Synthesis, docking, SAR and ADMET evaluation of novel pyrrolo[3,4-c]pyrazole-4,6-dione derivatives

Novel 1,6a-dihydropyrrolo[3,4-c]pyrazole-4,6(3aH,5 H)-dione derivatives were synthesized via the reaction of hydrazonoyl bromides with N-arylmaleimides and subsequently oxidized to pyrrolo[3,4-c]pyrazole-4,6(1 H,5 H)-diones. Molecular docking against the target protein (PDB ID: 4N9S) revealed that compounds 3c and 4c exhibited the highest binding affinities (- 7.45 and - 7.31 kcal/mol, respectively), forming stable π-cation and hydrogen-bond interactions with key residues (Arg176, Glu259, Tyr257). Structure-activity relationship analysis indicated that electron-donating substituents enhanced the predicted biological activity. In silico ADMET profiling demonstrated 100% intestinal absorption, favorable distribution, and absence of toxicity, confirming the compounds' potential as promising therapeutic leads.