In-vitro evaluation of antioxidant and anticholinesterase activities of novel pyridine, quinoxaline and s-triazine derivatives.

Cholinesterase enzymes such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) cause hydrolysis of acetylcholine (ACh), a neurotransmitter responsible for the cognitive functions of the brain such as acquiring knowledge and comprehension. Therefore, inhibition of these enzymes is an effective process to curb the progressive and fatal neurological Alzheimer's disease (AD). Herein, we explored the potential inhibitory activities of various pyridine, quinoxaline, and triazine derivatives (3a-k, 6a-j and 11a-h) against AChE and BuChE enzymes by following the modified Ellman's method. Further, anti-oxidant property of these libraries was monitored using DPPH (2,2'-diphenyl-1-picryl-hydrazylhydrate) radical scavenging analysis. From the studies, we identified that compounds 6e, 6f, 11b and 11f behaved as selective AChE inhibitors with IC50 values ranging from 7.23 to 10.35 µM. Further studies revealed good anti-oxidant activity by these compounds with IC50 values in the range of 14.80-27.22 µM. The kinetic studies of the active analogues demonstrated mixed-type of inhibition due to their interaction with both the catalytic active sites (CAS) and peripheral anionic sites (PAS) of the AChE. Additionally, molecular simulation in association with fluorescence and circular dichroism (CD) spectroscopic analyses explained strong affinities of inhibitors to bind with AChE enzyme at the physiological pH of 7.2. Binding constant values of 5.4 × 104, 4.3 × 104, 3.2 × 104 and 4.9 × 104 M-1 corresponding to free energy changes -5.593, -6.799, -6.605 and -8.104 KcalM-1 were obtained at 25 °C from fluorescence emission spectroscopic studies of 6e, 6f, 11b and 11f, respectively. Besides, CD spectroscopy deliberately explained the secondary structure of AChE partly unfolded upon binding with these dynamic molecules. Excellent in vitro profiles of distinct quinoxaline and triazine compounds highlighted them as the potential leads compared to pyridine derivatives, suggesting a path towards developing preventive or therapeutic targets to treat the Alzheimer's disease.

Asymmetric Oxidative Coupling of Phenols and Hydroxycarbazoles.

The first examples of asymmetric oxidative coupling of simple phenols and 2-hydroxycarbazoles are outlined. Generation of a more vanadium catalyst by ligand design and by addition of an exogenous Brønsted or Lewis acid was found to be key to coupling the more oxidatively resistant phenols. The resultant vanadium complex is both more Lewis acidic and more strongly oxidizing. Good to excellent levels of enantioselectivity could be obtained, and simple trituration readily provided the products with ≥95% ee.

New enantiopure NHCs derived from camphor.

A new class of enantiopure carbene precursors based on cheap camphor has been developed, and a restricted rotation of one N-substituent due to the C-10 methyl group of the camphor skeleton has been found; in situ prepared corresponding carbenes revealed the same behaviour.

Hindered Brønsted bases as Lewis base catalysts.

KHMDS and KOtBu are well established as strong, hindered, non-nucleophilic Brønsted bases. However, in the present work these bases are applied as highly active Lewis base catalysts for the formal [2+2] cycloaddition of ketenes with aldehydes and imines.

Synthesis of 2'-paclitaxel methyl 2-glucopyranosyl succinate for specific targeted delivery to cancer cells.

A novel glucose-conjugated paclitaxel 5 was synthesized using succinic acid as linker between 2'-paclitaxel and methyl 2'-glucopyranose. 5 has not only improved the pharmaceutical properties of paclitaxel, such as solubility and stability, but also enhanced the specific target delivery to MCF-7 cells without the cytotoxicity against normal cells. Therefore, the glucose conjugation may be potentially used in the targeted delivery of other drugs into cells via glucose transporters (GLUTs) for cancer therapy.