Design, synthesis, antibacterial activity and toxicity of novel quaternary ammonium compounds based on pyridoxine and fatty acids.

Autor: Sapozhnikov SV; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Sabirova AE; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Shtyrlin NV; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Druk AY; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Agafonova MN; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Chirkova MN; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Kazakova RR; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Grishaev DY; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Nikishova TV; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Krylova ES; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Nikitina EV; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Kayumov AR; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation., Shtyrlin YG; Kazan (Volga Region) Federal University, Kremlyovskaya St. 18, Kazan, 420008, Russian Federation. Electronic address: yurii.shtyrlin@kpfu.ru.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Feb 05; Vol. 211, pp. 113100. Date of Electronic Publication: 2020 Dec 17.
DOI: 10.1016/j.ejmech.2020.113100
Abstrakt: A diverse series of 43 novel "soft antimicrobials" based on quaternary ammonium pyridoxine derivatives which include six-membered acetals and ketals of pyridoxine bound via cleavable linker moieties (amide, ester) with a fragment of fatty carboxylic acid was designed. Nine compounds exhibited in vitro promising antibacterial activity against Gram-positive and Gram-negative bacterial strains with MIC values comparable with reference antiseptics miramistin, benzalkonium chloride and chlorohexidine. On various clinical isolates, the lead compounds 6i and 12a exhibited antibacterial activity comparable with that of benzalkonium chloride while higher than that of miramistin. Moreover, 6i and 12a were able to kill bacteria embedded into the matrix of mono- and dual species biofilms. The treatment of bacterial cells by either 6i and 12a lead to fast depolarization of the membrane suggesting that the membrane is an apparent molecular target of compounds. 6i and 12a were non mutagenic neither in SOS-chromotest nor in Ames test and non-toxic in vivo at acute oral (LD 50  > 2000 mg/kg) and cutaneous administration (LD 50  > 2500 mg/kg) on mice. Taken together, our data allow suggesting described active compounds as promising starting point for the new antibacterial agents development.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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