Structure–Activity Relationship, Quantum Chemical Analysis, and Molecular Docking Insights into Pyrazolo[3,4-b]pyridine Derivatives Against Plasmodium falciparum

Three Single crystals of biologically relevant pyrazolo[3,4-b]pyridine derivatives such as (4-(4-methoxyphenyl)-3-methyl-1-phenyl-1 H-pyrazolo[3,4-b]pyridin-5-yl)(p-tolyl)methanone (OME), (4-(3,4,5-trimethoxyphenyl)-3-methyl-1-phenyl-1 H-pyrazolo[3,4-b]pyridin-5-yl)(p-tolyl)methanone (TOME), and (4-(4-(methylthio)phenyl)-3-methyl-1-phenyl-1 H-pyrazolo[3,4-b]pyridin-5-yl) (p-tolyl)methanone (SME) were grown by slow evaporation method and their properties have been studied. OME crystallizes in the monoclinic system, while TOME and SME crystallize in the triclinic system. Crystal structure is stabilized by C‒H…N and C‒H…π interactions in addition to C–H···O interaction, resulting in one-dimensional chain formation in OME one-dimensional supramolecular tape in TOME and SME. Hirshfeld surface and two-dimensional fingerprint analyses indicate that H···H contacts dominate the intermolecular interactions contributing to crystal stability. Density functional theory (DFT) calculations performed at the B3LYP/6-311 + + G (d, p) level show good agreement with the experimental geometries. Structure–activity relationship analysis reveals that substituent-induced electronic modulation influences the HOMO–LUMO energy gaps (3.873 eV for OME, 3.836 eV for TOME, and 3.844 eV for SME), Mulliken charge distribution on ring nitrogen atoms, global reactivity descriptors (η = 1.918–1.937 eV; ω = 3.76–4.18 eV), and molecular docking binding affinities (− 8.2, − 7.8, and − 8.4 kcal mol^{− 1} for OME, TOME, and SME, respectively). Molecular docking studies against Plasmodium falciparum targets demonstrate favorable binding interactions, highlighting the role of substituent effects in governing electronic structure and ligand–receptor recognition. These results suggest that pyrazolo[3,4-b]pyridine derivatives represent promising scaffolds for further antimalarial drug development.