Investigating the impact of solvation on p-Phenylenediamine - 2-Amino pyrimidine - Formaldehyde Terpolymer (P2APF) ligand's reactivity and drug suitability for malaria treatment: Insights from experimental and quantum calculations

•Investigated P2APF ligand's effectiveness against drug-resistant Plasmodium falciparum, suggested significant results for malaria treatment in areas with limited options.•DFT investigations in various solvents highlighted solvation effects on P2APF ligand, suggesting optimal environments for reactivity.•Molecular docking revealed strong binding affinity between P2APF ligand and 5UMB chaperone protein receptor, indicating potential for targeted drug delivery against drug-resistant Plasmodium falciparum. This study aims at investigating the drug potential of p-Phenylenediamine – 2-Amino Pyrimidine – Formaldehyde terpolymer (P2APF) ligand against drug resistant Plasmodium falciparum. Plasmodium falciparum, an embodiment of cunning among malaria parasites, thrives in regions plagued by rampant mosquito transmission, subpar vector control, and limited access to effective treatments. To this end, this study explored the structural properties of the p-Phenylenediamine – 2-Amino Pyrimidine – Formaldehyde terpolymer (P2APF) ligand, (comprising p-Phenylenediamine, 2-Aminopyrimidine, and Formaldehyde) as a drug potent ligand against the common proteins coding for malaria infection. Various spectroscopic techniques such as FT-IR, UV–visible, and NMR (1H & 13C) spectroscopy were employed both experimentally and theoretically. Additionally, the ligand's surface morphology was investigated using scanning electron microscopy. To comprehend the influence of solvation, theoretical investigations utilizing density functional theory (DFT) at the B3LYPD(BJ)/6-311G++G (2d,2p) level were conducted in DMSO, water, and methanol solvents. The results from the frontier molecular orbital (FMO) analysis provided valuable insights into the electronic properties and solvation effects of P2APF. Specifically, the calculated energy gap of 3.671 eV for P2APF_methanol and 3.672 eV for P2APF_DMSO suggested these solvents as promising environments for reactivity and interactions. Molecular docking studies unveiled the most notable binding affinity between P2APF and the 5UMB chaperone protein receptor, exhibiting a binding affinity of -7.3 kcal/mol on serine and aspartic acid residues, with an average bond distance of 2.25 Å. This robust protein-ligand interaction signifies the promising potential of the P2APF ligand in targeting this specific receptor, thereby combating drug-resistant strains of Plasmodium falciparum for the present and the future.