Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

Abstract

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.

N-Aryl-2,6-dimethylbenzamides, a New Generation of Tocainide Analogues as Blockers of Skeletal Muscle Voltage-Gated Sodium Channels

“…The affinity increases when the channel is opened or inactivated, thus leading to a stronger drug potency in conditions of membrane depolarization or high frequency trains of action potentials, as occurs in pathological conditions. A large screening of newly synthesized analogues of Mex helped us to clarify the molecular requisites for this class of drugs. − Importantly, the critical structural requirements are the same, confirming the fact that those identified are the main pharmacophore groups and providing information useful for further docking energy studies. − In particular, our recent studies related to Mex show that the combination of the homologated alkyl chain with a lipophilic phenyl moiety on the asymmetric center increases up to 100-fold both potency and use-dependent block of sodium currents, resulting in active compounds in the low micromolar range. , Likewise, structural modifications of Toc carried out at the level of the amino terminal group, another main pharmacophore group, led to potent N-benzylated derivatives acting in the submicromolar range during use-dependent block. In particular, BnβPro (Figure ) was the strongest use-dependent blocker among Toc analogues .…”

X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors

“…Ester (RS)-60 was obtained following Williamson reaction of (RS)-bromopropanoate, (RS)-58 with 2,6-dimethylphenol, while (R)-and (S)-61 were obtained by Mitsunobu reaction [34,35] Compound 24 was obtained by reacting 2-(methoxycarbonyl)benzoic acid with p-toluidine in presence of EEDQ as previously described (Scheme 5) [36]. The nitration of (R)-63, followed by reduction of the nitro group gave (R)-7 and, successively, (R)-43 (Scheme 6), as reported in the literature [26,37,38]. Compounds 25 and 55 were prepared by protecting 4-phenylbutan-1amine with phthalimide or tetrachlorophthalimide, respectively (Scheme 7).…”

1,3-Benzothiazoles as Antimicrobial Agents

“…Elemental analyses were performed on a Eurovector Euro EA 3000 analyzer. Chromatographic separations were performed on silica gel columns by column chromatography on silica gel (Kieselgel 60, 0.040–0.063 mm, Merck, Darmstadt, Germany) as previously described . TLC analyses were performed on precoated silica gel on aluminum sheets (Kieselgel 60 F 254 , Merck).…”