Development and validation of LC-MS/MS method for determination of DNDI-VL-2098 in mouse, rat, dog and hamster blood.

Aim: To develop a bioanalytical method to support pharmacokinetic evaluation of DNDI-VL-2098 in mouse, rat, dog and hamster following oral administration. Results & methodology: A robust LC-MS/MS bioanalytical method was developed to quantify DNDI-VL-2098. DNDI-VL-2098 showed time-dependent recovery loss in acetonitrile precipitated plasma in all species. Acid-lysed whole blood was identified as a matrix in which recovery was stable over time. A two-step extraction procedure was used, with protein precipitation followed by liquid-liquid extraction with methyl tert-butyl ether. The assay was validated in the dynamic range of 5-5000 ng/ml for mouse, rat and dog blood, and a fit-for-purpose method was developed for hamster. Conclusion: A specific LC-MS/MS assay for DNDI-VL-2098 was developed and validated in hemolyzed blood.

Development and validation of a chiral LC-ESI-MS/MS method for simultaneous determination of the enantiomeric metabolites isosorbide 2-mononitrate and isosorbide 5-mononitrate of isosorbide dinitrate in rat and human plasma.

A specific liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) assay was developed and validated for simultaneous determination of two active metabolites of isosorbide dinitrate (ISDN), namely, isosorbide 2-mononitrate (IS 2-MN) and isosorbide 5-mononitrate (IS 5-MN). A simple protein precipitation extraction technique was employed using 13C6 isosorbide 5-mononitrate as the internal standard. The two isomers were separated on a chiral column and mass detection was carried out by electrospray ionization (ESI) in negative multiple reaction monitoring (MRM) mode (ESI -ve). As neutral organic nitrates do not ionize well in ESI ion source, adduct formation of IS 2-MN and IS 5-MN were evaluated. Acetate adduct ions of IS 2-MN and IS 5-MN were well ionized and fragmentable in the negative mode by liquid chromatography electrospray ionization/tandem mass spectrometry. These acetates adduct ions, of IS 2-MN and IS 5-MN were selected as parent mass for quantitation. The method was developed and validated in rat and human plasma with K2EDTA as an anticoagulant. This simultaneous quantitation method was shown to be linear over a working range of 25.0 ng/mL to 5050 ng/mL and 12.4 ng/mL to 2500 ng/mL for IS 2-MN (r2 > 0.99) and IS 5-MN (r2 > 0.99), respectively, in rat and human plasma. Sensitivity was determined as 25.0 ng/mL for IS 2-MN and 12.4 ng/mL for IS 5-MN in rat and human plasma. Inter- and intra-day accuracy and precision were within ±15% in both method validations. This validated method was subsequently applied to a pharmacokinetic (PK) study of ISDN in rat after oral administration.

Emerging Trends in the Syntheses of Heterocycles Using Graphene-based Carbocatalysts: An Update.

Graphene-based carbocatalysts owing to numerous amazing properties such as large specific surface area, high intrinsic mobility, excellent thermal and electrical conductivities, chemical stability, ease of functionalization, simple method of preparation, effortless recovery and recyclability have gained a superior position amongst the conventional homogeneous and heterogeneous catalysts. In this review, an endeavor has been made to highlight the syntheses of diverse heterocyclic compounds catalyzed by graphene-based catalysts. Further, the study also reveals that all the catalysts could be reused several times without significant loss in their catalytic activity. Additionally, most of the reactions catalyzed by graphene-based carbocatalysts were carried out at ambient temperature and under solvent-free conditions. Thus, the graphene-based catalysts do not merely act as efficient catalysts but also serve as sustainable, green catalysts. This review is divided into various sub-sections, each of which comprehensively describes the preparation of a particular heterocyclic scaffold catalyzed by graphene-derived carbocatalyst in addition to synthesis of graphene oxide and reduced graphene oxide, functionalization, and structural features governing their catalytic properties. Synthesis of heterocycles catalyzed by graphene-based carbocatalysts.

Synthesis and characterization of polyaniline-drug conjugates as effective antituberculosis agents.

