Development of novel chromones as antioxidant COX2 inhibitors: in vitro, QSAR, DFT, molecular docking, and molecular dynamics studies.

The chromone derivatives are playing a prominent role in many plant cycles, for instance, the regulation of growth, stimulation of oxygen uptake in plants, and essential food constituents with valuable pro-health properties. Determination of the antioxidant activity of these compounds is an interesting approach to drug design and development. The antioxidant activity of the novel fifteen chromone compounds was estimated by using a spectrophotometric Dichloro-5,6-dicyano 1,4-benzoquinone (DDQ) assay method and the mechanism of antioxidant activity was discussed based on the Density functional theory (DFT) calculations. The compounds showed significant antioxidant activity which was correlated to their molecular structure by considering various molecular descriptors. Further, by using regression analysis QSAR-modeled equation was proposed and it has shown a high correlation coefficient value (0.946. We perform molecular docking and molecular dynamics simulations against the cyclooxygenase (COX2) enzyme to investigate the molecule's anti-inflammatory activity and stability of protein-ligand complexes. Molecular docking and dynamics simulations revealed the compounds B3 and B8 were interacting with essential residues TYR385, HIS386, ASN382, TRP387, and HIS388 in the binding site that were crucial for optimizing heme and the resultant peroxidase and cyclooxygenase activities. The root mean square displacement and root mean square fluctuation plots revealed the stability of the B3-COX2 and B8-COX2 complexes. Based on our results, B3 and B8 compounds are considered as best antioxidants as well as COX2 inhibitors.Communicated by Ramaswamy H. Sarma.

Charge Transfer Complex between O-Phenylenediamine and 2, 3-Dichloro-5, 6-Dicyano-1, 4-Benzoquinone: Synthesis, Spectrophotometric, Characterization, Computational Analysis, and its Biological Applications.

UV-vis electronic absorption spectroscopy was used to investigate the new molecular charge transfer complex (CTC) interaction between electron donor O-phenylenediamine (OPD) and electron acceptor 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). The CTC solution state analysis was carried out by two different polarities. The stoichiometry of the prepared CTC was determined by using Job's, photometric, and conductometric titration methods and was detemined to be 1:1 in both solvents (at 298 K). The formation constant and molar extinction coefficient were determined by applying the modified (1:1) Benesi-Hildebrand equation. The thermodynamic parameter ΔG° result indicated that the charge transfer reaction was spontaneous.The stability of the synthesized CTC was evaluated by using different spectroscopic parameters like the energy, ionization potential, oscillator strength, resonance energy, dissociation energy, and transition dipole moment. The synthesized solid CTC was characterized by using different analytical methods, including elemental analysis, Fourier transform infrared, nuclear magnetic resonance, TGA-DTA, and powder X-ray diffraction. The biological evolution of the charge transfer (CT) complex was studied by using DNA binding and antibacterial analysis. The CT complex binding with calf thymus DNA through an intercalative mode was observed from UV-vis spectral study. The CT complex produced a good binding constant value (6.0 × 105 L.mol-1). The antibacterial activity of the CT complex shows notable activity compared to the standard drug, tetracycline. These results reveal that the CT complex may in future be used as a bioactive drug. The hypothetical DFT estimations of the CT complex supported the experimental studies.

New Charge Transfer Complex between 4-Dimethylaminopyridine and DDQ: Synthesis, Spectroscopic Characterization, DNA Binding Analysis, and Density Functional Theory (DFT)/Time-Dependent DFT/Natural Transition Orbital Studies.

A combined experimental and theoretical study of the electron donor 4-dimethylaminopyridine (4-DMAP) with the electron acceptor 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) has been made in acetonitrile (ACN) and methanol (MeOH) media at room temperature. The stoichiometry proportion of the charge transfer (CT) complex was determined using Job's and photometric titration methods and found to be 1:1. The association constant (K CT), molar absorptivity (ε), and spectroscopic physical parameters were used to know the stability of the CT complex. The CT complex shows maximum stability in a high-polar solvent (ACN) compared to a less-polar solvent (MeOH). The prepared complex was characterized by Fourier transform infrared, NMR, powder X-ray diffraction, and scanning electron microscopy-energy-dispersive X-ray analysis. The nature of DNA binding ability of the complex was probed using UV-visible spectroscopy, and the binding mode of the CT complex is intercalative. The intrinsic binding constant (K b) value is 1.8 × 106 M-1. It reveals a primary indication for developing a pharmaceutical drug in the future due to its high binding affinity with the CT complex. The theoretical study was carried out by density functional theory (DFT), and the basis set is wB97XD/6-31G(d,p), with gas-phase and PCM analysis, which supports experimental results. Natural atomic charges, state dipole moments, electron density difference maps, reactivity parameters, and FMO surfaces were also evaluated. The MEP maps indicate the electrophilic nature of DDQ and the nucleophilic nature of 4-DMAP. The electronic spectrum computed using time-dependent DFT (TD-DFT) via a polarizable continuum salvation approach, PCM/TD-DFT, along with natural transition orbital analysis is fully correlated with the experimental outcomes.

