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Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.

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A silver amperometric detector coupled to liquid chromatography (LC) was used for the determination of 6-thioguanine (6-TG) and two of its metabolites, thiouric acid (TU) and 2-amino-6-mercaptopurine riboside (6-TGR). The silver detector coupled to LC operated at a low applied potential (0.08 V vs Ag/AgCl) and offered a chromatogram with peak responses corresponding to molecules interacting with silver, namely, chloride ions and small soluble biothiols in addition to the organothiol drug compounds investigated. Online electrochemical surface cleaning permitted the improvement of the repeatability and peak shape of the recorded signal compared to direct current amperometric detection (AD) when operating in chloride containing media. The studied molecules were eluted isocratically within 5 min on a reversed-phase C18 column without interference from endogenous biothiols present in urine samples. Diluted urine samples (1:1) were directly injected in the LC setup; a linear calibration curve was obtained between peak area and analyte concentration between 0.1 and 10 μM for all the studied molecules. Limits of detection (LODs) were 0.03, 0.008, and 0.01 μM, and the limits of quantification (LOQs) were 0.1, 0.02, and 0.03 μM for TU, 6-TG, and 6-TGR, respectively. Within-day RSDs were 2%, 0.8%, and 1% and between-day RSDs were 2%, 0.9%, 2% for TU, 6-TG, and 6-TGR, respectively. Recoveries in spiked urine were 99.8%, 99.9%, and 99.0% for TU, 6-TG, and 6-TGR, respectively.

Screen printed electrodes (SPEs), in addition to their utility in the electrochemical quantification of compounds of pharmacological interest may be used (i) for studying the redox pattern of drug candidates by cyclic voltammetry, (ii) for electrochemical synthesis in microvolumes (microelectrosynthesis) at a selected applied potential with subsequent off-line LC-MS identification of the generated products, and (iii) for monitoring enzymatic reactions in microvolumes of samples. The resulting data are of valuable predictive value for in vitro metabolic stability assays. Acetaminophen (APAP) was used as relevant model drug compound to illustrate potential applications of SPEs in pharmaceutical research. The electrooxidation of APAP was studied, in the absence and presence of endogenous thiols, in microvolume sample by cyclic voltammetry and by microelectrolysis at a carbon based SPE (CSPE) and the generated products were identified off-line by liquid chromatography coupled to mass spectrometry (LC-MS).