DESIGN, SYNTHESIS AND MOLECULAR DOCKING STUDY OF HYBRID QUINOLINE-4-YL-OXADIAZOLES/OXATHIADIAZOLES AS POTENT ANTIFUNGAL AGENTS

Objective: The aim of the present work was to design and synthesize hybrid quinoline-4-yl-oxadiazoles/oxathiadiazole derivatives and evaluate them for in vitro antifungal activity against human disease causing pathogens.Methods: The compounds 5(a-d), 6(a-d) and 7(a-d) were efficiently synthesized in good yields. The synthesized compounds were characterized using 1H NMR, 13C NMR and Mass spectra. The synthesized compounds were screened for in vitro antifungal activity and minimum inhibitory concentration (MIC) values were determined using standard agar method. Molecular docking study was performed against fungal enzyme P450 cytochrome lanosterol 14α-demethylase using VLife MDS 4.3 software.Results: The synthesized compounds had shown good to moderate in vitro antifungal activity. The compound 6a (MIC range = 15-25 µg/ml) from 1,2,3,5-oxathiadiazole-2-oxide series showed most potent activity amongst the synthesized compounds when compared with standard clotrimazole (MIC range = 12.5-25 µg/ml). The molecular docking study of synthesized compounds showed good binding interactions against active site of fungal enzyme P450 cytochrome lanosterol 14α-demethylase.Conclusion: The results of in vitro antifungal activity and molecular docking study revealed that the synthesized compounds have potential antifungal activity and can be further optimized and developed as a lead compound.Â

TASTE MASKING OF DONEPEZIL HYDROCHLORIDE USING DIFFERENT ION EXCHANGE RESINS- A COMPARATIVE STUDY

Taste mainly depends on the physiology, sensitivity and structure of taste buds. It is an important parameter in administering drugs orally. Bitter taste is a major limitation to patient compliance. Donepezil hydrochloride (DH) is a bitter drug used in Alzheimer's disease. Amongst the many techniques for taste masking, using ion exchange resins has been extensively reported. The technique of forming tasteless complexes with bitter drugs involves selection of most appropriate exchanger and optimization of complexing ratio. The aim of the present work was to select the best cationic exchanger amongst Indion 414, Indion 234 and Indion 214. All parameters were optimized to produce drug-loaded tasteless complexes. Complexation was carried out using batch process prior to which, acid-alkali activation was performed to remove adsorbed impurities from the resin bed surface and hence improve loading efficiency. UV-spectrophotometric method was used to determine percent drug loading. The molecular properties of drug resin complexes were studied using Fourier Transform Infra-red Spectroscopy, Differential Scanning Calorimetry and Xray Powder Diffraction which confirmed complexation. Indion 414 was found to give highest drug loading and minimal drug was released from the complex at salivary pH. Key words: Donepezil HCl, Ion exchange resins, Molecular properties, Taste maskin

Application of Elements of Quality by Design to Development and Optimization of HPLC Method for Fingolimod

Purpose: A HPLC method for Fingolimod was developed using a Quality by Design concept. QbD has gained importance in recent times due to regulatory requirements. Actual study was started after determination of target profile and qualification of instrument. Methods: Separation was carried on a Grace C-8 column (4.6 x 250 mm, 5-μm particle size).The composition of mobile phase was methanol and 20 mM ammonium formate buffer of pH5.8 in gradient mode HPLC method development is affected by critical factors like pH, flow rate and mobile phase composition. Results: To study the effects of these three factors on USP tailing, Box Behnken optimization model was applied. Desirability of the model was set at Tailing less than 1.2.Analysis of results was done using surface diagrams. Verification of Software generated results was done by taking six replicates of the run. Thus developed and optimised method was Finally validated as per ICH guideline. Conclusion: A Quality by Design approach has been successfully utilised in method development of the Fingolimod in bulk. All key aspect of QbD were tried to be implemented in said study. Systematic approach was utilized for method development which includes beginning with determination of target profile characteristics, instrument qualification, risk assessment, design of experiment and validation. Three factors i.e. Ph, flow rate and methanol concentration were analysed for their effect on USP tailing as a responce. Interaction and quadratic effect of the factors were studied with least possible runs by using Box Behnken model. Response surface diagrams and contour plots were studied for coming to conclusion which factors are affecting response and their limits were recorded. Optimum run condition was obtained; Replicates of run having optimized condition were taken to confirm the predicted response with actual response

TASTE MASKING OF DONEPEZIL HYDROCHLORIDE USING DIFFERENT ION EXCHANGE RESINS- A COMPARATIVE STUDY

Taste mainly depends on the physiology, sensitivity and structure of taste buds. It is an important parameter in administering drugs orally. Bitter taste is a major limitation to patient compliance. Donepezil hydrochloride (DH) is a bitter drug used in Alzheimer's disease. Amongst the many techniques for taste masking, using ion exchange resins has been extensively reported. The technique of forming tasteless complexes with bitter drugs involves selection of most appropriate exchanger and optimization of complexing ratio. The aim of the present work was to select the best cationic exchanger amongst Indion 414, Indion 234 and Indion 214. All parameters were optimized to produce drug-loaded tasteless complexes. Complexation was carried out using batch process prior to which, acid-alkali activation was performed to remove adsorbed impurities from the resin bed surface and hence improve loading efficiency. UV-spectrophotometric method was used to determine percent drug loading. The molecular properties of drug resin complexes were studied using Fourier Transform Infra-red Spectroscopy, Differential Scanning Calorimetry and Xray Powder Diffraction which confirmed complexation. Indion 414 was found to give highest drug loading and minimal drug was released from the complex at salivary pH

Stability-indicating HPLC determination of pramipexole dihydrochloride in bulk drug and pharmaceutical dosage form

