Structural requirements for the antitubercular quaternized triflupromazine pharmacophore

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 17; pp. 5679 - 5680
• Main Authors: Kunciw, Dominique L., Liechty, Jacob J., Mitchell, Miguel O., Wan, Baojie, Franzblau, Scott G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2012
• Subjects: amines; Animals; Antitubercular; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Benzyl; Cell Survival - drug effects; Cercopithecus aethiops; chemistry; Halogens; Humans; mammals; Microbial Sensitivity Tests; Minimum inhibitory concentration; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Nitrogen; pharmacology; Pharmacophore; pharmacophores; Quaternary; Structure-Activity Relationship; Triazole; triazoles; Triflupromazine; Triflupromazine - analogs & derivatives; Triflupromazine - pharmacology; Tuberculosis - drug therapy; Vero Cells; Benzyl; Triazole; Quaternary; Antitubercular; Pharmacophore; Triflupromazine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.06.095

Quaternized triflupromazine derivatives (QTDs) must possess benzyl groups attached to the quaternary nitrogen in order to have significant antitubercular potency. Replacing the quaternary amine with a triazole abolishes antitubercular activity. A modest halogen substitution effect exists, with the 4-bromophenyl QTD 3 having the best selectivity index (>21). All N-benzyl QTDs 1–4 similarly inhibit non-replicating, persistent Mycobacterium tuberculosis with MIC<8μM, and compounds 1–3 were all nontoxic to mammalian cells in vitro (IC50>128μM).