Zinc Chloride Catalyzed Multicomponent Synthesis of Pyrazolopyridocoumarin Scaffolds

An efficient synthesis of a series of pyrazolopyridocoumarins is reported by condensation of 4hydroxycoumarin, benzaldehydes and 1-alkyl-5-amino-pyrazoles in the presence of 10 mol% zinc chloride in ethanol under reflux conditions through one-pot reaction. The significant attraction of this protocol is being a simple procedure, mild reaction condition, and excellent yield. The molecular structure of the compound (4e) is established by single crystal X-ray structure determination

Synthesis of N1 and N2 coumarin substituted 1,​2,​3-​triazole isomers via click chemistry approach

The synthesis of N1 and N2 coumarin substituted 1,​2,​3-​triazole isomers from terminal alkynes, sodium azide, and 4-​bromomethylcoumarins in the presence of triethylamine as a base and CuI as a catalyst in good yield were reported. The mol. structure of compds. and were established by single-​crystal ana

Identificationof Small Molecule Inhibitors of HumanAs(III) S-Adenosylmethionine Methyltransferase(AS3MT)

Arsenic is the most ubiquitous environmental toxin and carcinogen. Long-term exposure to arsenic is associated with human diseases including cancer, cardiovascular disease, and diabetes. Human As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT) methylates As(III) to trivalent mono- and dimethyl species that are more toxic and potentially more carcinogenic than inorganic arsenic. Modulators of hAS3MT activity may be useful for the prevention or treatment of arsenic-related diseases. Using a newly developed high-throughput assay for hAS3MT activity, we identified 10 novel noncompetitive small molecule inhibitors. In silico docking analysis with the crystal structure of an AS3MT orthologue suggests that the inhibitors bind in a cleft between domains that is distant from either the As(III) or SAM binding sites. This suggests the presence of a possible allosteric and regulatory site in the enzyme. These inhibitors may be useful tools for future research in arsenic metabolism and are the starting-point for the development of drugs against hAS3MT

Structural, Quantum Chemical and Spectroscopic Investigations on Photophysical Properties of Fluorescent Saccharide Sensor: Theoretical and Experimental Studies

Structure, Hirshfeld surface, spectra and photophysical properties of boronic acid-based carbohydrate sensor (5-fluoro-2-methoxyphenyl) boronic acid (BA8) has been reported by experimental methods (XRD/FT-IR/UV/steady state fluorescence) and theoretically by Density functional theory (DFT) model with most accurate functionals (B3LYP/CAM-B3LYP/ M06-2X). The comparison of theoretical and experimental data exhibited good agreement. Natural bond orbital (NBO) and frontier molecular orbitals (FMOs) have been analysed. The sensing ability of the compound with carbohydrates (D-glucose and D-fructose) were studied by UV/fluorescence spectra. The variation of absorbance and fluorescence on pH was rationale with the estimated acid-base dissociation constants (pKa). Quantum yield (phi) and fluorescence lifetimes (tau) for the compound and its esters with sugars were calculated. The results of absorbance, fluorescence measurements and calculated photophysical properties indicated fairly selectivity of BA8 with fructose more than the glucose, which is ascertained from both experimental and theoretical results

Effect of o-difluoro and p-methyl substituents on the structure, optical properties and anti-inflammatory activity of phenoxy thiazole acetamide derivatives: Theoretical and experimental studies

Thiazole derivatives (6a and 6b) have been synthesized and characterised by H-1 - C-13 NMR, as well as LC-MS spectra. The three-dimensional structures have been confirmed by single crystal X-ray diffraction method. 6a and 6b compounds have been crystallized in the Triclinic and the Orthorhombic systems with P-1 and Pbca space groups, respectively. Supramolecular structures revealed the stability of molecules with different intermolecular interactions and different crystal packing environment. Theoretical study by Density functional theory (DFT) with B3LYP functional based on highest basis set 6-311++G(d,p) was employed to calculate the geometry and compared to the experimental data. The electronic structures and intramolecular charge transfers have been investigated by using natural population and natural bond orbital analysis (HBO). Further, DFT studies were performed to assess the frontier molecular orbitals (FMOs), energy gap, softness, hardness, and others chemical reactivity. Hirshfeld surface was investigated to distinguish the different interatomic contacts and understand the crystal packing of molecules with aid of energy frameworks through different intermolecular interaction energies based on the anisotropy of the topology. Nonlinear optical property (NLO) of the synthesized molecules were predicted by (DFT) and examined experimentally by using second harmonic generation (SHG) and revealed the importance of high NLO based on the nature of substituents and conformation. Thiazole derivatives were assessed for anti-inflammation activity by in silico molecular docking studies against COX-1 and COX-2 protein receptors revealed prominent interactions with active site and further molecular dynamics confirms the stability of the protein-ligand model. In vitro assay against cyclooxygenase (COX) enzyme gave IC50 values of 6a and 6b molecules with ortho-difluoro and para-methyl positions on benzoyl group, showed better inhibitor for COX-1 and COX-2, respectively. (C) 2019 Elsevier B.V. All rights reserved

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells

Nano-ZrO₂-Catalyzed Biginelli Reaction and the Synthesis of Bioactive Dihydropyrimidinones That Targets PPAR-γ in Human Breast Cancer Cells

Bioactive dihydropyrimidinones (DHPs) were designed and synthesized by a multicomponent Biginelli reaction. The reaction was catalyzed by the polarized surface of nano-zirconium dioxide with partial positive charge of 0.52e at the Zr center and a negative charge of −0.23e at the oxygen center. There was good corroboration between the computed and experimental ZrO2 cell parameters and bond distances as determined by in silico and in vitro experimental methods. Since DHPs were found to target the peroxisome proliferator-activated receptor (PPAR)-γ, we tested these ligands toward MCF-7 cell toxicity, which revealed that the compounds 4d [ethyl-4-(4′-fluoro-[1,1′-biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] and 4e [ethyl-4-(3′-methoxy-[1,1′-biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] inhibited proliferation with IC50 values of 11.8 and 15.8 μM, respectively. Further, our bioinformatic analysis found that the active molecule 4d, fit into the enzyme’s catalytic site, almost in the same position as rosiglitazone, which was buried deep inside the cavity. In conclusion, we herein report novel DHPs which could be better structures to help explore a new class of synthetic PPAR-γ ligands