Theoretical and experimental investigation on newly synthesized pyrazolopyridine derivatives: Insight into the compound activity, NLO response, and molecular dynamics

Abstract

Pyrazolopyridine derivatives exhibiting biological activity are widely present in drug molecules. The title compound, ethyl 3-amino-6-methyl-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (II), was designed and synthesized and the structure characterized by spectroscopic techniques and confirmed by single-crystal X-ray diffraction. The pyrazolopyridine moiety is not quite planar and the thiophene and ester groups are rotated well out of the mean plane of the pyridine ring. N—H···N and C—H···O hydrogen bonds plus π-stacking interactions form thick layers of molecules parallel to (001). Based on structural activity relationship studies, II exhibits potent activity against fibroblast collagenase-1 complexed to a diphenyl-ether sulphone-based hydroxamic acid or Matrix Metalloproteinase (MMP-1). Theoretical simulations were performed to probe the reactivity and electronic properties of II where the quantum theory of atoms in molecules and NBO analysis was used to describe the bonding nature and charge transfer excitation. The optical and nonlinear characteristics of II are also evidenced by its hyperpolarizability response. The kinetic and thermodynamic stability of II was monitored through a computed ab-initio molecular dynamics study. In addition, a Hirshfeld surface analysis was performed to assess the intermolecular interactions. Efficient binding of II in the MMP-1 complex system has been achieved through classical molecular dynamics and molecular docking calculations. An ADMET analysis was also carried out to explore the potential future drug candidacy of II.