Multimodal characterization of a pyrazolo[3,4-b]pyridine aldehyde: quantum chemical insights, NLO activity and VEGFR-2 docking/molecular dynamics

Abstract

The aldehyde-functionalized pyrazolo[3,4-b]pyridine derivative CJ129 was examined in the solid state for the first time using single-crystal X-ray diffraction. The analysis showed that the molecule adopts a monoclinic P2₁/c arrangement, in which the packing is supported by π–π stacking interactions of 3.683 Å between the molecules. To gain a broader picture of its behavior, we combined several quantum-chemical approaches—DFT using M06-2X/def2-TZVPP and TD-DFT with CAM-B3LYP/6-311++G(d,p)—to explore its electronic properties, chemical reactivity, and nonlinear optical (NLO) response. CJ129 features a moderate HOMO–LUMO separation (6.17 eV), a notably high electrophilicity index (ω = 70.31 kcal mol⁻¹), and clear evidence of intramolecular charge transfer, all of which contribute to its strong NLO behavior (β = 26.81 × 10⁻³⁰ esu; γ = 118.34 × 10⁻³⁶ esu), which exceeds the values reported for chalcone-based systems. To complement the electronic analysis, we performed 500-nanosecond molecular dynamics simulations of the complex with VEGFR-2. Throughout the trajectory, CJ129 remained stably positioned in the active site, mainly through hydrophobic interactions and recurring hydrogen bonds involving Asp1046 and Asn923. Taken together, these results provide the first integrated crystallographic and computational description of CJ129 and suggest its potential as an NLO-active molecule and promising scaffold for targeting VEGFR-2 in antiangiogenic research.