Highly sensitive and selective liquid chromatography/tandem mass spectrometry (LC–MS/MS) method was developed and validated for the simultaneous estimation of the recently approved oral hypoglycemic mixture; metformin (MET) and canagliflozin (CFZ) in human plasma using propranolol HCl (PPL) and tadalafil (TDF) as internal standards (IS), respectively. Analytes were extracted using protein precipitation induced by acetonitrile then liquid–liquid extraction was performed using ethyl acetate. Reversed phase HPLC was carried out using C18 analytical column (50 mm × 4.6 mm i.d., 5 µm) with a simple isocratic mobile phase composed of 0.1% formic acid and acetonitrile (60:40, v/v ). Detection was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique, operating in multiple reaction monitoring (MRM), with the transitions of m/z 130.2 → 60.1, m/z 462.3 → 191.0, m/z 260.2 → 183.0 and m/z 390.2 → 268.2 for MET, CFZ, PPL and TDF, respectively, in the positive ion mode. The analysis was carried out within 5 min over a linear concentration range of 50–5000 ng/mL for MET and 10–1000 ng/mL for CFZ. The method was validated in accordance with the FDA guidelines for bioanalytical method. All obtained recoveries were higher than 90.0% while the accuracy was in the range of 88.14–113.05% and the relative standard deviation was below 10.0% for all investigated drugs by the proposed method. The achieved promising results has allowed for the successful application of the developed LC–MS/MS method to a pharmacokinetic study of the target drugs after their oral administration to Egyptian healthy volunteers. The pharmacokinetic study was accomplished after the agreement of the ethics committee. Electronic supplementary material The online version of this article (10.1186/s13065-019-0597-4) contains supplementary material, which is available to authorized users.

Cyclic peptides are capable of binding and modulating challenging drug targets including protein-protein interactions. However, their lack of membrane permeability prevents their applications against intracellular targets. In this study, we show that it is possible to design a cell-permeable and biologically active cycloheptapeptide inhibitor against intracellular enzyme peptidyl-prolyl isomerase Pin1 by integrating cell-penetrating and target-binding sequences.

Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.

SUMMARYSeveral methods for the specific deuteration of cannabmoids are described. Deuteration of the phenolic ring was accomplished by treatment with BF, .Et10 followed by quenching with a solution of Na, CO, in Da 0 resulting in deuterium incorporation in both the 2 and 4 positions. Regioselective incorporation of deuterium into either the 2 or 4 position of A*-THC was achieved using Florisil spiked with either D,O or H,O. Deuteration at positions 8, 10 and I1 was achieved by addition of DCI gas to the appropriate tetrahydrocannabinol to form 9-chlorohexahydrocannabmol labeled at either of the above positions, followed by elimination of hydrogen-or deuterium chloride with potassium-ten-amylate. W irradiation of specifically labeled Aa -THC gave the correspondingly labeled A9.II -THC.

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Acrylamide moiety is a pronounced Michael acceptor that has drawn much interest in a wide array of drugs designed for various therapeutic purposes. Herein we outline different synthetic pathways, scientific bases for its chemical reactivity and how it is functionalized for design of new therapeutic entities, in addition to a brief insight into spectrum of reported biological activities of acrylamide containing compounds up to date.

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