Search

Abstract: The objective of the present investigation was to separate, identify and characterize the major degradation products (DPs) of nelfinavir mesylate generated under hydrolytic, oxidative, photolytic and thermal stress conditions as advised in International Conference on Harmonization (ICH) guideline Q1A(R2). The drug was found to degrade under acidic, basic, oxidative and photolytic stress, while it was stable in neutral and thermal stress conditions. A total of three degradation products were formed, which were separated on a C-18 column employing a gradient HPLC method. A complete mass fragmentation pathway of the drug was first established with the help of multi-stage (MS n ) and MS/TOF accurate mass studies. Then stressed samples were subjected to LC–MS/TOF studies, which provided their fragmentation pattern and accurate masses. The mass spectral data were employed to characterize the DPs and assign structures to them. The total information was also used to establish the degradation pathway of the drug. The degradation products were identified as 3-hydroxy-N-((2R,3R)-3-hydroxy-1-(phenylthio)butan-2-yl)-2-methylbenzamide and (3S,4aS,8aS)-N-tert-butyl-2-((2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzamido)-4-(phenylsulfinyl)butyl)decahydroisoquinoline-3-carboxamide. [Copyright &y& Elsevier]

A series of N′-[3,4-disubstituted-1,3-thiazol-2(3H)-ylidene]-2-(pyrazin-2-yloxy)acetohydrazide 11–66 and N′-[(2Z)-3-(4-bromophenyl)-4-oxo-1,3-thiazolidin-2-ylidene]-2-(pyrazin-2-yloxy)acetohydrazide 68–74 were synthesized using appropriate synthetic route. The entire test compounds 11–66 and 68–74 were assayed in vitro for antibacterial activity against two different strains of Gram-negative (E. coli and S. typhi), Gram-positive (S. aureus and B. subtilis) bacteria and the antimycobacterial activity was evaluated against H37Rv strain of Mycobacterium tuberculosis. The minimum inhibitory concentration (MIC) was determined for test compounds and for reference standards. The test compounds showed significant antibacterial and antimycobacterial activity against the microbial strains used, when tested in vitro. In general, pyrazine ring and substituted thiazoline ring are essential for antimicrobial activity. Among the compounds tested, compounds 11, 12 and 40 were found to be most potent. The toxicity of most potent compounds 11, 12 and 40 were determined using hemolytic assay and minimal hemolytic concentration (MHCs) were determined. The test compounds were found to be nontoxic up to a dose level of 250 μg/mL. [Copyright &y& Elsevier]

In a search of new potentially active antitubercular agents, here we have initiated with pharmacophore development, virtual screening and molecular docking studies to know flexible binding modes with target cavity of DprE1 enzyme. We have designed and synthesized 6-(trifluoromethyl)-N-(4-oxothiazolidin-3-yl)quinazoline-2-carboxamide derivatives and evaluated for antitubercular activity with specific DprE1 inhibition. The various steps have been completed by performing condensation of 6-(trifluoromethyl)quinazoline-2-carboxylic acid, aromatic aldehydes, methanol, Hydrazine hydrate, -(trifluoromethyl)quinazoline-2-carbohydrazide, 6-(trifluoromethyl)-N′-methylenequinazoline-2-carbohydrazide to obtained 6-(trifluoromethyl)-N-(4-oxothiazolidin-3-yl)quinazoline-2-carboxamide derivatives (3a–r) in better yields. Synthesized derivatives were characterized for their spectral analysis. These compounds have been screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H 37 RV. The compounds 3a (MIC-1.27 μM); 3e (MIC-1.12 μM); 3p (MIC-1.18 μM); and 3r (MIC-0.96 μM); exhibited notable in vitro antitubercular activity compare to the reference standard, Isoniazid. These four compounds were screened for DprE1 enzyme assay. Among those 3e and 3r has shown strong DprE1 inhibition, these compounds were substituted with nitro and hydroxyl group. Image 1 • As per WHO report, tuberculosis (TB) is one of the leading cause of death in infectious disease across the globe. • Molecular modeling approach yielded 18 new quinazoline-2-carboxamide derivatives. • Newly synthesized derivatives studied for In vitro antitubercular activity. • Four compounds have shown better DprE1 Inhibitory Activity. [ABSTRACT FROM AUTHOR]

