Pharmacophore-based in Silico Design of HMI-CFPB, a Scaffold-Hopped Acteoside Analogue from Spathodea campanulata, Targeting blood-brain barrier Penetration and Multistage Plasmodium falciparum Inhibition

Natural products continue to provide valuable scaffolds for antimalarial drug discovery because of their structural diversity and biological relevance. Due to the rapid sequestration of parasite-infected red blood cells and catastrophic blood–brain barrier (BBB) breakdown, cerebral malaria, the most deadly neurovascular complication caused by Plasmodium falciparum , has alarmingly high death rates worldwide. This study employed a pharmacophore-based in silico strategy to design HMI-CFPB, a scaffold-hopped analogue of acteoside derived from Spathodea campanulata , with enhanced BBB penetration and multistage antiplasmodial potential. Computer-aided scaffold hopping was deployed to replace the bulky glycosidic core with a pharmacologically optimized scaffold. The generated analog, HMI-CFPB, was rigorously evaluated using in silico ADMET filters, molecular docking simulations against vital multi-stage targets which include P. falciparum cGMP-dependent protein kinase (PfPKG), P. falciparum phosphatidylinositol 4-kinase (PfPI4K) for asexual blood stages and AKT Serine/Threonine Kinase 1 (AKT1) for transmission stages and comprehensive 100-ns MDs to ascertain binding stability. In silico optimization delivered significant pharmacokinetic and therapeutic enhancements. Structural scaffold replacement successfully reduced the polar surface area topological polar surface area (TPSA ≤140 Å 2 ) achieving an optimal lipophilicity (LogP ≤5) demonstrating robust passive trans-cellular diffusion across BBB endothelial models. HMI-CFPB displayed exceptional binding affinities against the respective targets (with a binding score of -8.7 kcal/mol for PfPKG, -8.3 kcal/mol for PfPI4K and -10.5 kcal/mol for AKT1) significantly outperforming native inhibitors. MD simulations corroborated these findings, showing minimal root-mean-square deviation (RMSD) fluctuations and stable hydrogen-bonding networks over 100 ns. The scaffold-hopping approach successfully generated a chemically optimized analogue with improved pharmacodynamic and pharmacokinetic characteristics suitable for central nervous system accessibility and multistage antimalarial intervention. These findings highlight HMI-CFPB as a promising lead candidate for further in vitro and in vivo validation in the development of next-generation antimalarial therapeutics targeting resistant P. falciparum infections.