Synthesis, crystal structure, spectroscopic characterization, DFT calculations, Hirshfeld surface analysis, molecular docking, and molecular dynamics simulation investigations of novel pyrazolopyranopyrimidine derivatives.

A series of new pyrazolopyranopyrimidine derivatives (3-9) were synthesized from 5-amino-2,4-dihydro-3-methyl-4-phenylpyrano-[2,3-c]pyrazole-5-carbonitrile (2) by multicomponent reactions (MCR) involving malononitrile, benzaldehyde, and pyrazolone under refluxing ethanol in the presence of piperidine. Compound (2) was then converted to 2-acetylpyrazolopyranopyrimidine (3) through a reaction with acetic anhydride. The deprotection of 3 using ammonium hydroxide in ethanol, leads to 4. Subsequent chlorination of 4 by phosphorus oxychloride affords 5 which was alkylated using methyl iodide and ethyl bromoacetate in DMF, leading to regioisomers 6-9. The products were characterized by spectroscopic techniques (1H and 13C NMR) and confirmed by single crystal X-ray diffraction (XRD) studies for 2, 5, 6, and 9. Moreover, the geometrical parameters, molecular orbital calculations, and spectral data of 2, 5, 6, and 9 were compared by DFT at the B3LYP/6-311G(d,p) level of theory. There is good agreement between the calculated results and the experimental data. The intermolecular contacts for 2, 5, 6, and 9 were studied by Hirshfeld surface analysis. In addition, the molecular docky study was conducted to investigate the binding patterns of 2, 5, 6, and 9 within the binding site of cyclin-dependent kinase 2 (CDK2) and penicillin-binding protein 1 A. After the docking process, molecular dynamics (MD) simulations for 100 ns were performed on CDK2 and PBP 1 A proteins in the complex with 5.Communicated by Ramaswamy H. Sarma.