title: Identification of metal dithiocarbamates as a novel class of antileishmanial agents.
abstract: 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 chemotherapeutic weapon against the Leishmania parasite. We report here strong antileishmanial activity of three hitherto unexplored 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 0.56 μM, 0.61 μM, and 0.27 μM, respectively. These compounds were even more effective against parasites growing in acidic medium, in which their 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 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.
authors.affiliation: Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur Campus, West Bengal, India.
authors.forename: Dhiman Sankar
authors.initials: DS
authors.lastname: Pal
authors.affiliation: Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur Campus, West Bengal, India.
authors.forename: Dipon Kumar
authors.initials: DK
authors.lastname: Mondal
authors.affiliation: Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur Campus, West Bengal, India rupakdatta@iiserkol.ac.in.
authors.forename: Rupak
authors.initials: R
authors.lastname: Datta
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001822:Body Burden; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018320:Leishmania major / Q000187:drug effects*; D008344:Maneb / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D016053:RNA, Protozoan / Q000235:genetics; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D015038:Zineb / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000981:Antiprotozoal Agents; D002257:Carbonic Anhydrase Inhibitors; D016053:RNA, Protozoan; D013859:Thiocarbamates; C012509:propineb; D008344:Maneb; D015038:Zineb