Synthesis, biological evaluation and molecular docking studies of tricyclic guanidine derivatives for anti-malarial activity

Abstract

IntroductionMalaria is the most lethal among the parasitic diseases and challenge for developing counties. Globally, an estimated 3.3 billion people were at risk of malaria in 2011, with populations living in sub-Saharan Africa having the highest risk of acquiring malaria. Malarial infection caused by P. falciparum is the most deadly form among all pathogens. Moreover, there has been rapid increase in resistance to drugs by P. falciparum. This resistance is considered because of emergence through mutation or biochemical changes in the active site of drug targets. The lactate dehydrogenase of P. falciparum (PfLDH) has been used since long time as a potential molecular drug target for malaria. The LDH plays role in the inter-conversion of pyruvate to lactate in the glycolysis cycle, which is required for energy production in living cells. Objectives1) Synthesis of tricyclic guanidine derivatives and biological evaluation against resistant strain of P. falciparum (Lactate Dehydrogenase Inhibitor). 2) Molecular docking of synthesized derivatives to understand mechanism of inhibition. MethodsWe have synthesized fifty tricyclic guanidine derivatives based on batzelladine K backbone. All synthesized compounds were evaluated for anti-malarial activity against chloroquine resistant strains of P. falciparum by using plasmodial LDH activity as measure of inhibition. To understand the mechanism of inhibition and to identify pharmacophore required for activity, the molecular docking of tricyclic guanidine compounds was performed using CDOCKER program in Discovery Studio suit 3.5. Results & DiscussionWe have obtained many potent inhibitors. The docking studies showed that there is very strong correlation between in silico and in vitro results. The most active compound was found to have least CDOCKER interaction energy (–43.25 kcal/mol). It showed hydrophobic interaction with Gly27, Ala98, Asp53 and Ile54 residues in the enzyme binding pocket similar to that of chloroquine. ConclusionThe synthesized derivatives are potent inhibitor of chloroquine-resistant PfLDH and act on same binding site to that of chloroquine. Based on these results, more potent inhibitor against P. falciparum can be designed.