Synthesis, X-Ray Diffraction, Spectroscopic Characterization, Hirshfeld Surface Analysis, Molecular Docking Studies, and DFT Calculation of New Pyrazolone Derivatives

Pyrazolones derivatives are known for their pharmaceutical and therapeutic activities. In this regard, some new pyrazolone derivatives have been synthesized using cyclocondensation, nucleophilic substitution, and alkylation reactions. Their corresponding structures were elucidated using X-ray diffraction and NMR spectroscopic techniques. The experimental spectral data were compared with the predicted ones obtained at the B3LYP/6-311++G(d,p) level of theory. Geometrical parameters and chemical shifts are relatively well reproduced with correlation coefficients higher than 90%. The intercontacts in crystal units were investigated by the analysis of their corresponding Hirshfeld surfaces and fingerprint maps, which reveal that the major contacts are found for H…H intercontacts. Finally, the inhibition efficiency of the novel pyrazolone derivatives as SARS-CoV-2 Mpro is estimated by determining their binding affinities into the binding site of SARS-CoV-2 Mpro. The docking results reveal that the current pyrazolone derivatives may act as potent inhibitors of SARS-CoV-2 Mpro and that their inhibition efficiency may be strongly influenced by the substituted functional groups of pyrazolone moiety. Synthesis of new 4-Substituted Pyrazolone derivativesGood correlations are obtained between the spectra and X-ray data with the predicted ones.Hirshfeld surface analysis is used to analyze intermolecular interaction.3D molecular structure is characterized using x-Ray and spectroscopic techniques.Interactions for of the newly synthesized compounds 2b, 3b, 3a, and 4 docked SARS-CoV-2 Mpro/PDB: 6LU7-A chain protein. Synthesis of new 4-Substituted Pyrazolone derivatives Good correlations are obtained between the spectra and X-ray data with the predicted ones. Hirshfeld surface analysis is used to analyze intermolecular interaction. 3D molecular structure is characterized using x-Ray and spectroscopic techniques. Interactions for of the newly synthesized compounds 2b, 3b, 3a, and 4 docked SARS-CoV-2 Mpro/PDB: 6LU7-A chain protein.</p

Chalcone-based imidazo[2,1-<i>b</i>]thiazole derivatives: synthesis, crystal structure, potent anticancer activity, and computational studies

In this work, two novel chalcone-based imidazothiazole derivatives ITC-1 and ITC-2 were synthesized and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry with electrospray ionization, and chemical structure of ITC-1 was confirmed by single-crystal X-ray diffraction. Also, the anticancer activity of ITC-1 and ITC-2 was evaluated. First, antiproliferative activity tests were performed against cancer cells namely, human-derived breast adenocarcinoma (MCF-7), lung carcinoma (A-549), and colorectal adenocarcinoma (HT-29) cell lines, and mouse fibroblast healthy cell line (3T3-L1) by XTT assay. Afterward, mitochondrial membrane disruption (MMP), caspase activity, and apoptosis tests were performed on MCF-7 cells to elucidate the anticancer mechanism of action of the test compounds by flow cytometry analysis. XTT results revealed that both compounds exhibited a very high degree of antiproliferative effects on each tested cancer cell line with very low IC50 values while showing much lower antiproliferation on 3T3-L1 normal cells with much higher IC50 values. Besides, ITC-2 was determined to have a striking cytotoxic power competing with the chemotherapeutic drug carboplatin. Flow cytometry results demonstrated the mitochondrial-mediated apoptotic effects of both compounds through membrane disruption and multi-caspase activation in MCF-7 cells. Finally, molecular docking studies were performed to determine the structural understanding of the test compounds by their interactions on caspase-3 and DNA dodecamer enzymes, respectively. The interactions between the compound and the crystal structure were determined according to parameters such as free binding energies (ΔGBind), Glide score values, and determination of the active binding site. The obtained data suggest that ITC-1 and ITC-2 may be considered remarkable anticancer drug candidates. In addition to molecular docking via in silico approaches, the pharmacokinetic properties of compounds ITC-1 and ITC-2 were calculated using the Schrödinger 2021-2 Qikprop wizard. Communicated by Ramaswamy H. Sarma</p

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</p