2D and 3D QSAR studies and antibacterial activity of 4-methyl-3-(6-{[arylmethylene] amino}pyridin-3-YL)-2H-chromen-2-one derivatives

4-methyl-3-(6-{[arylmethylene] amino} pyridin-3-yl)-2H-chromen-2-one derivatives containing different functional groups have been synthesized and screened for their antibacterial activity against four different strains of bacteria. 2D and 3D QSAR analysis of synthesized derivatives were performed on Vlife MDS 3.5 software. The data set for QSAR studies encompassed activities of 64 molecules divided into training and test set. The best models were selected on basis of correlation coefficient (r2) and internal and external predictivity (Pred_r2) of the QSAR model. QSAR models reveled that electronic, steric and liphophillic parameters have correlation with antibacterial activity. The 3D interactions and their contributions indicate multi-targeted mode of action of the compounds.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Application of group-based QSAR and molecular docking in the design of insulin-like growth factor antagonists

Purpose: To identify the structural requirements for designing a lead key for insulin-like growth factor (IGF-1R) inhibition using group-based quantitative structure activity relationship (GQSAR) and molecular docking. Methods: GQSAR method requires fragmentation of molecules. The molecules in the current dataset were fragmented into three (R1, R2 and R3) by applying common fragmentation pattern, and fragment- based 2D descriptors were then calculated. GQSAR models were derived by applying various methods including multiple linear regressions and partial least square or k-nearest neighbour. Results: Four generated GQSAR models were selected based on the statistical significance of the model. It was found that the presence of flexible and non-aromatic groups on fragment R1 was conducive for inhibition. Additionally, the existence of amino groups as hydrogen bond donors at fragments R2 and R3 was fruitful for inhibition. Docking studies revealed the binding orientation adopted by the active compounds at several amino acid residues, including Met 1126, Arg, 1128, Met 1052, GLU 1050, Met 1112, Leu 1051, Met 1049, Val 1033, and Val 983 at ATP binding sites of IGF-1R kinase domain. Conclusion: The generated models provide a site-specific insight into the structural requirements for IGF-1R inhibition which can be used to design and develop potent inhibitors. Keywords: Insulin-like growth factor 1 (IGF-1) receptor, Quantitative structure-activity relationship, Adenosine triphosphate, Competitive inhibitors, Electrotopological state index

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

QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP (QSAR) STUDIES ON 5-CYANO, N1, 6-DISUBSTITUTED, 2-THIOURACIL DERIVATIVES AS CENTRAL NERVOUS SYSTEM DEPRESSANTS

Quantitative structure activity relationship (QSAR) studies of twenty four 5-cyano, N1, 6-disubstituted, 2-thiouracil derivatives were performed for their central nervous system (CNS) depressant (locomotor) activity using VlifeMDS3.5 software. Partial least square (PLS) linear regression analysis coupled with stepwise variable selection method was applied to derive QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The best QSAR model was selected, having correlation coefficient r 2 = 0.9014 and cross validated squared correlation coefficient q 2 = 0.8120 with external predictive ability of pred_r 2 = 0.6692. The QSAR model indicated that the vdWSurfaceArea (van der Waals surface area of the molecule), dipole moment, YcompDipole (y component of the dipole moment) and T_2_F_1 (count of number of double bounded atoms (i.e. any double bonded atom, T_2) separated from fluorine atom by 1 bond in a molecule) were the important determinants for CNS depressant (locomotor) activity

Multiple Linear Regression Study of 2,4-Disubstituted 1,5- Benzodiazepine as Potential Antiinfectives: 2,4-Disubstituted 1,5-Benzodiazepine as Potential Antiinfectives

This paper describes 3D-QSAR analysis and biological evaluation of 1,5-benzodiazepine analogues. Benzodiazepine nucleus with its simple structure gives a good opportunity for further modification regarding an increase of its antimicrobial activity. We synthesized a series of benzodiazepine analogues from condensation of various chalcones and halo substituted o-phenelynene diamines. All compounds were assayed in vitro against, E. coli, P. aeruginosa, S. aureus. The models were generated on the Vlife MDS 3.5; selected models showed a correlation coefficient (r2) above 0.9 with cross-validated correlation coefficient (q2) above 0.8, respectively, for all the selected organisms. The 3D-QSAR models generated were externally validated for all models using a test set of 6 molecules for which the predictive r2 (r2-pred) was found to be above 0.45. The results of 3D-QSAR indicate that contours can be used to design some potent antibacterial agents

