Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and to ...relieve neuropathic pain. The present study aims at investigating the direct blockade of hERG potassium channel by mexiletine and its metabolite m‐hydroxymexiletine (MHM). Our data show that mexiletine inhibits hERG in a time‐ and voltage‐dependent manner, with an IC50 of 3.7 ± 0.7 μmol/L. Analysis of the initial onset of current inhibition during a depolarizing test pulse indicates mexiletine binds preferentially to the open state of the hERG channel. Looking for a possible mexiletine alternative, we show that m‐hydroxymexiletine (MHM), a minor mexiletine metabolite recently reported to be as active as the parent compound in an arrhythmia animal model, is a weaker hERG channel blocker, compared to mexiletine (IC50 = 22.4 ± 1.2 μmol/L). The hERG aromatic residues located in the S6 helix (Tyr652 and Phe656) are crucial in the binding of mexiletine and the different affinities of mexiletine and MHM with hERG channel are interpreted by modeling their corresponding binding interactions through ab initio calculations. The simulations demonstrate that the introduction of a hydroxyl group on the meta‐position of the aromatic portion of mexiletine weakens the interaction of the drug xylyloxy moiety with Tyr652. These results provide further insights into the molecular basis of drug/hERG interactions and, in agreement with previously reported results on clofilium and ibutilide analogs, support the possibility of reducing hERG potency and related toxicity by modifying the aromatic pattern of substitution of clinically relevant compounds.
Enterococcus faecalis is a Gram-positive commensal inhabitant of the intestinal tract of humans, animals, and insects. However, it is also an opportunistic pathogen and has emerged as a leading cause ...of hospital-acquired extraintestinal infections. Fluoroquinolones have been frequently used to treat E. faecalis infections, and the emergence of fluoroquinolone-resistant E. faecalis strains has recently been reported in several countries. Thus, the identifications of new antibiotics specifically directed to E. faecalis may be envisaged. In this paper, a new series of N-1,3-benzothiazol-2-ylbenzamides have been designed, synthesized, and evaluated for their in vitro antimicrobial activities. Among the tested compounds, 3i was active against E. faecalis.
A new series of 6-substituted 2-aminobenzothiazole derivatives were synthesized and screened in vitro as potential antimicrobials. Almost all the compounds showed antifungal activity. In particular, ...compounds 1n,o, designed on the basis of molecular modeling studies, were the best of the series, showing MIC values of 4–8 μg/mL against Candida albicans, Candida parapsilosis and Candida tropicalis. None of the two compounds did show any cytotoxicity effect on human THP-1 cells.
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•Search for new drugs for the treatment of infectious diseases.•A new series of 2-aminobenzothiazole derivatives were synthesized.•All the newly synthesized compounds were fully characterized by spectroscopic studies.•Their antibacterial and antifungal activities were evaluated.•Two compounds were antifungal agents against Candida krusei more potent than fluconazole.
Starting from 2‐amino‐1,3‐mercaptobenzothiazoles recently reported (1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h), a series of the corresponding 2‐mercapto‐1,3‐benzothiazole isosters (2a, 2b, 2c, 2d, 2e, 2f, 2g, ...2h) were screened for their in vitro antibacterial and antifungal activities. Results underline that the presence of the mercapto moiety at the 2‐position of the heterocyclic nucleus is crucial for activity against bacteria. The biological screening against Candida spp. identified commercial 2f as the most promising compound as antifungal against Candida albicans and tropicalis. Molecular modeling studies supported these results. Then, to enlarge structure‐activity relationship (SAR) studies on series 1, newly synthesized compounds (1k, 1l, 1m, 1n, 1o, 1p) were reported. All the compounds belonging to this series and bearing a bulky substituent at the 6‐position of the aryl moiety showed high antifungal activity.
Mexiletine is a very well-known class IB antiarrhythmic drug, whose enantiomers differ in both pharmacodynamic and pharmacokinetic properties, the (R)-isomer being the eutomer on experimental ...arrhythmias and in binding studies on cardiac voltage-gated sodium channels. meta-Hydroxymexiletine (MHM) is a minor metabolite of mexiletine, which has demonstrated to be more potent than the parent compound. Herein we report the synthesis and biological evaluation of MHM enantiomers for their potential antiarrhythmic activity. The same stereoselectivity pattern observed for mexiletine was found for MHM: the (R)-enantiomer of MHM was the eutomer on ac-arrhythmia also showing a negative inotropism higher than the one displayed by mexiletine and, at the same time, a decreased vasorelaxant activity on guinea-pig left atrium and guinea-pig ileum longitudinal smooth muscle.
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•meta-Hydroxymexiletine (MHM) is a metabolite of mexiletine more potent than mexiletine.•MHM enantiomers were synthesized.•(R)-MHM exhibited high antiarrhythmic activity.•(R)-MHM represents a valid candidate for a chiral switch.
m-Hydroxymexiletine (MHM) is a metabolite of mexiletine, a well known class IB anti-arrhythmic drug, which presents almost twice the activity of the parent compound on cardiac voltage-gated sodium ...channels. Given the different activity of mexiletine enantiomers on sodium currents (being the R-isomer the eutomer), it is conceivable that (R)- and(S)-MHM could differ in pharmacodynamic and pharmacokinetic properties, too. Herein we report the efficient synthesis of MHM enantiomers that could represent useful tools for further investigations on stereospecific requirements of the voltage-gated sodium channel binding site. MHM enantiomers and all the homochiral intermediates were fully characterized. The ee values for (R)- and (S)-MHM were >99%, as assessed by capillary electrophoresis using β-cyclodextrin sulfated sodium salt as a chiral selector.
m-Hydroxymexiletine (MHM), a minor metabolite of the class IB anti-arrhythmic drug mexiletine, is about two fold more potent than the parent compound on human cardiac voltage-gated sodium channels ...(hNav1.5), and equipotent to mexiletine on human skeletal-muscle voltage-gated sodium channels (hNav1.4). Herein, an alternative and simplified synthesis of this promising compound has been accomplished. This route, as well as being more efficient, has the advantage, over the first, to avoid the use of oxidizing agents, such as the meta-chloroperoxybenzoic acid.
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