Polyaniline (PANI) and its drug composites with some drugs like Neomycin (NM), Trimethoprim (TMP) and Streptomycin (ST) have been prepared by oxidative polymerization of aniline using hydrochloric acid (HA) and ammonium persulfate (APS) as a dopant and as an oxidant, respectively. The structures of PANI and PANI-drug composites were elucidated by FTIR and NMR spectroscopy, which confirmed the presence of benzenoid and quinoid rings in the synthesized compound. Molecular weight and thermal stability were determined by gel permeation chromatography (GPC) and thermogarvimetric analysis, respectively. From the GPC, PDI values of PANI-NM, PANI-TMP and PANI-ST were found to be 1.37, 1.23 and 1.56, respectively. For the study of antibacterial behavior of the synthesized PANI and PANI-drug composites, different micro-organisms, namely, four Gram positive (S. aureus MTCC 96, B. subtilis MTCC 441, S. pyogenes MTCC 442 and S. mutans MTCC 890) and four Gram negative (S. typhi MTCC 98, KL. pneumoniae MTCC 109, E. coli MTCC 443 and P. aeruginosa MTCC 1688) bacteria were selected due to their pharmacological importance. Some of the PANI-drug composites were found to show excellent results as compared to components polyaniline and drugs used for composite formation. Antituberculosis activity of the PANI and its drug composites against Mycobacterium tuberculosisH37RV (acid fast Bacilli) was determined. MIC values for PANI-NM and PANI-TMP were found to be 0.12 and 0.20 µg/mL, respectively. Results suggested that some of the drug composites may be tried as potential candidates for use as an antituberculoid agent to reduce TB transmission.

A simple and sensitive LC-MS/MS method for quantification of Bepridil in rat plasma and its application to pharmacokinetic studies.

Bepridil is potent inhibitor of Na+, K+ and Ca+ channel in cardiomyocytes. It has demonstrated strong antianginal effect with type I antiarrhythmic and with minimum antihypertensive therapeutic effect. Till date, a specific LC-MS/MS method to quantify Bepridil concentrations in biological matrix have not been reported yet. In current study, a highly sensitive, specific and simple LC-MS/MS method for quantification of antianginal drug Bepridil in rat plasma is presented. The LC-MS/MS method was validated in terms of selectivity, specificity, sensitivity, accuracy and precision, matrix effect, extraction recovery and stability as per USFDA's bioanalytical method validation guideline. The validated assay was applied for quantification of Bepridil from pharmacokinetic study in rats following oral and intravenous administration. The lower limit of quantification (LLOQ) of Bepridil was 1 ng/mL. The calibration curve ranges from 1 ng/mL to 1000 ng/mL with desirable linearity and r2 > 0.99. The method exhibited 10-fold dilution integrity. The intra-day and inter-day accuracy were within 101.32-96.80% and 102.87-95.35% with coefficient of variation 10.11-2.89% and 10.45-3.97% respectively. No significant interference observed by endogenous peak at the retention time of Bepridil and IS. The assay was free from any matrix effect, precise recovery across the calibration curve range and samples were stable under all experimental conditions. The validated assay was successfully applied to analyze plasma samples of pharmacokinetic study in rat to determine concentrations of Bepridil. In summary, a novel method for analyzing Bepridil in rat plasma has been successfully validated and is now being utilized for quantification of Bepridil from pre-clinical studies.

Kinetics of sonophotocatalytic degradation of an anionic dye nigrosine with doped and undoped zinc oxide.

The current research focuses on the photocatalytic, sonocatalytic and sonophotocatalytic degradation of nigrosine dye with nitrogen-doped and undoped zinc oxide powders. The sonophotocatalytic degradation of dye was found to occur at a higher rate than during photo- or sonocatalytic processes. Nitrogen-doped and undoped zinc oxide powders were synthesized by a wet chemical method. Further, scanning electron microscopy (FESEM), electron dispersive X-ray (EDX), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), UV-VIS spectroscopy (UV-VIS) and transmission electron microscopy (TEM) were used for the characterization of N-doped ZnO. The kinetics of nigrosine degradation were also studied and the results indicated that the degradation kinetics of nigrosine followed the first-order kinetics. The rate constant and the percentage of degradation were found to be highest, 7.33 × 10-4 (s-1) and 92% respectively, for sonophotocatalytic process after 90 min of reaction. Due to an increase in the available surface area or active sites of the catalyst, a higher rate constant and degradation efficiency was observed in the sonophotocatalytic system than in the photocatalysis system.