• Potent E. coli DNA gyrase inhibitors obtained. • Compound 11b (IC 50 = 0.28 µM), 17b (IC 50 = 0.43 µM), 11a (IC 50 = 0.90 µM) and 17a (IC 50 = 0.72 µM) exhibited excellent E. coli DNA gyrase inhibitory activity. • Compounds 11b (MIC = 1.56 µg/ mL) and 17b (MIC = 3.125 µg/ mL) displayed encouraging anti-tubercular activity against M. tuberculosis H 37 Rv. • Compound 11b establishes good physicochemical properties and in vitro safety profiles. • Molecular docking studies were analysed. Bacterial DNA gyrase remains a prominent and vital target in discovering new antibacterial drugs. In the present research work, we designed and synthesized a series of novel 4,5-dibromo-N-phenyl-1H-pyrrole-2-carboxamide hybrids containing substituted 1,2,3-triazole and isoxazole moieties which could serve as potential E. coli DNA gyrase inhibitors. The title compounds were synthesized with a good to excellent yield, and all the newly synthesized compounds were characterized by physicochemical and spectral analysis (FTIR, 1H NMR, and 13C NMR). The DNA gyrase (E. coli) inhibitory assay was performed for all synthesized compounds. Results showed that four compounds, 11a (IC 50 = 0.90 µM), 11b (IC 50 = 0.28 µM), 17a (IC 50 = 0.72 µM) and 17b (IC 50 = 0.43 µM), exhibited good DNA gyrase inhibitory activity. In-silico molecular docking study was performed to understand the mode of interaction of compounds with the target enzyme. A docking study on the E. coli DNA gyrase protein revealed that compounds 11b (-7.011 kcal/mol) and 17b (-6.60 kcal/mol) interact with ARG136 and ASP73, two key amino acid residues, with docking scores of −7.01 and −6.60, respectively. The MD simulation was further employed to elucidate the thermodynamic binding energy, RMSD, and RMSF of compounds 11b and 17b. They exhibited binding energies of -47.598 kcal/mol and -41.682 kcal/mol, respectively. This provides valuable information on the binding mode and structure-activity relationship of these new hybrids of 4,5-dibromo-N-phenyl-1H-pyrrole-2-carboxamides as promising E. coli DNA gyrase B inhibitors. In addition, these hybrid derivatives showed more prominent antibacterial action on Gram-negative rather than Gram-positive organisms. Surprisingly, compounds 11b (MIC = 1.56 µg/mL) and 17b (MIC = 3.125 µg/mL) also displayed promising anti-mycobacterial activity. [Display omitted] [ABSTRACT FROM AUTHOR]

• SFC and NP-LC technique is used to separate itraconazole stereoisomers. • We developed a rapid and green method for the separation of itraconazole stereoisomers. • This platform will aid in the Quality control Laboratories to adapt Eco-friendly method. Separation of the stereoisomers of the antifungal drug itraconazole using supercritical fluid chromatography and normal-phase liquid chromatography is presented. The performances of the two methods are evaluated based on their speed, resolution, and the analytical method greenness score. Both methods achieve baseline separation and meet the United States Pharmacopeia-recommended resolution of ≥1.5 between the four stereoisomers. The methods are validated following the International Conference on Harmonization guidelines and evaluated in terms of specificity, precision, linearity, accuracy, and range; they are thus appropriate for purposes of quantification. Supercritical fluid chromatography achieves separation more rapidly and is found to be more eco-friendly than normal-phase liquid chromatography. To emphasize the use of ecofriendly alternatives, the assessment is performed using a metric termed as the analytical method greenness score. The method can thus be implemented for determination of chiral purity in various Quality control laboratories. [ABSTRACT FROM AUTHOR]