Design, synthesis, and biological investigation of oxadiazolyl, thiadiazolyl, and pyrimidinyl linked antipyrine derivatives as potential non-acidic anti-inflammatory agents

A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (4a-d), 1,3,4-thiadiazoles (6a-d), and pyrimidines (8a-d), was preparedand assessed for its potential in vitro COX-2 inhibitors. Compared to Celecoxib, compounds 4b-d and 8d were the most potent derivatives c with a half-maximal inhibitory concentration range of 53-69 nM. Considering COX-2 selectivity index, compounds 4 b and 4c were chosen among these most potent derivatives for further investigation. The in vivo ability of compounds 4 b and 4c to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations

Numerical modelling of 2-dimensional shallow-water flows

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Detailed Experimental and In Silico Investigation of Indomethacin Binding with Human Serum Albumin Considering Primary and Secondary Binding Sites

The interaction of indomethacin with human serum albumin (HSA) has been studied here considering the primary and secondary binding sites. The Stern–Volmer plots were linear in the lower concentration range of indomethacin while a downward curvature was observed in the higher concentration range, suggesting the presence of more than one binding site for indomethacin inside HSA due to which the microenvironment of the fluorophore changed slightly and some of its fraction was not accessible to the quencher. The Stern–Volmer quenching constants (KSV) for the primary and secondary sites were calculated from the two linear portions of the Stern–Volmer plots. There was around a two-fold decrease in the quenching constants for the low-affinity site as compared to the primary binding site. The interaction takes place via a static quenching mechanism and the KSV decreases at both primary and secondary sites upon increasing the temperature. The binding constants were also evaluated, which show strong binding at the primary site and fair binding at the secondary site. The binding was thermodynamically favorable with the liberation of heat and the ordering of the system. In principle, hydrogen bonding and Van der Waals forces were involved in the binding at the primary site while the low-affinity site interacted through hydrophobic forces only. The competitive binding was also evaluated using warfarin, ibuprofen, hemin, and a warfarin + hemin combination as site markers. The binding profile remained unchanged in the presence of ibuprofen, whereas it decreased in the presence of both warfarin and hemin with a straight line in the Stern–Volmer plots. The reduction in the binding was at a maximum when both warfarin and hemin were present simultaneously with the downward curvature in the Stern–Volmer plots at higher concentrations of indomethacin. The secondary structure of HSA also changes slightly in the presence of higher concentrations of indomethacin. Molecular dynamics simulations were performed at the primary and secondary binding sites of HSA which are drug site 1 (located in the subdomain IIA of the protein) and the hemin binding site (located in subdomain IB), respectively. From the results obtained from molecular docking and MD simulation, the indomethacin molecule showed more binding affinity towards drug site 1 followed by the other two sites

Crystal structure of ethyl 4-{[5-(adamantan-1-yl)-2-sulfanylidene-2,3-dihydro-1,3,4-oxadiazol-3-yl]methyl}piperazine-1-carboxylate, C20H30N4O3S

C20H30N4O3S, orthorhombic, P212121 (no. 19), a = 7.7152(3) Å, b = 10.6132(2) Å, c = 25.5990(7) Å, V = 2096.12(11) Å3, Z = 4, Rgt(F) = 0.0579, wRref(F2) = 0.1216, T = 293 K. CCDC no.: 222080

Crystal structure of ethyl 4-{[5-(adamantan-1-yl)-2-sulfanylidene-2,3-dihydro-1,3,4-oxadiazol-3-yl]methyl}piperazine-1-carboxylate, C20H30N4O3S

C20H30N4O3S, orthorhombic, P212121 (no. 19), a = 7.7152(3) Å, b = 10.6132(2) Å, c = 25.5990(7) Å, V = 2096.12(11) Å3, Z = 4, Rgt(F) = 0.0579, wRref(F2) = 0.1216, T = 293 K. CCDC no.: 2220806 The molecular structure is shown in the figure. Table 1 contains crystallographic data and Table 2 contains the list of the atoms including atomic coordinates and displacement parameters.Deanship of Scientific Research at Jouf University under grant no. DSR-2021-01-03116.Peer reviewe

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity

In the current medical era, spirooxindole motif stands out as a privileged heterospirocyclic scaffold that represents the core for a wide range of bioactive naturally isolated products (such as Strychnofoline and spirotryprostatins A and B) and synthetic compounds. Interestingly, no much attention has been paid to develop spirooxindole derivatives with dual antioxidant and anticancer activities. In this context, a series of spirooxindoles 6a-p was examined for their anticancer effect towards HepG2 hepatocellular carcinoma and PC-3 prostate cancer cell lines. Spirooxindole 6a was found to be an efficient anti-proliferative agent towards both HepG2 and PC-3 cells (IC50 = 6.9 and 11.8 µM, respectively). Afterwards, spirooxindole 6a was assessed for its apoptosis induction potential in HepG2 cells, where its pro-apoptotic impact was approved via the significant elevation in the Bax/Bcl-2 ratio and the expression levels of caspase-3

Lyophilized equine platelet-rich plasma (L-GFequina) antagonize the Reproductive toxicity and oxidative stress Induced by Cyclophosphamide in female rats

Abstract Background The antineoplastic agent Cyclophosphamide (CP) induces reproductive toxicity. New strategies for protecting ovarian tissue damage in women with chemotherapy-induced reproductive toxicity are essential. This study was designed to evaluate the possible protective effect of combined treatment with L-GFequina on CP-induced reproductive toxicity in the mature female rat. Methodology Forty mature female rats were assigned into four groups: First group, control: rats were intraperitoneally injected (IP) with 200 µl sterile saline solution on days 1 and 10; Group 2 (CP): were IP injected with 75 mg/kg on days 1 and 10 to induce POI); Group 3 (CP + L-GFequina): as in group 2 + IP injected with 200 µl rehydrated L-GFequina half-hour after CP injection on day 1 and 10); Group 4 (L-GFequina): rats were IP injected with 200 µl L-GFequina on day 1 and 10). Blood samples were collected for a complete blood picture and determinations of nitric oxide and malondialdehyde. Animals were sacrificed on Day-21, and genitalia was dissected, weighed, and fixed in 10% formalin for histopathological and morphometric evaluation. Results On day 21 of the experiment, body weight, ovarian parameters (Ovarian weight, uterine weight, the number of ovarian follicles, and corpora lutea (CL) were determined, and histopathological changes, blood profile, as well as antioxidant activity assessment, were performed. CP significantly suppresses ovarian and uterine functions and increased MAD, NO levels, RBCs, hemoglobin, WBCs, and platelet count compared to the control group ( P < 0.05). While, in CP + L-GFequina group, gross, histomorphometry parameters, blood, and biochemical markers were similar to that in the control. IP injection of L-GFequina alone significantly (P < 0.05) increased body weight, and ovarian and uterine morphometry compared with the control. Conclusion co-administration of L-GFequina with CP might protect the reproductive organs in rats through its high antioxidant capacity