Coumarin Derivatives as New Toxic Compounds to Selected K12, R1-R4 E. coli Strains.

Paweł Kowalczyk,Arleta Madej,Daniel Paprocki,Ryszard Ostaszewski,Mateusz Szymczak

doi:10.3390/ma13112499

Abstract

Coumarins are natural compounds that were detected in 80 species of plants. They have numerous applications including the medical, food, tobacco, perfumery, and spirit industries. They show anti-swelling and diastolic effects. However, excess consumption of coumarins may adversely affect our health, because they are easily absorbed from the intestines into the lymph and blood, causing cirrhosis of the liver. Peptidomimetics are molecules whose structure and function are similar to those of peptides. They are an important group of compounds with biological, microbiological, anti-inflammatory, and anti-cancer properties. Therefore, studies on new peptidomimetics, which load the effect of native peptides, whose half-life in the body is much longer due to structural modifications, are extremely important. A preliminary study of coumarin analogues and its derivatives as new potential antimicrobial drugs containing carboxylic acid or ester was performed to determine their basic structure related to their biological features against various types of Gram-stained bacteria by lipopolysaccharide (LPS). We hypothesized that the toxicity (antibacterial activity) of coumarin derivatives is dependent on the of LPS in bacteria and nature and position of the substituent which may be carboxylic acid, hydroxyl groups, or esters. In order to verify this hypothesis, we used K12 (smooth) and R1–R4 (rough) Escherichia coli strains which are characterized by differences in the type of LPS, especially in the O-antigen region, the outermost LPS layer. In our work, we synthesized 17 peptidomimetics containing a coumarin scaffold and checked their influence on K12 and R1–R4 E. coli strains possessing smooth and rough LPS. We also measured the damage of plasmid DNA caused by target compounds. The results of our studies clearly support the conclusion that coumarin peptidomimetics are antagonistic compounds to many of the currently used antibiotics. The high biological activity of the selected coumarin peptidomimetic was associated with identification of the so-called magic methyl groups, which substantially change the biochemical properties of target compounds. Investigating the effects of these compounds is particularly important in the era of increasingly common resistance in bacteria.

Highlights

The Passerini reaction can be used for simple synthesis of libraries of compounds like coumarins and their derivatives, with can be later used for biological studies [1,2,3,4,5,6,7]
The antibacterial effect of the tested compounds was significantly different compared to the tested E. coli strains K12 and R1–R4
We showed that the peptidomimetics used may be toxic to E. coli R1–R4 strains containing different lengths of LPS, with a specificity in growth rate and metabolic activity, based on minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) tests

Summary

Introduction

The Passerini reaction can be used for simple synthesis of libraries of compounds like coumarins and their derivatives, with can be later used for biological studies [1,2,3,4,5,6,7]. Materials 2020, 13, 2499 as secondary metabolites of plants, and they were isolated from more than 80 species of plants and microorganisms [8] They were first discovered in 1820 and synthesized in 1868. These aromatic compounds are widely used in medicine; for example, coumarin derivatives have a toxic effect on cancer cells, preventing inflammation and working against blood clots [9,10,11,12,13]. Pure coumarins are much more reactive than commonly used antibiotics [12,13] Drugs such as captopril, acenocoumarol, and warfarin are vitamin K antagonists widely used as anticoagulants [14]. Anti-inflammatory and antiviral properties of coumarin derivatives were evaluated on Mycobacterium tuberculosis [16,17,18]

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Conclusion