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

Abstract

A series of new pyrazolopyranopyrimidine derivatives (<b>3-9</b>) were synthesized from 5-amino-2,4-dihydro-3-methyl-4-phenylpyrano-[2,3-c]pyrazole-5-carbonitrile <b>(2)</b> by multicomponent reactions (MCR) involving malononitrile, benzaldehyde, and pyrazolone under refluxing ethanol in the presence of piperidine. Compound <b>(2)</b> was then converted to 2-acetylpyrazolopyranopyrimidine (<b>3)</b> through a reaction with acetic anhydride. The deprotection of <b>3</b> using ammonium hydroxide in ethanol, leads to <b>4</b>. Subsequent chlorination of <b>4</b> by phosphorus oxychloride affords <b>5</b> which was alkylated using methyl iodide and ethyl bromoacetate in DMF, leading to regioisomers <b>6</b>-<b>9</b>. The products were characterized by spectroscopic techniques (¹H and ¹³C NMR) and confirmed by single crystal X-ray diffraction (XRD) studies for <b>2</b>, <b>5</b>, <b>6,</b> and <b>9</b>. Moreover, the geometrical parameters, molecular orbital calculations, and spectral data of <b>2</b>, <b>5</b>, <b>6,</b> and <b>9</b> 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 <b>2</b>, <b>5</b>, <b>6,</b> and <b>9</b> were studied by Hirshfeld surface analysis. In addition, the molecular docky study was conducted to investigate the binding patterns of <b>2</b>, <b>5</b>, <b>6,</b> and <b>9</b> within the binding site of cyclin-dependent kinase 2 <b>(</b>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 <b>5</b>.Communicated by Ramaswamy H. Sarma.