Phytochemical investigation and anti-inflammatory potential of Atriplex leucoclada Boiss.

BACKGROUND: The plant kingdom has long been considered a valuable source for therapeutic agents, however, some plant species still untapped and need to be phytochemically and biologically explored. Although several Atriplex species have been investigated in depth, A. leucoclada, a halophytic plant native to Saudi Arabian desert, remains to be explored for its phytochemical content and biological potentials. Herein, the current study investigated the metabolic content and the anti-inflammatory potential of A. leucoclada. METHODS: Powdered aerial parts of the plant were defatted with n-hexane then the defatted powder was extracted with 80% methanol. n-Hexane extract (ATH) was analyzed using GC-MS, while the defatted extract (ATD) was subjected to different chromatographic methods to isolate the major phytoconstituents. The structures of the purified compounds were elucidated using different spectroscopic methods including advanced NMR techniques. Anti-inflammatory activity of both extracts against COX-1 and COX-2 enzymes were examined in vitro. Molecular docking of the identified compounds into the active sites of COX-1 and COX-2 enzymes was conducted using pdb entries 6Y3C and 5IKV, respectively. RESULTS: Phytochemical investigation of ATD extract led to purification and identification of nine compounds. Interestingly, all the compounds, except for 20-hydroxy ecdysone (1), are reported for the first time from A. leucoclada, also luteolin (6) and pallidol (8) are isolated for the first time from genus Atriplex. Inhibitory activity of ATD and ATH extracts against COX-1 and COX-2 enzymes revealed concentration dependent activity of both fractions with IC50 41.22, 14.40 µg/ml for ATD and 16.74 and 5.96 µg/ml for ATH against COX-1 and COX-2, respectively. Both extracts displayed selectivity indices of 2.86 and 2.80, respectively as compared to 2.56 for Ibuprofen indicating a promising selectivity towards COX-2. Molecular docking study supported in vitro testing results, where purified metabolites showed binding affinity scores ranged from -9 to -6.4 and -8.5 to -6.6 kcal/mol for COX-1 and 2, respectively, in addition the binding energies of GC-MS detected compounds ranged from -8.9 to -5.5 and -8.3 to -5.1 kcal/mol for COX-1 and 2, respectively as compared to Ibuprofen (-6.9 and -7.5 kcal/mol, respectively), indicating high binding affinities of most of the compounds. Analysis of the binding orientations revealed variable binding patterns depending on the nature of the compounds. Our study suggested A. leucoclada as a generous source for anti-inflammatory agents.

Phthalazone tethered 1,2,3-triazole conjugates: In silico molecular docking studies, synthesis, in vitro antiproliferative, and kinase inhibitory activities.

New phthalazone tethered 1,2,3-triazole derivatives 12-21 were synthesized utilizing the Cu(I)-catalyzed click reactions of alkyne-functionalized phthalazone 1 with functionalized azides 2-11. The new phthalazone-1,2,3-triazoles structures 12-21 were confirmed by different spectroscopic tools, like IR; 1H, 13C, 2D HMBC and 2D ROESY NMR; EI MS, and elemental analysis. The antiproliferative efficacy of the molecular hybrids 12-21 against four cancer cell lines was evaluated, including colorectal cancer, hepatoblastoma, prostate cancer, breast adenocarcinoma, and the normal cell line WI38. The antiproliferative assessment of derivatives 12-21 showed potent activity of compounds 16, 18, and 21 compared to the anticancer drug doxorubicin. Compound 16 showed selectivity (SI) towardthe tested cell lines ranging from 3.35 to 8.84 when compared to Dox., that showed SI ranged from 0.75 to 1.61. Derivatives 16, 18 and 21 were assessed towards VEGFR-2 inhibitory activity and result in that derivative 16 showed the potent activity (IC50 = 0.123 µM) in comparison with sorafenib (IC50 = 0.116 µM). Compound 16 caused an interference with the cell cycle distribution of MCF7 and increased the percentage of cells in S phase by 1.37-fold. In silico molecular docking of the effective derivatives 16, 18, and 21 against vascular endothelial growth factor receptor-2 (VEGFR-2) confirmed the formation of stable protein-ligand interactions within the pocket.