Design, synthesis and molecular modeling study of substituted indoline-2-ones and spiro[indole-heterocycles] with potential activity against Gram-positive bacteria.

Longstanding and firsthand infectious diseases are challenging community health threats. A new series of isatin derivatives bearing ß-hydroxy ketone, chalcone, or spiro-heterocycle moiety, was synthesized in a good yield. Chemical structures of the synthesized compounds were elucidated using spectroscopic techniques and elemental analysis. Antibacterial activities of the compounds were then evaluated in vitro and by in silico modeling. The compounds were more active against Gram-positive bacteria, Staphylococcus aureus (MIC = 0.026-0.226 mmol L-1) and Bacillus subtilis (MIC = 0.348-1.723 mmol L-1) than against Gram-negative bacteria (MIC = 0.817-7.393 mmol L-1). Only 3-hydroxy-3-(2-(2,5-dimethylthiophen-3-yl)-2-oxoethyl)indolin-2-one (1b) was found as active as imipenem against S. aureus (MIC = 0.026 mmol L-1). In silico docking of the compounds in the binding sites of a homology modeled structure of S. aureus histidine kinase-Walk allowed us to shed light on the binding mode of these novel inhibitors. The highest antibacterial activity of 1b is consistent with its highest docking score values against S. aureus histidine kinase.

Cholesterol-Conjugate as a New Strategy to Improve the Cytotoxic Effect of 5-Fluorouracil on Liver Cancer: Impact of Liposomal Composition.

PURPOSE: Hepatocellular carcinoma (HCC) is a common liver malignancy, which has a low survival rate of all cancers. 5-fluorouracil (5-FU) is clinically recognized to treat HCC. However, the success of this therapy is highly limited due to rapid clearance and non- selective distribution. Cholesterol- conjugate (5-FUC) loaded liposomes proposed to facilitate the transport of 5-FUC into tumor cells via Low-Density Lipoprotein receptor (LDL receptor) that overexpressed in HCC. Thus, the aim of this study was to use 5-FUC loaded liposome as a promising strategy to combat HCC and improve the response of HCC to chemotherapy. METHODS: 5-FUC and 5-FU loaded liposomes were optimized based on Cholesterol (CHO) ratio and type of phospholipid to achieve a potential effect on HCC. Liposomes were prepared by the thin-film hydration method, and evaluated in terms of particle size, polydispersity, zeta potential, Entrapment Efficiency (EE), morphology, drug release and cytotoxicity. RESULTS: The obtained liposomes had a suitable nano-range particle size with negative zeta potential, and acceptable EE%. In vitro drug release of 5-FUC loaded liposomes showed a lower cumulative release over 24 h as compared to 5-FU loaded liposomes. 5-FUC loaded liposomes exhibited a higher in vitro cytotoxic effect as compared to the free drug and 5-FU loaded liposomes against HepG2 cell lines after 48 h via MTT assay. CONCLUSION: These results concluded that 5-FUC loaded liposomes could be used as an alternative tactic to increase the therapeutic index of 5-FU and pave the way for potential clinical applications.

1, 3, 4-Thiadiazole and 1, 2, 4-triazole-3(4 H )-thione bearing salicylate moiety: synthesis and evaluation as anti- Candida albicans

Abstract Dramatically increased occurrence of both superficial and invasive fungal infections has been observed. Candida albicans appear to be the main etiological agent of invasive fungal infections. The anti-C. albicans activity of thiosemicarbazide, 1,3,4-Thiadiazole, and 1,2,4-triazole-3(4H)-thione compounds (compounds 3-23) were investigated. The MIC values of thiadiazole and triazole derivatives 10-23 were in the range of 0.08-0.17 µmol mL-1, while that of fluconazole was 0.052 µmol mL-1. Compound 11 (5-(2-(4-chlorobenzyloxy)phenyl)-N-allyl-1,3,4-thiadiazol-2-amine) and compound 18 (5-(2-(4-chlorobenzyloxy)phenyl)-4-allyl-2H-1,2,4-triazole-3(4H)-thione) were found to be the most active compounds, with MIC values of 0.08 µmol mL-1. The newly synthesized thiadiazole and triazole compounds (compounds 10-23) showed promising anti-Candida activity. The allyl substituent-bearing compounds 11 and 18 exhibited significant anti-Candida albicans activity and showed a binding mode as well as the fluconazole x-ray structure.

Pharmacophore elucidation and molecular docking studies on phosphodiesterase-5 inhibitors.

cGMP-binding cGMP-specific PDE, PDE5 plays a key role in the hydrolysis of cyclic guanidine monophosphate. Because cGMP mediates vascular functions, a PDE5 inhibitor that elevates cGMP level is an attractive means for vasodilatation and treatment of erectile dysfunction. In this paper we report the elucidation of the common pharmacophore hypothesis of different classes of PDE5 inhibitors. Using LigandScout program, pharmacophore modelling studies were performed on prior reported potent PDE5 inhibitors with a variety of scaffolds in order to identify one common set of critical chemical features of these PDE5 inhibitors 1-52. The best pharmacophore model, model-1, characterized by four chemical features: one aromatic ring, one hydrophobe, one hydrogen acceptors and one hydrogen donor. Using Dock6 program, docking studies were performed in order to investigate the mode of binding of these compounds. The molecular docking study allowed confirming the preferential binding mode of different classes of PDE5 inhibitors inside the active site. The obtained binding mode was as same as that of vardenafil, X-ray ligand with different orientation with varied PDE5 inhibitors׳ scaffold.