Identification of Metal Dithiocarbamates as a Novel Class of Antileishmanial Agents

Abstract

ABSTRACTDithiocarbamates have emerged as potent carbonic anhydrase (CA) inhibitors in recent years. Given that CAs are important players in cellular metabolism, the objective of this work was to exploit the CA-inhibitory property of dithiocarbamates as a chemotherapeutic weapon against theLeishmaniaparasite. We report here strong antileishmanial activity of three hitherto unexplored metal dithiocarbamates, maneb, zineb, and propineb. They inhibited CA activity inLeishmania majorpromastigotes at submicromolar concentrations and resulted in a dose-dependent inhibition of parasite growth. Treatment with maneb, zineb, and propineb caused morphological deformities of the parasite andLeishmaniacell death with 50% lethal dose (LD50) values of 0.56 μM, 0.61 μM, and 0.27 μM, respectively. These compounds were even more effective against parasites growing in acidic medium, in which their LD50values were severalfold lower. Intracellular acidosis leading to apoptotic and necrotic death ofL. majorpromastigotes was found to be the basis of their leishmanicidal activity. Maneb, zineb, and propineb also efficiently reduced the intracellular parasite burden, suggesting that amastigote forms of the parasite are also susceptible to these metal dithiocarbamates. Interestingly, mammalian cells were unaffected by these compounds even at concentrations which are severalfold higher than their antileishmanial LD50s). Our data thus establish maneb, zineb, and propineb as a new class of antileishmanial compounds having broad therapeutic indices.