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 ϳ10 Ϫ6 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.

Search for New Antileishmanial Chemotherapeutics

“…and also inducing apoptosis effect in the intracellular amastigotes of L. donovani as reported in earlier investigations [45]. Several studies are also reported for the antileishmanial properties of derivatives of betulinic acid [46,47].…”

“…of 8.9 µM against L. donovani amastigotes. Chowdhury et al [45] have published that synthesized betulin derivatives have been found to inhibit the growth of the parasite and it was also found that they can act by relaxing the activity of L. donovani topoisomerase I in a reversible manner. No significant data have been found for the antileishmanial activity of spikenard oil.…”

A systematic review of pentacyclic triterpenes and their derivatives as chemotherapeutic agents against tropical parasitic diseases

“…In a different study, oral and intraperitoneal administration of 10 mg kg −1 bw DHBA to infected golden hamsters caused >90% reduction in parasite load in the spleen and liver of the infected animals. The compound was proposed to exert its effect via a mechanism that involves inhibition of DNA topoisomerases thereby essentially destroying the parasites (Chowdhury et al 2003(Chowdhury et al , 2011. As observed with other PT, the chemical entities on the C3 and C28 position of the lupeol-type PT is critical for the anti-parasitic activity of the group.…”

Bioactive compounds ofCrocus sativusL. and their semi-synthetic derivatives as promising anti-Helicobacter pylori, anti-malarial and anti-leishmanial agents

“…Disuccinyl betulin, diglutaryl dihydrobetulin and disuccinyl dihydrobetulin, derivatives of the natural triterpene betulin present in the Betula spp. cork layer, inhibit the relaxation activity of the enzyme IB type topoisomerase of L. donovani; this effect decreases the intracellular parasites number in macrophages 21 .…”