Synthesis, Anti-inflammatory Activity, Molecular Docking and ADMET Study of Pyrazolo-phthalazine Derivatives

Abstract

We herein disclose a simple, efficient, and straightforward one-pot multicomponent approach for the synthesis of 1 H -pyrazolo[1,2- b ]phthalazine-5,10-dione derivatives through the reaction of substituted aldehydes, malononitrile, and phthalhydrazide in H₂O-EtOH (8:2) at 80 °C, using boric acid as an inexpensive and environmentally benign promoter. The highlights of the present method include a non-toxic, easily available and cost-effective compound. The desired products were obtained in a shorter reaction time with good to excellent yields, simple purification without chromatography and an environmentally benign aqueous solvent system. All synthesized compounds were evaluated for anti-inflammatory activity using the protein denaturation method. Compounds 5a , 5d , 5e and 5i showed excellent anti-inflammatory activities. The in vitro anti-inflammatory results were further validated by computational approaches, including in silico ADMET profiling, drug-likeness prediction, and molecular docking studies. In silico analysis demonstrated that all compounds met Veber’s Rule and Lipinski's Rule of Five criteria and exhibited high binding affinities for bovine xanthine oxidase ( PDB ID: 3NVY ), highest for 5d (-8.0 Kcal/mol) and lowest for 5g (-7.1 Kcal/mol). Collectively, these findings underscore the efficacy and robustness of the methodology employed.

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