High-throughput virtual screening, ADME analysis, and estimation of MM/GBSA binding-free energies of azoles as potential inhibitors of Mycobacterium tuberculosis H37Rv.

Isoniazid, also known as isonicotinyl hydrazide (INH), was used as a frontline drug to treat Mycobacterium tuberculosis. The in silico virtual screening is used to identify the effective inhibitor for CYP 121 of M. tuberculosis. Nearly, 10,000 triazole compounds from various databases have been virtually screened against CYP121 by using the module Glide. A total of 15 molecules with a better docking score compared to marketed drugs and cocrystal ligand were chosen for the MM/GBSA study to recheck the binding affinity. A total of five hit molecules which show significant binding-free energies were chosen for QikProp studies. The triazole molecules which contain 3-benzaimidine moiety interact with a heme cofactor and active site residues of CYP121. These protein-ligand complexes were taken to calculate the potential binding region of the ligand in the receptor using the solvent accessible surface area (SASA). The amino residues Phe168, Val228, Gln385, Trp182, Asp185, Val83, and heme 401 cofactor of the target protein are the important binding residues with the ligands. The in silico ADME studies for the ligand dataset are calculated to determine the druggability of the molecules.

Synthesis of new chromeno-carbamodithioate derivatives and preliminary evaluation of their antioxidant activity and molecular docking studies.

New chromeno carbamodithioates (7a-i), have been synthesized from 2, 3-dimethyl-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (5), carbondisulphide and commercially available acyclic and cyclic secondary amines in acetonitrile with good to excellent yields. The free radical scavenging activity of novel chromone-carbamodithioate analogues was quantitatively estimated by spectrophotometric method. Whereas, molecular docking studies were performed with the active site of cyclooxygenase-2 to identify hydrogen bonding, hydrophobic and ionic interactions between protein and ligands. The compounds 7g and 7h demonstrated potent antioxidant activity with IC50 of 1.405±0.019mM and 1.382±0.35mM respectively compared to Ascorbic acid.

DNA Cleavage, Cytotoxic Activities, and Antimicrobial Studies of Ternary Copper(II) Complexes of Isoxazole Schiff Base and Heterocyclic Compounds.

Novel mixed ligand bivalent copper complexes [Cu. L. A. ClO 4 ] and [Cu. L. A] where "L" is Schiff bases, namely 2-((3,4-dimethylisoxazol-5-ylimino)methyl)-4-bromophenol (DMIIMBP)/2-((3,4-dimethylisoxazol-5-ylimino)methyl)-4-chlorophenol (DMIIMCP), and "A" is heterocyclic compound, such as 1,10-phenanthroline (phen)/2,2(1)-bipyridyl (bipy)/8-hydroxyquinoline (oxine)/5-chloro-8-hydroxyquinoline (5-Cl-oxine), have been synthesized. These complexes have been characterized by IR, UV-Vis, ESR, elemental analysis, magnetic moments, TG, and DTA. On the basis of spectral studies and analytical data, five-coordinated square pyramidal/four-coordinated square planar geometry is assigned to all complexes. The ligands and their ternary complexes with Cu(II) have been screened for antimicrobial activity against bacteria and fungi by paper disc method. The antimicrobial studies of Schiff bases and their metal complexes showed significant activity and further it is observed that the metal complexes showed more activity than corresponding Schiff bases. In vitro antitumor activity of Cu(II) complexes was assayed against human cervical carcinoma (HeLa) cancer cells and it was observed that few complexes exhibit good antitumor activity on HeLa cell lines. The DNA cleavage studies have also been carried out on pBR 322 and it is observed that these Cu(II) complexes are capable of cleaving supercoiled plasmid DNA in the presence of H2O2 and UV light.