Novel betulin derivatives as antileishmanial agents with mode of action targeting type IB DNA topoisomerase
ABSTRACT Toward developing antileishmanial agents with mode of action targeted to DNA topoisomerases of Leishmania donovani, we have synthesized a large number of derivatives of betulin. The compound, a natural triterpene isolated from the cork layer of Betula spp. plants exhibits several pharmacological properties. Three compounds (disuccinyl betulin, diglutaryl dihydrobetulin, and disuccinyl dihydrobetulin) inhibit growth of the parasite as well as relaxation activity of the enzyme type IB topoisomerase [Leishmania donovani topoisomerase I (LdTOP1LS)] of the parasite. Mechanistic studies suggest that these compounds interact with the enzyme in a reversible manner. The stoichiometry of these compounds binding to LdTOP1LS is 1:1 (mole/mole) with a dissociation constant on the order of ∼10(-6) M. Unlike CPT, these compounds do not stabilize the cleavage complex; rather, they abrogate the covalent complex formation. In processive mode of relaxation assay condition, these compounds slow down the strand rotation event, which ultimately affects the relaxation of supercoiled DNA. It is noteworthy that these compounds reduce the intracellular parasite burden in macrophages infected with wild-type L. donovani as well as with sodium antimony gluconate resistant parasite (GE1). Taken together, our data suggest that these betulin derivatives can be exploited as potential drug candidates against threatening drug resistant leishmaniasis.
- SourceAvailable from: Chinmay Pal
Article: Redox-active antiparasitic drugs.[Show abstract] [Hide abstract]
ABSTRACT: Parasitic diseases affect hundreds of millions of people worldwide and represent major health problems. Treatment is becoming extremely difficult due to the emergence of drug resistance, the absence of effective vaccines, and the spread of insecticide-resistant vectors. Thus, identification of affordable and readily available drugs against resistant parasites is of global demand. RECENT ADVANCES: Susceptibility of many parasites to oxidative stress is a well-known phenomenon. Therefore, generation of reactive oxygen species (ROS) or inhibition of endogenous antioxidant enzymes would be a novel therapeutic approach to develop antiparasitic drugs. This article highlights the unique metabolic pathways along with redox enzymes of unicellular (Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei, Leishmania donovani, Entamoeba histolytica, and Trichomonas vaginalis) and multicellular parasites (Schistosoma mansoni), which could be utilized to promote ROS-mediated toxicity. Enzymes involved in various vital redox reactions could be potential targets for drug development. The identification of redox-active antiparasitic drugs along with their mode of action will help researchers around the world in designing novel drugs in the future.Antioxidants & Redox Signaling 11/2011; 17(4):555-82. · 8.20 Impact Factor