Chemically synthesised flavone and coumarin based isoxazole derivatives as broad spectrum inhibitors of serine ß-lactamases and metallo-ß-lactamases: a computational, biophysical and biochemical study.

The ß-lactam antibiotics are the most effective medicines for treating bacterial infections. Resistance to them, particularly through the production of ß-lactamases, which can hydrolyse all kinds of ß-lactams, poses a threat to their continued use. The synthesised flavone and coumarin based isoxazole derivatives have the potential to be used as broad-spectrum inhibitors of the mechanistically different serine-(SBL) and metallo-ß-lactamases (MBL). The synthesised compounds were discovered as potent ß-lactamase inhibitors using molecular docking and in silico pharmacokinetic analysis. We studied the binding of chemically synthesised inhibitors to clinically significant ß-lactamases of class A, B, and C using biophysical and biochemical approaches, and computational analyses. These molecules follow Lipinski's rule of five and have acceptable solubility, permeability, and oral bioavailability. These molecules were found to be non-toxic and non-carcinogenic. MIC results suggest that these molecules restore the antibiotic efficacy against class A, B, and C ß-lactamases. Kinetics data showed that these molecules reduce the catalytic efficiency of clinically relevant class A, B, and C ß-lactamases. Fluorescence study showed significant interaction between these flavone-/coumarin-based isoxazole derivatives and class A/B/ C ß-lactamases. This study showed promising effect of these new generation compounds as broad spectrum ß-lactamase inhibitors of both SBLs and MBLs.Communicated by Ramaswamy H. Sarma.

One-pot synthesis of 1,5-diketones from 3-acetyl-4-hydroxycoumarin and effective cyclization to unexpected 3,4-dihydropyridines.

A facile synthesis of 1,5-diketones from 3-acetyl-4-hydroxycoumarin, aldehydes and cyclic-ketones via a one-pot aldol condensation and subsequent Michael addition reaction in the presence of a single catalyst of l-proline under mild reaction conditions has been developed. Novel 1,5-diketones were further cyclized to unexpected 3,4-dihydropyridines rather than generally formed pyridine analogues with ammonium acetate in acetic acid. One pot, high yields (72-92%) for novel 1,5-diketones and (70-90%) for the 3,4-dihydropyridine adducts, easy work-up and purification of products are the key advantages of this method.

Standardization of the Unani drug - Myristica fragrans Houtt. (Javetri) - with modern analytical techniques.

Today, there is a tremendous demand of herbal medicine in the global market and the scarcity of data regarding the parameters and methods employed for assessing the quality of medicines. Aril (Mace) of Myristica fragrans Houtt., known as "Javetri," belonging to the Myristicaceae family, plays a foremost role in the Unani system of medicine. It contains Myristicin, an active principle of drug isolated by column chromatography, and its structure was established by spectroscopic methods. Different solvent drug extracts posses pharmacological properties like hypocholesteremic, anti-inflammatory, anti-diarrheal, chemopreventive action, etc. and hence there is a great need to determine the amount of myristicin present in the different extracts. The proposed method employed the High Performance Thin Layer Chromatography (HPTLC) DESAGA Sarstedt Gruppe and pre-coated aluminum sheets of silica gel developed with 100% chloroform to quantitatively determine the myristicin concentrations present in various extracts that are responsible for their different pharmacological actions. An attempt was made through instrumental analysis for quantitative estimations that are widely accepted for the quality assessment of herbal drugs such as TLC and HPTLC studies, etc. Physicochemical parameters, microbial load, aflatoxin and heavy metals and fluorescence studies were also carried out to lay down the standard for genuine drug. HPTLC studies were carried out in petroleum ether, chloroform, ethyl acetate, ethanol and methanol extracts and detected at 254 nm. Estimated high amount of myristicin in the petroleum ether extract w.r.t. the other extracts was confirmed by spectroscopy. The present paper describes the isolation, characterization and quantification of myristicin along with chemical standardization in order to develop standard parameters for the genuine drug.