Indole based antimalarial compounds targeting the melatonin pathway: Their design, synthesis and biological evaluation

Abstract

Malaria, one of the most severe global diseases, infects nearly 300 million people causing death of about a million population annually. Herein we have reported design, synthesis and biological evaluation of potent antimalarial compounds that target melatonin hormone as a potential pathway for the inhibition of the parasite proliferation. The molecular design is based on melatonin and indole based synthetic and natural antimalarial agents. The library of compounds was accessed via an iodine catalyzed one pot organocatalytic ring opening of 1-aryltetrahydro-β-carbolines followed by in situ imination of the resulting C₂-aroyl intermediates. Inhibition of parasite growth progression (3D7 and chloroquine resistant RKL9 strain) in the presence of the tested compounds indicated that few of the compounds substantially inhibited the parasite survival and the most potent compound 2j blocked the parasite growth at the trophozoite stage. Compound 2j also disrupted the melatonin induced synchronization of the parasite culture in vitro. The active compounds were screened against melatonin receptor MT1 to demonstrate substantial binding.

Keywords: C(2)-aryliminoindole; Malaria; Melatonin; Molecular docking; Oxidative ring opening.