(E)-N'-(4-chlorobenzylidene)-5-methyl-1H-pyrazole-3-carbohydrazide as a potential PI3Kα targeting scaffold, synthesis, X-ray crystallography, DFT, molecular docking, molecular dynamics simulations, and MMGBSA analysis

Cancer remains a major global health challenge. Targeting the PI3K/Akt/mTOR pathway, particularly PI3Kα, is a promising anticancer strategy. In this study, a novel pyrazole derivative, E-CMPC, was designed, synthesized, and structurally characterized, including ¹H NMR, ¹³C NMR, ESI-MS, and single-crystal X-ray diffraction. Quantum chemical calculations, Molecular docking, molecular dynamics simulations, and MMGBSA analysis indicated favourable binding behaviour and dynamic stability within a PI3K-like catalytic environment, modelled using the VPS34 kinase domain as a structural surrogate. In silico ADMET analysis indicated favorable pharmacokinetic properties and low toxicity. However, the in silico studies were conducted using a class III phosphoinositide 3-kinase (VPS34) catalytic domain as a structural surrogate to explore conserved PI3K family binding features. Therefore, these computational results highlight E-CMPC as a promising in silico lead candidate, warranting further experimental validation as a PI3Kα-targeted anticancer agent.