Synthetic route optimization of Sumepirin antiepileptic drug candidate

In this work we describe the transformation of synthetic route of the antiepileptic drug candidate Sumepirin starting from discovery stage. Initial method included six step process requiring two steps of purification using colon chromatography and has poor overall yield of target compound. The process developed is convenient, scalable, technological and meet the most of conditions of green chemistry. The overall yield was increased up to 62.5% in four steps without colon chromatography purification which allows to obtain the target compound with purity of 99.5+% which is especially important for the active ingredient

SYNTHETIC ROUTE OPTIMIZATION OF SUMEPIRIN ANTIEPILEPTIC DRUG CANDIDATE

Epilepsy is one of the most common chronic diseases of the nervous system in the world, which affects both children and adults. 30% of patients with epilepsy are pharmacoresistant. Sumepirin 1 is a novel antiepileptic drug candidate developed in the Scientific and Educational Center of Pharmaceutics of the Kazan Federal University and having pronounced antiseizure effect and improved safety profile. This compound is pyridoxine-based molecule with residue of methanesulfonic acid in the 6th position of pyridoxine ring.This work was supported by subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientificactivities (project number 0671-2020-0053

Kinetics of the conformer reactions: II. 1 significance of media in the electrophilic addition reactions

The kinetics of electrophilic addition reaction of bromine to a multiple bond in a series of conformationally unhomogenous 2-substituted 1,3-dioxa-5-cycloheptenes was studied. We found that the compounds with trans structure are formed. The partial reaction rate constant for chair and twist forms and the reaction susceptibility parameters to the substituent electronic effect at the C2 atom are obtained. Relative reactivity of the alternative steric structures is defined by the specific solvation of the substrate. The result obtained are compared with those achieved without accounting for conformational term

New Mixed-Ligand Complexes of Cobalt(II), Nickel(II), and Copper(II) with Adenosine 5′-Triphosphate and Amino Acids

In the systems metal [Co(II), Ni(II), Cu(II)]-adenosine 5′-triphosphate-amino acid (glycine, α-alanine, valine, proline) new mixed-ligand complexes with the adenosine 5′-triphosphate coordinated by deprotonated hydroxy groups of the ribose moiety were found; the stability and lability parameters of the compexes were determined, and their structures were assessed

Stereochemistry of seven-membered heterocycles: XLII. A theoretical study of stereochemistry of H complexes formed by conformationally nonuniform 2-R-1,3-dioxacyclohept-5-enes with some proton donors

According to semiempirical AM1 calculations, the stability of the boat and twist forms of 2-R-1,3-dioxacyclohept-5-enes depends on the size of substituents at the acetal carbon atom. The twist form gives diastereomeric H complexes with chloroform and methanol of the cis and trans structure, containing monocentered hydrogen bonds, whereas the chair conformation preferably forms complexes with a two-centered hydrogen bond. Based on theoretical data (ΓOH, ΔH, geometry of complexes), the specific features of H complexes of the conformers in electrophilic addition and cycloaddition were revealed. Considerable preferableness of the exo attack of the diastereotopic double bond in the H complex having the chair form is due to the steric accessibility of the exo side, whereas in the complexes of the twist form the facial selectivity is appreciably lower

Stereochemistry of seven-membered heterocycles: XLII. A theoretical study of stereochemistry of H complexes formed by conformationally nonuniform 2-R-1,3-dioxacyclohept-5-enes with some proton donors

According to semiempirical AM1 calculations, the stability of the boat and twist forms of 2-R-1,3-dioxacyclohept-5-enes depends on the size of substituents at the acetal carbon atom. The twist form gives diastereomeric H complexes with chloroform and methanol of the cis and trans structure, containing monocentered hydrogen bonds, whereas the chair conformation preferably forms complexes with a two-centered hydrogen bond. Based on theoretical data (ΓOH, ΔH, geometry of complexes), the specific features of H complexes of the conformers in electrophilic addition and cycloaddition were revealed. Considerable preferableness of the exo attack of the diastereotopic double bond in the H complex having the chair form is due to the steric accessibility of the exo side, whereas in the complexes of the twist form the facial selectivity is appreciably lower

