Genotoxic effects and mitosis aberrations of chromium (VI) on root cells of Vicia faba and its molecular docking analysis.

Like other heavy metals, Cr (VI) is a powerful carcinogen and mutagen agent. Its toxic effects on plants are well considered. In order to elucidate its adverse effects, the present work aims to study the mitosis aberrations of Cr (VI) on the Vicia faba root-cells and its molecular docking analysis to understand the genotoxicity mechanisms. In-vivo, Vicia faba plants were exposed to 50 and 100 µM Cr (VI) for 48 h. In-silico, molecular docking and molecular dynamics simulation were used to study the interactions between dichromate and tubulin tyrosine ligase T2R-TTL (PDBID: 5XIW) with reference to Colchicine (microtubule inhibitor). According to our results, Cr (VI) affects growth and cell division and also induces many mitosis aberrations such as chromosome sticking, anaphase/telophase bridges, lagging chromosomes and fragmentation during all phases of mitosis. On the one hand, Cr (VI) reduces mitotic index and promotes micronuclei induction. The in-silico results showed that dichromate establishes very strong bonds at the binding site of the tubulin tyrosine ligase T2R-TTL, with a binding affinity of -5.17 Kcal/Mol and an inhibition constant of 163.59 µM. These interactions are similar to those of colchicine with this protein, so dichromate could be a very potent inhibitor of this protein's activity. TTL plays a fundamental role in the tyrosination/detyrosination of tubulin, which is crucial to the regulation of the microtubule cytoskeleton. Its inhibition leads to the appearance of many morphogenic abnormalities such as mitosis aberrations. In conclusion, our data confirm the highest genotoxicity effects of Cr (VI) on Vicia faba root-cells.

Design, synthesis, In-vitro, In-silico and DFT studies of novel functionalized isoxazoles as antibacterial and antioxidant agents.

A series of new isoxazolederivatives incorporating the sulfonate ester function has been synthesized from 2-benzylidenebenzofuran-3(2 H)-one, known as aurone. The synthesis of the target compounds was carried out following an efficient methodology that allows access to the desired products in a reproducible way and with good yield. The structures of the synthesized compounds were established using NMR (1H and 13C) spectroscopy and mass spectrometry. A theoretical study was performed to optimize the geometrical structures and to calculate the structural and electronic parameters of the synthesized compounds. The calculations were also carried out to understand the influence and the effect of substitutions on the chemical reactivity of the studied compounds. The synthesized isoxazoles were screened for their antioxidant and antibacterial activities. The findings demonstrate that the studied compounds exhibit good to moderate antibacterial activity against the tested bacteria (Staphylococcus aureus, Bacillus subtilis, and Escherichia coli). Moreover, a number of the tested isoxazole derivatives exhibit high effectiveness against DPPH free radicals. Besides that, molecular docking studies were carried out to predict binding affinity and identify the most likely binding interactions between the active molecules and the target microorganisms' proteins. A 100 ns molecular dynamics study was then conducted to examine the dynamic behavior and stability of the highly potent isoxazole 4e in complex with the target bacterial proteins. Finally, the ADMET analyses suggest that all the synthesized isoxazoles have good pharmacokinetic profiles and non-toxicity and non-carcinogenicity in biological systems.

In vitro and in silico analysis for elucidation of antioxidant potential of Djiboutian Avicennia Marina (Forsk.) Vierh. phytochemicals.

The present work aims to study the phytochemical composition, the antioxidant capacity of the crude extracts, and the fraction of extract giving the best antioxidant activity of Avicennia marina. The leaves contain high TFC compared to other parts of the plant, whereas fruits have the highest amount of TPC. Fat-soluble pigments are strongly present in the leaves of Avicennia marina i.e. ß-carotene, lycopene, chlorophyll a, and chlorophyll b. The crude methanolic flower extracts showed strong DPPH and ABTS radical scavenging activity with IC50 values of 0.30 and 0.33 mg/mL respectively compared to the leaf and stem methanolic extracts for the DPPH and ABTS models with a value IC50 greater than 1 mg/mL. The crude fruit extract shows good activity with the ABTS model, unlike the DPPH model whose IC50 values are 0.95 and 0.38 mg/mL, respectively. Fractionation improved the antioxidant effect of crude flower extract. The ethyl acetate fraction exhibits the best antioxidant activity for both DPPH and ABTS methods with IC50 values of 0.125 and 0.16 mg/mL. The HR-LCMS/MS led to the identification of 13 compounds: 6 flavonoids and 7 iridoid glycoside compounds in the different parts of the plant. A bioinformatics study was performed to evaluate the antioxidant activity of the three major Iridoid glycosides towards the target protein Catalase compound II through free binding energy. Out of these three iridoid glycosides, compound C10 does not represent any toxicity, unlike C8 and C9 which showed an irritancy effect. Furthermore, molecular dynamics shows good stability of the C10-2CAG complex. HighlightsExtraction and fractionation of different part (leaf, stem, flower and fruit) of Avicennia marina.Botanical description and phytochemical analysis of crude extract methanolic. Investigation by HR-LCMS characterization of polyphenols and iridoid glycosides.Evaluation the antioxidant activity of crudes extracts methanolics by two methods in vitro DPPH and ABTS.Antioxidant activity of the fraction of the crude flower extracts presenting the best biological response.Evaluate the contribution of three major compounds 2'-Cinnamoylmussaenosidic acid, 10-O-[E-Cinnamoyl]-geniposidic acid and 10-O-[(E)-p-Coumaroyl]-geniposidic acid in the ethyl acetate fraction on the antioxidant activity through docking and dynamic molecular.Communicated by Ramaswamy H. Sarma.

A computer-aided drug design approach to explore novel type II inhibitors of c-Met receptor tyrosine kinase for cancer therapy: QSAR, molecular docking, ADMET and molecular dynamics simulations.

Small molecules such as 4-phenoxypyridine derivatives have remarkable inhibitory activity against c-Met enzymatic activity and proliferation of cancer cell lines. Since there is a relationship between structure and biological activity of these molecules, these little compounds may have great potential for clinical pharmaceutical use against various types of cancer caused by c-Met activity. The purpose of this study was to remodel the structures of 4-phenoxypyridine derivatives to achieve strong inhibitory activity against c-Met and provide favorable pharmacokinetic properties for drug design and discovery. Therefore, this paper describes the structure-activity relationship and the rationalization of appropriate pharmacophore sites to improve the biological activity of the investigated molecules, based on bioinformatics techniques represented by a computer-aided drug design approach. Accordingly, robust and reliable 3D-QSAR models were developed based on CoMFA and CoMSIA techniques. As a result, 46 lead molecules were designed and their biological and pharmacokinetic activities were predicted in silico. Screening filters by 3D-QSAR, Molecular Docking, drug-like and ADME-Tox identified the computer-designed compounds P54 and P55 as the best candidates to achieve high inhibition of c-Met enzymatic activity compared to the synthesized template compound T14. Finally, through molecular dynamics simulations, the structural properties and dynamics of c-Met free and complex (PDB code: 3LQ8) in the presence of 4-phenoxypyridine-derived compounds in an aqueous environment are discussed. Overall, the rectosynthesis of the designed drug inhibitors (P54 and P55) and their in vitro and in vivo bioactivity evaluation may be attractive for design and discovery of novel drug effective to inhibit c-Met enzymatic activity.Communicated by Ramaswamy H. Sarma.