The Synthesis and Evaluation of Aminocoumarin Peptidomimetics as Cytotoxic Agents on Model Bacterial E. coli Strains

Paweł Kowalczyk; Monika Wilk; Parul Parul; Mateusz Szymczak; Karol Kramkowski; Stanisława Raj; Grzegorz Skiba; Dorota Sulejczak; Patrycja Kleczkowska; Ryszard Ostaszewski

doi:10.3390/ma14195725

The Synthesis and Evaluation of Aminocoumarin Peptidomimetics as Cytotoxic Agents on Model Bacterial E. coli Strains

Materials (Basel). 2021 Sep 30;14(19):5725. doi: 10.3390/ma14195725.

Authors

Affiliations

¹ Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland.
² Institute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland.
³ Department of Molecular Virology, Faculty of Biology, Institute of Microbiology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland.
⁴ Department of Physical Chemistry, Medical University of Bialystok, Kilińskiego 1 Str., 15-089 Białystok, Poland.
⁵ Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
⁶ Centre for Preclinical Research (CBP), Department of Pharmacodynamics, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
⁷ Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-163 Warsaw, Poland.

Abstract

This work presents the successful synthesis of a library of novel peptidomimetics via Ugi multicomponent reaction. Most of these peptidomimetics contain differently substituted aminocoumarin; 7-amino-4-methylcoumarin and 7-amino-4-(trifluoromethyl) coumarin. Inspired by the biological properties of coumarin derivatives and peptidomimetics, we proposed the synthesis of coumarin incorporated peptidomimetics. We studied the potential of synthesized compounds as antimicrobial drugs on model E. coli bacterial strains (k12 and R2-R4). To highlight the importance of coumarin in antimicrobial resistance, we also synthesized the structurally similar peptidomimetics, using benzylamine. Preliminary cellular studies suggest that the compounds with coumarin derivatives have more potential as antimicrobial agents compared to the compounds without coumarin. We also analyzed the effect of aldehyde, free acid group and ester group on the course of their antimicrobial properties.

Keywords: DNA-N-glycosylase; Fpg protein-formamidopyrimidine; Ugi multicomponent reaction; coumarin derivatives; lipopolysaccharide (LPS); oxidative stress.