Synthesis, Characterization, DFT, and In Silico Investigation of Two Newly Synthesized ß-Diketone Derivatives as Potent COX-2 Inhibitors.

Despite extensive genetic and biochemical characterization, the molecular genetic basis underlying the biosynthesis of ß-diketones remains largely unexplored. ß-Diketones and their complexes find broad applications as biologically active compounds. In this study, in silico molecular docking results revealed that two ß-diketone derivatives, namely 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione and 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione, exhibit anti-COX-2 activities. However, recent docking results indicated that the relative anti-COX-2 activity of these two studied ß-diketones was influenced by the employed docking programs. For improved design of COX-2 inhibitors from ß-diketones, we conducted molecular dynamics simulations, density functional theory (DFT) calculations, Hirshfeld surface analysis, energy framework, and ADMET studies. The goal was to understand the interaction mechanisms and evaluate the inhibitory characteristics. The results indicate that 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione shows greater anti-COX-2 activity compared to 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione.

Crystal structure, Hirshfeld surface analysis and DFT study of (5E,5'E,6Z,6'Z)-6,6'-[ethane-1,2-diyl-bis(aza-nylyl-idene)]bis-{5-[2-(4-fluoro-phen-yl)hydra-zono]-3,3-di-methyl-cyclo-hexa-none} 2.5-hydrate.

The title compound, C30H34F2N6O2·2.5H2O, was obtained by condensation of 2-[2-(4-fluoro-phen-yl)hydrazono]-5,5-di-methyl-cyclo-hexan-1,3-dione with ethyl-enedi-amine in ethanol and crystallized as a 1:2.5 hydrate in space group C2/c. The two independent mol-ecules, with approximate crystallographic C 2 symmetries, have different conformations and packing environments, are stabilized by intra-molecular N-H⋯N hydrogen bonds and linked by O-H⋯O hydrogen bonds involving the water mol-ecules. A Hirshfeld surface analysis showed that H⋯H contacts make by far the largest (48-50%) contribution to the crystal packing. From DFT calculations, the LUMO-HOMO energy gap of the mol-ecule is 0.827 eV.

Computational Binding Analysis of Ethyl 3,3,5,5-Tetracyano-2-Hydroxy-2-Methyl-4,6-Diphenylcyclohexane-1-Carboxylate in Calf Thymus DNA.

In the present paper, several computational binding analyses were performed on ethyl 3,3,5,5-tetracyano-2-hydroxy-2-methyl-4,6-diphenylcyclohexane-1-carboxylate which was newly synthesized by three-component condensation of benzaldehyde with ethyl acetoacetate and malononitrile in the presence of trichloroacetic acid, and the structure was finally proved by X-ray analysis. The visualization of molecular interaction was carried out through Hirshfeld surface analysis and ESP. The atomic charges, HOMO, LUMO, and electrostatic potential were also studied to explore the insight of the molecule deeper, and then, natural bonding orbitals (NBO) and non-linear optical properties (NLO) were calculated to reveal the interactions that happen to be between the filled and vacant orbitals. Afterwards, molecular docking studies predicted the compound binding mode fits in the minor groove of DNA and remained interacts via stable bonding as validated by molecular dynamics simulations. The binding energy estimation also affirmed domination van der Waals and electrostatic energies. Lastly, the compound was found as good drug-like molecule and had good pharmacokinetic profile with exception of toxic moieties.

Synthesis, crystal structure, and biological evaluation of optically active 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-3-carbonitriles: Antiepileptic, antidiabetic, and anticholinergics potentials.

In the presence of chiral organic catalysts, the optically active 4H-chromine was synthesized from the multicomponent condensation of 5,5-dimethylcyclohexane-1,3-dione with malononitrile and methylene-active compound, and the specific angle of rotation of the compounds was determined in the AUTOPOL-III polarimeter and their structures were confirmed by the X-ray spectroscopic analysis method. These optically active 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-3-carbonitriles were effective inhibitors of α-glycosidase, the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with Ki values in the range of 21.33 ± 1.11 to 40.24 ± 10.78 µM for hCA I, 28.91 ± 6.51 to 59.97 ± 15.62 µM for hCA II, 18.16 ± 3.18 to 66.57 ± 1.36 µM for α-glycosidase, and 8.68 ± 0.93 to 102.61 ± 24.96 µM for AChE.