Rational design of novel diaryl ether-linked benzimidazole derivatives as potent and selective BACE1 inhibitors.

Due to the large size and high flexibility of the catalytic active site of BACE1 enzyme, the development of nonpeptide inhibitors with optimal pharmacological properties is still highly demanding. In this work, we have discovered 2-aminobenzimidazole-containg ether scaffolds having potent and selective inhibitory potentials against BACE1 enzyme. We have synthesized novel 29 compounds and optimization of aryl linker region resulted in highly potent BACE1 inhibitory activities with EC50 values of 0.05-2.71 µM. The aryloxy-phenyl analogs 20j showed the EC50 value as low as 0.07 µM in the enzyme assay, whereas, the benzyloxyphenyl dervative 24b was comparatively less effective in the enzyme assay. But interestingly the latter was more effective in the cell assay (EC50 value 1.2 µM). While comparing synthesized derivatives in the cell assay using PC12-APPSW cell, compound 27f appeared as the most potent BACE1 inhibitor having EC50 value 0.7 µM. This scaffold also showed high selectivity over BACE2 enzyme and cathepsin D. Furthermore, the research findings were bolstered through the incorporation of molecular docking, molecular dynamics, and DFT studies. We firmly believe that these discoveries will pave the way for the development of a novel class of small-molecule selective BACE1 inhibitors.

Synthesis of (3S,4S)-4-aminopyrrolidine-3-ol derivatives and biological evaluation for their BACE1 inhibitory activities.

Synthesis, SAR study and BACE1 inhibitory activity of (3S,4S)-4-aminopyrrolidine-3-ol derivatives (2) were described. The compound 7c exhibited more inhibition activity than 11a (IC50: 0.05µM vs 0.12µM, respectively), but the latter was more effective in cell-based assay (IC50: 1.7µM vs 40% inhibition by 7c @ 10µM) due to the relatively higher cell permeability. Most of the compounds showed high selectivity over BACE2 and cathepsin D. This work will provide useful information for further structural modifications to develop potent BACE1 inhibitors in cell.

Report: in vitro dissolution studies of different brands of sustained release diclofenac sodium matrix tablet available in Bangladesh.

Commercially available national thirteen brands and three international brands of diclofenac sodium sustained release matrix tablets were studied in simulated gastric medium (pH 1.2) for 2 hours time period and simulated intestinal medium (pH 6.8) for 10 hours time period using USP reference dissolution apparatus. All the national and international brands complied with the USP in-vitro dissolution specification for drug releases in simulated gastric medium. However, four of the national brands (Code: DS-5, DS-8, DS-12, and DS-13) failed to fulfill their official requirement of 80% drug release within 8th hour in simulated intestinal medium. Drug release of those four national brands were 78.1%, 74.9%, 72.1%, and 77.8% respectively within the specified time period, however one national brand (Code: DS-2) released 83.2% drug within 6th hour in intestinal medium. Drug release profiles were analyzed for Higuchi equation, zero order, and first order to reveal the release kinetics perspective of diclofenac sodium sustained release matrix tablets. It was found that zero order release kinetics was predominant release mechanism than first order and Higuchi release kinetics for those brands (Code: DS-1, DS-3, DS-4, DS-6, DS-7, DS-9, DS-10, DS-11, DS-X, DS-Y and DS-Z) which complied with the USP in vitro dissolution specification for drug releases. On the other hand, first order release kinetics was predominant for five national substandard formulation brands (Code: DS-2, DS-5, DS-8, DS-12 and DS-13).

Anti-inflammatory activity of indanyltetrazole derivatives.

A number of indanyl tetrazolederivatives namely 5-(6'-chloroindan-1'-yl)tetrazole (CIT), 5-(6'-bromoindan-1'-yl)tetrazole (BIT), 5-(6'-chloroindan-1'-yl)methyltetrazole (CIMT), 5-(6'-bromoindan-1'-yl)methyl-tetrazole (BIMT) were evaluated for the anti-inflammatory activity in carragennan induced rat paw edema in Swiss albino Wister rats for 24-hour period at the dose of 100 mg/kg of body weight by intraperitoneal route where phenylbutazone (PBZ) was used as the standard. All of these compounds exhibited inhibition on rat paw edema with peak actions observed following 3 hours after administration. Moreover, compounds CIMT and BIMT were further evaluated at dose of 50 mg/kg of body weight. Among the compounds, CIMT showed higher activity than others and was very close to standard phenylbutazone.

Hepatoprotective activity of Phyllanthus reticulatus.

Two partially purified organic fractions designated by PR1 and PR2 of the fat free ethanol (95%) extract of aerial parts of Phyllanthus reticulatus were tested for the hepatoprotective activity in rats against CCl(4)-induced liver damage. The rats receiving the fractions showed promising hepatoprotective activity as evident from significant changes of pentobarbital-induced sleeping time, changes in serum levels of sGPT, sGOT, sALP and bilirubin and also from histopathological changes as compared to CCl(4)-intoxicated rats.