Identification of Metal Dithiocarbamates as a Novel Class of Antileishmanial Agents

Dithiocarbamates 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 che-motherapeutic weapon against the Leishmania parasite. We report here strong antileishmanial activity of three hitherto unex-plored metal dithiocarbamates, maneb, zineb, and propineb. They inhibited CA activity in Leishmania major promastigotes 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 and Leishmania cell death with 50 % lethal dose (LD50) values of 0.56M, 0.61M, and 0.27M, respectively. These compounds were evenmore effective against parasites growing in acidic medium, in which their LD50 values were severalfold lower. Intracellular acidosis leading to apoptotic and necrotic death of L. major promastigotes was found to be the basis of their leishmanicidal activity. Maneb, zineb, and propineb also efficiently re-duced the intracellular parasite burden, suggesting that amastigote forms of the parasite are also susceptible to these metal di-thiocarbamates. Interestingly, mammalian cells were unaffected by these compounds even at concentrations which are several-fold higher than their antileishmanial LD50s). Our data thus establish maneb, zineb, and propineb as a new class of antileishmanial compounds having broad therapeutic indices. Leishmaniasis is a vector-borne disease caused by the protozoanparasite of the genus Leishmania. The disease is manifested in various clinical forms, ranging from self-healing skin ulcers t