An Environmentally-Benign Synthesis of Spiro-benzo[1,4]diazepines Using Multi Phase Nano-titania as a Highly Efficient Catalyst via MAOS Technique.

AIM AND OBJECTIVE: Benzodiazepines and indole fused heterocycles are pharmacologically significant scaffolds. Trivial work on indole fused benzodiazepine compounds is reported in the literature. Hence, it is imperative to explore the synthesis of indole-fused benzodiazepines that may act as a template for biological studies in the future. Hence, in the present work, the synthesis of indole fused benzodiazepine derivatives was undertaken using multi-phase nano-titania as catalyst under microwave irradiation. MATERIALS AND METHODS: MAOS technique was used to carry out the synthesis of spiro-benzo [1,4]diazepine derivatives in the presence of multiphase nano-titania as a catalyst. Nano-titania was prepared by sol-gel method and characterized by XRD, FT-IR, FESEM, EDS and thermogravimetric techniques. The synthesized spiro-benzo [1,4] diazepine derivatives were identified by physical and spectral methods. RESULTS: Synthesized compounds were obtained in excellent yields in a short span of time. The synthesis was also carried out in the presence of conventional catalysts in addition to nano-titania. Among all the catalysts, the best result was obtained with nano-titania. The amount of nano-titania was optimized to be 0.05g giving 93- 95% yield of products. The study of reusability of nano-titania revealed that it could be reused up to four times with a negligible change in efficiency. CONCLUSION: The paper reports an efficient, cost-effective and environmentally benign approach for the synthesis of spiro-benzo [1,4] diazepine derivatives in the presence of multiphase nano-titania catalyst under microwave irradiation.

Glutathione S-transferase M1 and T1 null genotype frequency distribution among four tribal populations of western India.

Glutathione S transferase (GST) family is a key contributor in the detoxification mechanism of our body.Deletion of the genes within this family has been reported in the failure of detoxification system, to some extent leading to various types of cancers and other life threatening diseases. The existing data and reports on the association of null genotype of both GSTM1 and GSTT1 genes for various diseases are inconsistent. But knowledge of the polymorphic distributions of genotypes in different populations is important for investigating the risk factors in different epidemiological studies. The present study thus aims to determine thefrequency of GSTM1 and GSTT1 null genotype frequency among four tribal groups, i.e. Mina, Garasia, Damor and Saharia of western India. A comparative analysis with different tribal as well as world population has also been undertaken to have a view of its worldwide frequency distribution. Our results reveal a frequency distribution varying from 22.6% to 66.9% with respect to GSTM1gene polymorphism and from 19.1% to 33.0% with respect to GSTT1 gene in the studied populations. To the best of our knowledge this is the first report on the GSTM1and GSTT1frequency distribution among the tribal population of western India and our study shows that the Mina tribal population has the highest frequency of GSTM1.

Spectral and thermal characterization of halogen-bonded novel crystalline oligo(p-bromoacetophenone formaldehyde).

A novel oligomer p-bromoacetophenone-formaldehyde (OPBAF) was prepared by condensation polymerization in the presence of an acid as catalyst. It was characterized by FT-IR, NMR, pyrolysis GC/MS, XRD, GPC, and TG-DTG. The crystallographic parameters and space group for hexagonal OPBAF were a = b = 2.0810 Å and c = 9.2340 Å and P3̅m1, respectively. The degradation activation energy of the oligomer was studied by the Kissinger method. The kinetic parameters were also obtained. Halogen bonding interactions in the crystalline oligomers are identified between halogen···carbonyl and halogen···halogen. Little correlation was found in the halogen bonding motifs exhibited as a function of bromine present in this oligomer, and a unique bifurcated Br···Br/Br···O═C halogen bonding synthon was identified. This newly developed oligomer may be used as an interesting material for the development of 3D-designed structural products.