Understanding the impact of methoxy groups of undescribed atropisomer biflavonoids of methanol leaf extract of Ochna rhizomatosa against chloroquine-resistant Plasmodium falciparum strain NF54: Insight from experimental, DFT and molecular docking studies

Abstract

This study investigated the suitability of three as yet undescribed Ochna rhizomatosa biflavonoids, 2,3-dihydroochnaflavone-7ʹʹ,7-O-dimethylether (compound 1), 7,4ʹ-dihydroxyflavonol-[(C(3ʹ)-O-C(4ʹ)]-7-hydroxyflavonol (compound 2) and 7-O-methylkaempferol-[C-3′(I)-O-C-3′(II)]-luteolin (compound 3), against drug-resistant Plasmodium falciparum, the most virulent human malarial parasite. Increase in resistance to available drugs warrants the need to search for new potent agents. Here we interacted compounds 1, 2, 3 and other isolates with the receptor protein (6YCX) responsible for P. falciparum survival and virulence, using the molecular docking approach. We employed FT-IR, NMR (1H and 13C), HR-ESIMS, UV–visible spectroscopy, biological activity and geometrical analysis, while electronic computations were performed using DFT/B3LYP6–31+G(2d,2p) level of theory. Result shows that compounds 1 (0.72 μM) and 3 (4.60 μM) exhibited promising antiplasmodial activity than the rest of the isolates which is largely attributed to the presence of methoxy groups at C7ʹ atoms. Frontier molecular orbital (FMO) analysis result shows that compounds 1 and 3 are better chelating agents, forming stable complexes with much better electrophilic and nucleophilic interactions than compounds 2, 4, and 5. Molecular docking results reveal that compounds 1, 2, 3 and 5 exhibit stronger binding affinities and contains higher conventional hydrogen bonding contributed by specific amino acid residues at the active site of 6YCX than the standard drugs; -10.0 kcal/mol, -9.4 kcal/mol, -9.8 kcal/mol, and -9.1 kcal/mol for compounds 1, 2, 3, and 5 respectively while artesunate and chloroquine had -8.7 kcal/mol and -5.7 kcal/mol respectively. This study contributes favorably to the ongoing quest for new drugs against devastating drug-resistant P. falciparum malaria parasite.