Synthesis, Characterization, Molecular Docking, and In Silico ADMET Analysis of Newly Bioactive Pyrazolophosphonate and Spiro-Pyrazole Derivatives

Abstract

Introduction: This study presents an efficient and simple method for synthesizing novel bioactive organophosphorus compounds 4 and 5 via a three-component condensation reaction of aminophenylpyrazolinone, an aromatic aldehyde, and triethyl phosphite, using L-proline as the organocatalyst. Furthermore, a series of spiro-pyrazolone derivatives was successfully obtained by a simple condensation reaction between aminophenylpyrazolinone and various aromatic aldehydes. In addition, molecular docking studies demonstrated that all compounds effectively interact with the target protein's active site, forming stable ligand–protein complexes. ADMET analysis against E. coli also reveals favorable pharmacokinetic properties for most compounds. However, compounds 6a, 6g, and 7j show potential toxicity, which may limit their applicability as drugs. Methods: 3-amino-1-phenyl-2-pyrazolin-5-one, aromatic aldehydes, and triethyl phosphite were used in condensation reactions and Kabachnik–Fields/Pudovik-type reactions to create the compounds. HRMS and NMR (1H, 13C, 2D) were used for characterization. Pharmacokinetic characteristics were predicted using pKCSM, and binding affinities were evaluated using molecular docking with the E. coli protein 1FJ4. Results: The produced compounds showed stable docking conformations and strong binding affinities (-7.0 to -9.2 kcal/mol). The compounds with the best interaction profiles were 6d, 6e, 6f, and 7i. Compounds 6a, 6g, and 7j showed potential toxicity, but ADMET analysis indicated good intestinal absorption and acceptable metabolism. Discussion: The synthetic method worked well and did not harm the environment. Several derivatives show promising pharmacological potential, as indicated by docking and ADMET results. Conclusion: This study introduces a simple synthesis of biologically active pyrazolophosphonate and spiro-pyrazole derivatives with promising antibacterial and pharmacokinetic profiles, highlighting compounds 6d, 6e, 6f, and 7i as potential drug candidates.