Global assembling of Academicians, Researchers, Scholars & Industry to disseminate and exchange information at 100+ Allied Academics Conferences
Plasmodium falciparum dihydrofolate reductase (PfDHFR) enzyme is one of the validated targets for antimalarial drug discovery. The quadruple mutant of PfDHFR is resistant to the known anti-PfDHFR drugs (e.g. proguanil, pyrimethamine and trimethoprim). Recently, P218 was identified as a potential lead molecule. In this work, a rational drug design strategy was adopted to identify guanylthiourea (GTU) derivatives as a potential PfDHFR inhibitor. Electronic structure analysis of the GTU moiety was carried out to determine the correct tautomeric form which was 11.99 kcal/mol more stable than the previously reported structure in the literature. Once acceptable structure was established; in silico investigations on the wild type/quadruple mutant PfDHFR and various ligands (including MESP analysis, molecular docking studies) were performed to design novel GTU derivatives as potential PfDHFR inhibitors. Three series of GTU derivatives were synthesised, by reacting bromides with GTU under reflux and microwave condition. The synthesized compounds were first evaluated for in vitro PfDHFR inhibitory activity, resulting in the identification of two compounds (100 ?M and 0.4 ?M). Further, in vivo studies recognized six compounds with high mean survival time, out of which one compound was identified to be curative. This work reports a systematic rational approach for the structure-based design of potential antimalarial agents.