Cell Survival - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Genotoxicity; Life Sciences & Biomedicine; Macrophages - drug effects; Mice; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium avium - drug effects; Mycobacterium avium - growth & development; Mycobacterium bovis - drug effects; Mycobacterium bovis - growth & development; Mycobacterium ulcerans - drug effects; Mycobacterium ulcerans - growth & development; Pharmacology & Pharmacy; SAR; Science & Technology; Structure-Activity Relationship; Triazenes - chemical synthesis; Triazenes - chemistry; Triazenes - pharmacology; Tuberculosis; 1,3-Diaryltriazene; Tuberculosis; SAR; Antibiotic lead; Genotoxicity; Acute toxicity; TRIAZENES; ASSAY; MECHANISM; ANALOGS; BIOLOGICAL EVALUATION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.02.065

The rapid generation and spread of the drug resistant tuberculosis has led to an ongoing demand for novel compounds for therapeutic use. Identification and study of compounds with the ability to inhibit Mycobacterium tuberculosis is of paramount importance. For this reason, a library of substituted 1,3-diaryltriazenes based on the acting component of the anti-trypanosomal drug, diminazene aceturate was created and evaluated for its potential as anti-tubercular agent. Several compounds were identified with sub-micro molar inhibitory concentrations against M. tuberculosis and other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. Although the library of the compounds showed a considerable acute cytotoxicity, a genotoxicity could not be observed. Finally, the triazene 14 was selected with the best biological properties (IC50 = 3.26 μM, NI50 = 24.22 μM, SI = 7.44). The compound 14 showed the ability to inhibit the growth of intracellular replicating and multi-drug resistant M. tuberculosis. The results suggest the molecule to be an interesting scaffold for further study and optimization. [Display omitted] •A Library of 26 1,3-diaryltriazene analogues were screened for potency against Mycobacterium tuberculosis.•Hits were identified and the activity verified towards other mycobacterial species.•In vitro acute toxicity was observed and the selectivity was calculated.•CF3 substitution was important to prevent the generation of genotoxic metabolites.•The activity against MDR M. tuberculosis and intracellular M. tuberculosis was confirmed.