Enzymatic Synthesis of a Novel Coumarin Aminophosphonates: Antibacterial Effects and Oxidative Stress Modulation on Selected E. coli Strains

Abstract

The objective of the present study was to evaluate the synergistic effect of two important pharmacophores, coumarin and α-amino dimethyl phosphonate moieties, on antimicrobial activity toward selected LPS-varied E. coli strains. Studied antimicrobial agents were prepared via a Kabachnik–Fields reaction promoted by lipases. The products were provided with an excellent yield (up to 92%) under mild, solvent- and metal-free conditions. A preliminary exploration of coumarin α-amino dimethyl phosphonate analogs as novel antimicrobial agents was carried out to determine the basic features of the structure responsible for the observed biological activity. The structure–activity relationship revealed that an inhibitory activity of the synthesized compounds is strongly related to the type of the substituents located in the phenyl ring. The collected data demonstrated that coumarin-based α-aminophosphonates can be potential antimicrobial drug candidates, which is particularly crucial due to the constantly increasing resistance of bacteria to commonly used antibiotics.

3-Substituted Coumarins Inhibit NorA and MepA Efflux Pumps of Staphylococcus aureus

“…Similar results were obtained with coumarin aminophosphonates, using propidium iodide as the fluorescent compound [47]. The findings of these studies differ from our results due to the types of chemical groups added to the coumarin structure, which have properties related to the cell membrane [48,49].…”

Evaluation of Antibacterial Activity against Nosocomial Pathogens of an Enzymatically Derived α-Aminophosphonates Possessing Coumarin Scaffold

“…Enzymes are very effective catalysts and have the advantage of being heavy-metal-free [47,48]. The target coumarin-based α-aminophosphonates 1-13 were prepared with yields of up to 92% according to the published procedure [42] (Figure 2). The structures of the compounds obtained were confirmed by NMR, provided in the Supplementary Materials (Figures S1-S26), and were consistent with published data.…”

“…The noxious activity of the 14 agents examined (Figure 2) is determined in bacterial cells, according to a previously published protocol [42], after the analysis of the MIC and MBC tests, for which the MIC values were recorded in the range of 2-8.3 µM, and the MBC values in the range of 2-9 (+/−0.5) µM for the Gram-negative investigated strains of A. baumannii (ATCC 17978), P. aeruginosa (ATCC 15442), Enterobacter cloacae (E. cloacae) (ATCC 49141), Porphyromonas gingivalis (P. gingivalis) (ATCC 33277), and Treponema denticola (T. denticola) (ATCC 35405) (Figures 3-5). The minimal inhibitory concentration (MIC) defines in vitro levels of susceptibility or resistance of specific bacterial strains to the antibiotic applied.…”

“…The appropriate combination of coumarin and phosphonate scaffolds was found to lead to the formation of compounds with the desired synergistic antimicrobial properties [39][40][41]. Our previous studies revealed that compounds possessing an aminocoumarin scaffold with fluorine and trifluoromethyl groups were effective inhibitors of the growth of various strains of LPS E. coli [42][43][44]. Thus, the objective of the present work is to identify the characteristics of the coumarin α-amino phosphonate structure that could be important for antibacterial activity against selected pathogenic strains with a particular emphasis on Gram-positive S. aureus and Gram-negative Enterobacter spp., which are responsible for nosocomial infection in all over the world.…”

Syntheses, reactivity, and biological applications of coumarins

“…Coumarin aminophosphonates ( Koszelewski et al, 2023 ) are considered new antibacterial agents, able to combat bacterial resistance, as reported by Zhou and co-workers ( Yang et al, 2023 ). Derivative 188 exhibited excellent inhibition potency against S. aureus (MIC = 0.5 µM; standard MIC = 16 µM) in vitro and showed considerable antibacterial potency in vivo ( Figure 2A ).…”