Designing, In-Silico Based Virtual Screening, Synthesis, Biological Evaluation and Molecular Dynamics Simulation of Novel Pyrazoleanalogs for the Treatment of Malaria

Abstract: Malaria, possibly a life-threatening disease, primarily affects the African and South Asian populations worldwide. The development of resistance to current treatment regimens for malaria is a major concern among the medical fraternity. This leads to the need to discover novel antimalarial agents that can attenuate the resistant malarial parasite. To discover novel pyrazole-based molecules that can be used to cure malaria. Initially, a 2D-QSAR-based virtual screening of the 16 pyrazolebased molecules designed for malaria was performed. Further virtual screening was conducted through the molecular docking simulations. Based on the results of the QSAR and molecular docking-based screening, hit compounds were synthesized and evaluated in vitro against malaria. Molecular dynamics simulations were performed for the top two molecules obtained from in vitro evaluation (Compounds 7b & 7d) to validate our results. From the QSAR-based and molecular docking-based virtual screening, we obtained a total of 6 hit molecules. These 6 hit molecules were synthesized, and their in vitro evaluation against malaria was performed. The top two best molecules, namely compounds 7b and 7d, showed EC50 values of 1.98 and 1.95 µg/ml, respectively. We further performed molecular dynamics simulations of these two molecules for 200 ns. From our study, we found that compounds 7b and 7d showed adequate anti-malarial activity. These compounds can be further explored for the development of more potent anti-malarial drugs.