Synthesis of 6‐Fluoro‐7‐cyclic Amino‐substituted Dicarboxylic Acid Quinolones and their Antibacterial Activity

Novel 1‐carboxymethyl‐6‐fluoro‐7‐cyclic amino‐substituted‐4‐oxo‐1,4‐dihydroquinolone‐3‐carboxylic acids 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i , 7j , 7k , 7l , 7m , 7n were synthesized as a new class of quinolones. Ethyl‐6‐fluoro‐7‐chloro‐1,4‐dihydro‐4‐quinoline‐3‐carboxylic acid was prepared from conventional method and reacted with ethyl bromoacetate to furnish N‐carboxymethyl derivatives. The compounds were screed against various Gram‐positive and Gram‐negative bacterial strains. Antibacterial activity data is validated by molecular docking studies.     

Ultra‐performance liquid chromatography tandem mass spectrometry method for the determination of AZ66, a sigma receptor ligand,in rat plasma and its application to in vivo pharmacokinetics

Methamphetamine abuse continues as a major problem in the USA owing to its powerful psychological addictive properties. AZ66, 3‐[4‐(4‐cyclohexylpiperazine‐1‐yl)pentyl]‐6‐fluorobenzo[d]thiazole‐2(3H)‐one, an optimized sigma receptor ligand, is a promising therapeutic agent against methamphetamine. To study the in vivo pharmacokinetics of this novel sigma receptor ligand in rats, a sensitive ultra‐performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed in rat plasma and validated. The developed method requires a small volume of plasma (100 μL) and a simple liquid–liquid extraction. The chromatographic separations were achieved in 3.3 min using an Acquity UPLC BEH Shield RP₁₈ column. The mass spectrophotometric detection was carried out using a Waters Micromass Quattro MicroTM triple‐quadrupole system. Multiple reaction monitoring was used for the quantitation with transitions m/z 406 → m/z 181 for AZ66 and m/z 448 → m/z 285 for aripiprazole. The method was validated over a concentration range of 1–3500 ng/mL and the lower limit of quantitation was determined to be 1 ng/mL. Validation of the assay demonstrated that the developed UPLC/MS/MS method was sensitive, accurate and selective for the determination of AZ66 in rat plasma. The present method has been successfully applied to an i.v. pharmacokinetic study in Sprague–Dawley rats. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis,spectroscopic, and computational studies of charge‐transfer complexation between benzidine with 2,3‐dichloro‐5,6‐dicyano‐p‐benzoquinone and chloronil

The solid charge transfer (CT) complexes that have been formed from the reactions of donor benzidine (BZ) and the π‐acceptors such as 2,3‐dichloro‐5,6‐dicyano‐p‐benzoquinone (DDQ) and chloronil (CHL) have been studied and characterized experimentally and theoretically. The experimental work which includes the use of UV‐visible spectroscopy to identify the CT band of the CT‐complex. The composition of the complexes has been investigated successfully by using spectrophotometric titration and Job method of continuous variation to be 1:1. Furthermore, to calculate the formation constant and molar extinction coefficient, we have used the Benesi‐Hildebrand equation. Infrared and proton nuclear magnetic resonance spectral studies were used to characterize and confirm the formation of CT‐complex. The experimental studies were well supported by quantum chemical simulations by using density functional theory. The computational analysis of molecular geometry, Mulliken charges, and molecular electrostatic potential surfaces of reactants and complexes is very much helpful in assigning the CT route. The C═O bond length of DDQ and CHL increased upon complexation with BZ. We have also observed that the substantial amount of charge has been transferred from BZ to DDQ and CHL in the process of complexation. An excellent consistency has been achieved between experimental and theoretical results.     

Development and validation of a UPLC‐MS/MS method for the determination of 7‐hydroxymitragynine,a μ‐opioid agonist,in rat plasma and its application to a pharmacokinetic study

A simple, sensitive and specific ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) method was developed and validated to determine the concentrations of 7‐hydroxymitragynine in rat plasma. Following a single‐step liquid–liquid extraction of plasma samples using chloroform, 7‐hydroxymitragynine and the internal standard (tryptoline) were separated on an Acquity UPLC^TM BEH C₁₈ (1.7 µm, 2.1 × 50 mm) column using an isocratic elution at a flow rate of 0.2 mL/min. The mobile phase consisted of 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile (10:90, v/v). The run time was 2.5 min. The analysis was carried out under the multiple reaction‐monitoring mode using positive electrospray ionization. Protonated ions [M + H]⁺ and their respective product ions were monitored at the following transitions: 415 → 190 for 7‐hydroxymitragynine and 173 → 144 for the internal standard. The calibration curve was linear over the range of 10–4000 ng/mL (r² = 0.999) with a lower limit of quantification of 10 ng/mL. The extraction recoveries ranged from 62.0 to 67.3% at concentrations of 20, 600 and 3200 ng/mL). Intra‐ and inter‐day assay precisions (relative standard deviation) were <15% and the accuracy was within 96.5–104.0%. This validated method was successfully applied to quantify 7‐hydroxymitragynine in rat plasma following intravenous administration. Copyright © 2013 John Wiley & Sons, Ltd.     

Simple, Sensitive, High-Throughput Method for the Quantification of Mitragynine in Rat Plasma Using UPLC-MS and Its Application to an Intravenous Pharmacokinetic Study

A simple, sensitive and rapid ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method was developed and validated for the quantification of mitragynine in rat plasma using amitriptyline hydrochloride as an internal standard. Sample preparation involved a one-step liquid?Cliquid extraction using methyl t-butyl ether. Mitragynine was separated on an Acquity UPLC^? BEH HILIC column using isocratic elution with a mobile phase of 10 mM ammonium formate buffer containing 0.1% formic acid:acetonitrile (15:85, v/v). At a flow rate of 0.2 mL min^?1, the retention time of mitragynine was found to be 1.3 min. Ionization was performed in the positive ion electrospray mode. The selected mass-to-charge (m/z) ratio transition of mitragynine ion [M + H]⁺ used in the selected ion recording (SIR) was 399.1. The calibration curve was found to be linear over a concentration range of 1?C5,000 ng mL^?1 (r = 0.999) with a lower limit of quantification (LLOQ) of 1 ng mL^?1. Intra- and inter-day assay variations were found to be less than 15%. The extraction recoveries ranged from 85?C93% at the three concentrations (2, 400 and 4,000 ng mL^?1) in rat plasma. This method was successfully used to quantify mitragynine in rat plasma following intravenous administration of the compound.