Synthesis, structural characterization, and ADMET analysis of new pyrazol-pyrimidine derivatives

• Published in: Journal of molecular structure 2025-03, Vol.1325, p.140939, Article 140939
• Main Authors: Mladenović, Tamara M., Matejić, Vesna M., Novaković, Slađana B., Bogdanović, Goran A., Milenković, Dejan A., Avdović, Edina H., Antonijević, Marko R., Marković, Zoran S., Simijonović, Dušica M.
• Format: Article
• Language: English
• Subjects: ADMET analysis; Barbituric acid; Density functional theory; Pyrazol-pyrimidine derivatives; Structural characterization; X-ray diffraction
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140939

•Green synthesis of six novel pyrazol-pyrimidine derivatives was achieved.•Structures of examined derivatives were confirmed by X-ray, NMR, IR, and DFT.•New crystal structure of compound 4a was determined and analyzed.•The pharmacokinetic profile of obtained compounds was established.•Molecular docking confirmed inhibitory potential of investigated compounds. New pyrazol-pyrimidine derivatives were obtained starting from pyrazolone, barbituric acid, and different substituted benzaldehydes, by reflux in a mixture of ethanol/water (1:1) as a solvent and without any catalyst. All isolated products were characterized by employing various techniques, including melting point, elemental analysis, IR, and NMR spectroscopy. Experimentally obtained IR and NMR spectra of all pyrazol-pyrimidine derivatives were compared to the simulated ones acquired with TD-DFT. The obtained results show that there is a very good agreement between the theoretical and recorded spectra. Moreover, the structure of 5-((4-fluorophenyl)(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)methyl)-6-hydroxypyrimidine-2,4(1H,3H)‑dione was explained using single-crystal X-ray diffraction analysis. It was shown that a barbiturate ring plays a dominant role in the formation of strong intramolecular hydrogen bond with pyrazole moiety and the mutual interconnection of molecules in crystal packing. Pyrazol-pyrimidine derivatives have the capacity to exist in various keto and enol tautomer forms which can be converted into the matching zwitterion. This finding is confirmed by experimental and theoretical results. Additionally, this study explores the pharmacokinetic profile of obtained compounds and the inhibitory activities of selected compounds against Human Carbonic Anhydrase II using molecular docking simulations. [Display omitted]