New derivatives of pyridoxine exhibit high antibacterial activity against biofilm-embedded staphylococcus cells

© 2015 Airat R. Kayumov et al. Opportunistic bacteria Staphylococcus aureus and Staphylococcus epidermidis often form rigid biofilms on tissues and inorganic surfaces. In the biofilm bacterial cells are embedded in a self-produced polysaccharide matrix and thereby are inaccessible to biocides, antibiotics, or host immune system. Here we show the antibacterial activity of newly synthesized cationic biocides, the quaternary ammonium, and bisphosphonium salts of pyridoxine (vitamin B6) against biofilm-embedded Staphylococci. The derivatives of 6-hydroxymethylpyridoxine were ineffective against biofilm-embedded S. aureus and S. epidermidis at concentrations up to 64 g/mL, although all compounds tested exhibited low MICs (2 g/mL) against planktonic cells. In contrast, the quaternary ammonium salt of pyridoxine (N,N-dimethyl-N-((2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methyl)octadecan-1-aminium chloride (3)) demonstrated high biocidal activity against both planktonic and biofilm-embedded bacteria. Thus, the complete death of biofilm-embedded S. aureus and S. epidermidis cells was obtained at concentrations of 64 and 16 g/mL, respectively. We suggest that the quaternary ammonium salts of pyridoxine are perspective to design new synthetic antibiotics and disinfectants for external application against biofilm-embedded cells

The nature of lithium perchlorate and gallium chloride salt effect in cycloaddition reactions

Comparing the acceleration effects of (4 + 2)-, (3 + 2)- and (2 + 2)-cycloaddition reactions in the presence of the salts of two types: gallium chloride in inert solvents and lithium perchlorate (LP) in diethyl ether (DE) it was observed that in the presence of GaCl3 the acceleration effect is approximately the same (104 times) for the studied reactions, while in LPDE medium for the same reactions strong increase (up to 104 times), weak increase or even decrease of the rate and equilibrium constants take place even with the common dienophile depending on the nature of the second reagent. it was suggested that the acceleration effect of cycloaddition reactions in the presence of such Lewis acids as aluminum, gallium or boron halides is due to the sharp increase of Π-acceptor properties of dienophiles and therefore increasing energy of orbital interaction, whereas LPDE medium demonstrates strong stabilization of static and/or dynamic polar forms and favors reactions with charge control

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

© 2017 The Author(s). Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD 50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity

Complexation and ligand exchange in aqueous of Cu(II) and Ni(II) with hydrazides of some aromatic acids

Solvation and complexation of Cu(II) and Ni(II) with benzoic (L′), p-methoxybenzoic (L″), and isonicotinic (L) acid hydrazides in aqueous-ethanol solutions (ethanol mole fraction 0.07-0.68) were studied by pH-metry, spectrophotometry, and nuclear magnetic relaxation. The formation constants of the species M(L′)2+, M(L′) 2 2+ , M(L″)2+, M(L″) 2 2+ , M(LH)3+, M(L)2+, M(L)(LH)3+, and M(L) 2 2+ , where M = Cu2+ and Ni2+, were determined. With isonicotinic acid hydrazide, a change in the coordination mode was observed in an isomer of Cu(L) 2 2+ , with one of the ligands coordinating in the bidentate fashion, and the other, in the monodentate fashion via the pyridine nitrogen atom. The suggested structures were confirmed by analysis of the parameters of the ESR and electronic absorption spectra of the complexes. The rate constants of ligand exchange and formation of the complexes Cu(L′)2+, Cu(L′) 2 2+ , Cu(L″)2+, and Cu(L″) 2 2+ in aqueous solutions were determined from nuclear magnetic relaxation measurements; the reactions occur by the associative mechanism. A cyclic process of reduction of Cu(II) to colloidal copper in the presence of L″ and atmospheric oxygen is described. © Pleiades Publishing, Inc., 2006