IMPROVED SYNTHESIS OF SUBSTITUTED PYRIMIDIN-2-ONE DERIVATIVES USING MICROWAVE AND ULTRASOUND IRRADIATION

ABSTRACT Various substituted 4-oxo-2-thioxo tetrahydropyrimidine, 2-oxo dihydropyrimidine, 3,6-disubstituted and 4,5-disubstituted tetrahydropyrimidin-2-one derivatives containing different functional groups have been synthesized under microwave and ultrasound irradiation. The 3,6-disubstituted derivatives were prepared by reacting substituted pyrimidine derivatives synthesized under ultrasound irridation, with ethybromoacetate and product formed was converted to respective hydrazide derivatives, which were further condensed with various aromatic aldehydes. The 4,5-disubstituted tetrahydropyrimidines derivatives were synthesized simply by reacting substituted pyrimidine derivatives synthesized using modified biginelli reaction with various aromatic amines. The IR, 1 H NMR and mass spectral data confirmed the structure of the newly synthesized compounds. Keywords: Biginelli reaction, pyrimidine, Microwave, Ultrasound. INTRODUCTION Pyrimidine is a parent group of various heterocyclic compounds, which have attracted attention for long time. Pyrimidine derivatives play a vital role in many biological processes, the ring system being present in nucleic acids, several vitamins and coenzymes, uric acid and other purines. Uracil, thymine, and cytosine are three of the six bases found in the nucleotides, which contain pyrimidine ring. It is evident from the literature that pyrimidine derivatives have been found to have various pharmacological activities. Pyrimidine ring is the backbone of several calcium channel blocker[1], antibacterial[2], antifungal Step-I:Synthesis of 5-carbonitrile-6-aryl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine:[10 ] A mixture of ethyl cyanoacetate (0.01 mol), an aldehyde (0.01 mol) and thiourea (0.01 mol) in ethanol (20 ml) containing potassium carbonate (0.01 mol) was refluxed for 5 h. The potassium salt of product, which is precipitated during reaction, was collected and washed with ethanol and tetrahydrofuran. The crude salt was stirred in water at approximately 80° C; stirring was continued until the clear solution is obtained. After cooling the solution was acidify by acetic acid, and stirring was continued for 30 min. The deposited crystals thus formed were collected and washed well with water and dried in air. Recrystallization from acetic acid gave pure product. Desai Sujit Arun et al

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

Association Between Progesterone Elevation on the Day of Human Chronic Gonadotropin Trigger and Pregnancy Outcomes After Fresh Embryo Transfer in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles

Progesterone elevation (PE) during the late follicular phase of controlled ovarian stimulation in fresh embryo transfer in vitro fertilization (IVF)/intracytoplasmic sperm injection cycles has been claimed to be associated with decreased pregnancy rates. However, the evidence is not unequivocal, and clinicians still have questions about the clinical validity of measuring P levels during the follicular phase of stimulated cycles. We reviewed the existing literature aimed at answering four relevant clinical questions, namely (i) Is gonadotropin type associated with PE during the follicular phase of stimulated cycles? (ii) Is PE on the day of human chorionic gonadotropin (hCG) associated with negative fresh embryo transfer IVF/intracytoplasmic sperm injection (ICSI) cycles outcomes in all patient subgroups? (iii) Which P thresholds are best to identify patients at risk of implantation failure due to PE in a fresh embryo transfer? and (iv) Should a freeze all policy be adopted in all the cycles with PE on the day of hCG? The existing evidence indicates that late follicular phase progesterone rise in gonadotropin releasing analog cycles is mainly caused by the supraphysiological stimulation of granulosa cells with exogenous follicle-stimulating hormone. Yet, the type of gonadotropin used for stimulation seems to play no significant role on progesterone levels at the end of stimulation. Furthermore, PE is not a universal phenomenon with evidence indicating that its detrimental consequences on pregnancy outcomes do not affect all patient populations equally. Patients with high ovarian response to control ovarian stimulation are more prone to exhibit PE at the late follicular phase. However, in studies showing an overall detrimental effect of PE on pregnancy rates, the adverse effect of PE on endometrial receptivity seems to be offset, at least in part, by the availability of good quality embryo for transfer in women with a high ovarian response. Given the limitations of the currently available assays to measure progesterone at low ranges, caution should be applied to adopt specific cutoff values above which the effect of progesterone rise could be considered detrimental and to recommend “freeze-all” based solely on pre-defined cutoff points