CATIONIC AMPHIPHILIC INDOLES: SYNTHESIS AND EVALUATION AS ANTIMYCOBACTERIAL AGENTS

Abstract

Targeting the mycobacterial membrane is attractive for several reasons. A common characteristic of these compounds is the presence of cationic amphiphilicity. In this thesis, two cationic amphiphilic motifs were investigated – Series A which comprised Mannich bases of substituted indoles and Series E which were alkyltriphenylphosphonium analogues of substituted-indoles. The inclusion of azaspiroketal Mannich bases resulted in Series A analogues with improved selectivity and submicromolar potencies against Mtb H37Rv. The potency-enhancing chemotype of the spirocyclic motif was also validated by in vivo activity in an acute mouse model of TB. As anticipated, these compounds perturbed phospholipid vesicles, permeabilised bacterial cultures and induced the mycobacterial cell envelope stress reporter piniBAC, but without membrane depolarization. Contrastingly, Series E compounds did not induce mycobacterial membrane permeabilization or the cell envelope stress reporter piniBAC. Rather, their bactericidal effects stemmed from rapid depolarization of mycobacterial membranes and disruptive effects on electron transfer and cell division.