Structural requirements for the antitubercular quaternized triflupromazine pharmacophore

  • Bioorg Med Chem Lett. 2012 Sep 1;22(17):5679-80. doi: 10.1016/j.bmcl.2012.06.095.
Dominique L Kunciw  1 ,  Jacob J Liechty ,  Miguel O Mitchell ,  Baojie Wan ,  Scott G Franzblau
Affiliations
  • 1. Department of Chemistry, Salisbury University, Salisbury, MD 21801, USA.
PMID: 22850215 DOI: 10.1016/j.bmcl.2012.06.095
Abstract

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<8 μM, and compounds 1-3 were all nontoxic to mammalian cells in vitro (IC(50)>128 μM).