Pyrazole based Furanone Hybrids as Novel Antimalarial: A Combined Experimental, Pharmacological and Computational Study

Background: Malaria parasite strains are resistant to the therapeutic effect of prophylactics medicines presently available. This resistance now poses a significant challenge to researchers to beat malaria parasitic infections. Strategies such as investigating newer hybrid chemical entities and specified drug targets may help us spot new efficient derivatives that bind to the parasites in a more specific manner and inhibit their growth. Objective: To scientifically perform the experimental, pharmacological, and computational studies of pyrazole-based furanone hybrids as novel antimalarial agents. Methods: A series of new furanone-based pyrazole derivatives were synthesized and investigated as potential antimalarial agents by performing in vitro antimalarial activity. To get further optimization, these synthesized derivatives were virtually screened based on ADME-T filters, and molecular docking studies were also accomplished on the crystal structures of Plasmodium falciparum lactate dehydrogenase (PfLDH). Furthermore, the in-silico prediction was supported by performing an LDH assay. Results: The docking data suggested that the designed hybrid of furanone-pyrazole may act as PfLDH inhibitors. It was found that the results of experimental in vitro antimalarial activity and in silico analysis correlate well to each other to a good extent. The compounds (7d), (7g), and (8e) were found to be the most potent derivatives with IC50 values of 1.968, 1.983, and 2.069 μg/ml, respectively. Conclusion: From the results, it may be concluded that compounds that are active in low doses might be adopted as a lead compound for the development of more active antimalarial agents. The synthesized compounds (7d), (7g), and (8e) exhibited good antimalarial activity with PfLDH inhibition. The best compounds can be explored further in the future for designing the potent inhibitors of PfLDH as new potent antimalarial agents.