Anti-mycobacterial Mannich Bases of N-Geranyl Indoles

Abstract

One of the greatest challenges faced by the medical world in batting tuberculosis (TB) is the emergence of multidrug-resistant tuberculosis (MDR-TB), which has led to the loss of efficacies of several existing anti-TB drugs. Thus, there is an urgent need for new anti-TB drugs acting preferably on novel targets. In this report, 2 series of cationic amphiphilic indoles (G6M and G4F) were synthesized and evaluated for antimycobacterial activity on Mycobacterium bovis BCG. It is proposed that these cationic amphiphilic compounds would affect bacterial viability by disrupting the mycobacterial cell membranes or act on enzymes involved in cell wall biosynthesis. A lipophilic geranyl side chain was present in both series of compounds and the aim was to determine if its presence would provide an activity advantage over another lipophilic N-octyl residue. It was found that for the same substitutions at other parts of the indole ring, analogs with the geranyl side chain were either comparable or less active than their N-octyl counterparts. However, mycobacterial activities were found in all of the synthesized compounds and the most active analogs had low micromolar growth inhibitory activities with more than 10 fold selectivity for mycobacteria compared to mammalian cell lines. These compounds meet the requirements of a validated TB hit and will be investigated for their membrane targeting effects in future work.