Synthesis, Characterization and Quantification of Simvastatin Metabolites and Impurities

Simvastatin is used in treatment of hypercholesterolemia because it regulates cholesterol synthesis as a result of its β-hydroxy acid acting as an inhibitor of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA). The present communication deals with synthesis, characterization and development of accurate, precise and sensitive Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method for simultaneous estimation of simvastatin and its synthetic impurities. The impurities methyl ether and β-hydroxy acid of simvastatin were synthesized in the laboratory and characterized by MS, NMR and FT-IR spectroscopy. The separation of simvastatin and its impurities was carried out on an isocratic JASCO RP-HPLC system using KYA TECH HIQ SIL C18 column (150 × 4.6 mm internal diameter, particle size 5 μm) operating at ambient temperature using acetonitrile:water (80:20 v/v) with 0.1% orthophosphoric acid as mobile phase. The method developed for HPLC analysis of three impurities along with simvastatin was validated using ICH Q2B (R1) guidelines and it complied with these guidelines. The results of analysis were found to be in the range of 98.14% to 101.89% for all analytes with acceptable accuracy and precision. The method can be used for detection and quantification of synthetic impurities in bulk or formulations of simvastatin

2 D QSAR and docking of novel N-substitutedAryl amine derivatives as potential inhibitors of lumazine synthase

Fungi play a predominant role in microbial infections with serious health risk to immunocompromised individuals, including AIDS, cancer, diabetics, newborns and elderly patients. Fungi specific riboflavin metabolism involves lumazine synthase catalyzed synthesis of 6,7-dimethyl-8-D-ribityl lumazine which is converted to riboflavin by a riboflavin synthase. Therefore lumazine synthase has been targeted for design of newer antifungal agents. 32 novel N-substituted aryl amine derivatives have been designed, synthesized, characterized and screened as antifungals. Molecular modelling and docking studies with fungal lumazine synthase using the 32 inhibitors have elucidated unique binding areas within the active site of the enzyme. Amongst the selected 2-D QSAR descriptors, chiV3Cluster and Most +ve Potential show positive correlation with antifungal activity while XX Polarizability, XY Polarizability, Heat of Formation and Quadruple 3 show negative correlation with antifungal activity.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Two- and three-dimensional quantitative structure-activity relationships studies on a series of diuretics

Diuretics are an attractive class of drugs for the treatment of various disorders and in combination with some cardiovascular drugs. In the present work, 2D and 3D quantitative structure-activity relationship studies have been conducted on a series of diuretics. Significant correlation coefficients (r2 = 0.81 and q2 = 0.65, r2 = 0.91 and q2 = 0.85) were obtained, indicating potential of the models generated for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values obtained from the 2D and 3D models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D steric and electrostatic contour maps and 2D contributions should be useful for the design of diuretics having improved potency.Colegio de Farmacéuticos de la Provincia de Buenos Aire

3D QSAR ANALYSIS OF 2,4-DISUBSTITUTED 1,5-BENZODIAZEPINE DERIVATIVES AS CNS DEPRESSANTS

New 2,4-disubstituted-1,5-benzodiazepine derivatives containing different functional groups have been screened for their CNS depressant activity. The synthesized benzodiazepine derivatives were screened for CNS depressant activity using the actophotometer model for mice. QSAR studies of synthesized derivatives were performed on Vlife MDS 3.5 software. The data set for QSAR studies encompassed activities of 45 molecules and 252 descriptors calculated by Vlife MDS 3.5. The training set comprised of 36 molecules and test set of 9 molecules. QSAR equation revealed that some electronic, steric and liphophillic parameters have correlation with CNS depressant activity. The best equation was selected on basis of correlation coefficient (r 2 ) and predicitivity of equation

Pharmacophore modeling and 3D QSAR studies of aryl amine derivatives as potential lumazine synthase inhibitors

Design and discovery of novel antifungal compounds is the need of time, more than ever before due to the unavailability of effective antifungal therapy to treat resistant fungal infections. Due to morphological and functional similarities of fungi both with plant cell and human cell, the search for effective targets leading to specificity of antifungal drug action becomes all that more difficult. For the design of novel antifungal agents, it is necessary to comprehend the life cycle, morphology, metabolic pathways, etc. of fungi scientifically and systematically to identify critical targets for antifungal drug design. Fungi specific riboflavin metabolism involves lumazine synthase catalyzed synthesis of 6,7-dimethyl-8-D-ribityl lumazine which is converted to riboflavin by a riboflavin synthase. Therefore lumazine synthase has been targeted for the design of newer antifungal agents. The pharmacophore modeling and 3D QSAR studies were carried out on 32 N-substituted aryl amine derivatives as fungal lumazine synthase inhibitors. The selected model of 3D QSAR showed positive correlation of electronic descriptors with antifungal activity while steric and hydrophobic descriptors showed negative correlation with antifungal activity. The resulting model exhibited good q2 and r2 values up to 0.9109 and 0.845 respectively