A novel stability-indicating high-performance liquid chromatographic assay method was developed and validated for quantitative determination of pramipexole dihydrochloride in bulk drugs and in pharmaceutical dosage form in the presence of degradation products. An isocratic, reversed phase HPLC method was developed to separate the drug from the degradation products, using an Ace5-C18 (250×4.6 mm, 5 µm) advance chromatography column, and 10 mmol L-1 ammonium acetate and acetonitrile (75:25 v/v) as a mobile phase. The detection was carried out at a wavelength of 260 nm. The pramipexole was subjected to stress conditions of hydrolysis (acid, base), oxidation, photolysis and thermal degradation. Degradation was observed for pramipexole in base, in acid and in 30% H2O2. The drug was found to be stable in the other stress conditions attempted. The degradation products were well resolved from the main peak. The percentage recovery of pramipexole was from (99.87 to 99.98%) in the pharmaceutical dosage form. The developed method was validated with respect to linearity, accuracy (recovery), precision, system suitability, specificity and robustness. The forced degradation studies prove the stability indicating power of the method

Ultrasound- and Molecular Sieves-Assisted Synthesis, Molecular Docking and Antifungal Evaluation of 5-(4-(Benzyloxy)-substituted phenyl)-3- ((phenylamino)methyl)-1,3,4-oxadiazole-2(3H)-thiones

A novel series of 5-(4-(benzyloxy)substituted phenyl)-3-((phenyl amino)methyl)-1,3,4-oxadiazole-2(3H)-thione Mannich bases 6a–o were synthesized in good yield from the key compound 5 (4(benzyloxy)phenyl)-1,3,4-oxadiazole-2(3H)-thione by aminomethylation with paraformaldehyde and substituted amines using molecular sieves and sonication as green chemistry tools. The antifungal activity of the new products was evaluated against seven human pathogenic fungal strains, namely, Candida albicans ATCC 24433, Candida albicans ATCC 10231, Candida glabrata NCYC 388, Cryptococcus neoformans ATCC 34664, Cryptococcus neoformans PRL 518, Aspergillus fumigatus NCIM 902 and Aspergillus niger ATCC 10578. The synthesized compounds 6d, 6f, 6g, 6h and 6j exhibited promising antifungal activity against the tested fungal pathogens. In molecular docking studies, derivatives 6c, 6f and 6i showed good binding at the active site of C. albicans cytochrome P450 enzyme lanosterol 14 α-demethylase. The in vitro antifungal activity results and docking studies indicated that the synthesized compounds have potential antifungal activity and can be further optimized as privileged scaffolds to design and develop potent antifungal drugsS

Green synthesis and anxiolytic activity of some new dibenz-[1,4] diazepine-1-one analogues

AbstractA facile, green approach for the synthesis of some new dibenz[1,4]-diazepine-1-one by a three component reaction of Diamine, 1,3 diketone and aromatic aldehyde using oxalic acid as catalyst in water is described. The products are formed in good yields (92–94%). Newly synthesized dibenz [1,4]-diazepine-1-one analogues were evaluated for the anxiolytic activity by the elevated plus maze method. From the activity data it is observed that compounds, 4g, 4h and 4k show promising anxiolytic activity

Ionic liquid-catalyzed green protocol for multi-component synthesis of dihydropyrano[2,3-c]pyrazoles as potential anticancer scaffolds

A series of 6-amino-4-substituted-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 5a–j were synthesized via one-pot, four-component condensation reactions of aryl aldehydes 1a–j, propanedinitrile (2), hydrazine hydrate (3) and ethyl acetoacetate (4) under solvent-free conditions. We report herein the use of the Brønsted acid ionic liquid (BAIL) triethylammonium hydrogen sulphate [Et3NH][HSO4] as catalyst for this multi-component synthesis. Compared with the available reaction methodology, this new method has consistent advantages, including excellent yields, a short reaction time, mild reaction conditions and catalyst reusability. Selected synthesized derivatives were evaluated for in vitro anticancer activity against four human cancer cell lines viz. melanoma cancer cell line (SK-MEL-2), breast cancer cell line(MDA-MB-231), leukemia cancer cell line (K-562) and cervical cancer cell line (HeLa). Compounds 5b, 5d, 5g, 5h and 5j exhibited promising anticancer activity against all selected human cancer cell lines, except HeLa. Molecular docking studies also confirmed 5b and 5d as good lead molecules. An in silico ADMET study of the synthesized anticancer agents indicated good oral drug-like behavior and non-toxic nature.UDN is very much thankful to Babasaheb Ambedkar Research and Training Institute (BARTI, Pune, India) for financial supportS

Development of a Stability Indicating RP-HPLC Method for Determination of Rupatadine Fumarate in Tablet Dosage Form and its Validation

ABSTRACT A simple, precise, cost effective stability indicating RP-HPLC method has been developed and validated for the determination of Rupatadine Fumarate in pharmaceutical tablet. The developed method gave discrete identification and determination of rupatadine in presence of degradant products under a variety of stress conditions. A Spherisorb CN, 250 x 4.6mm, 5µ (Water, Ireland) was used for chromatographic separation. The mobile phase comprised of a mixture of Phosphate buffer pH 4.4 and acetonitrile in the ratio 40:60 at a flow rate of 1.5 ml / min, which was filtered and degassed prior to use. The detection was performed at 242 nm using a PDA detector. Subjecting the drug solution to stress degradation proved that the drug was susceptible to acid-base hydrolysis, hydrogen peroxide thermal and UV degradation. The degradants were well separated from its active pharmaceutical ingredient. The method was also validated according to ICH guidelines. Hence, the developed method was found to be both specific and stability indicating