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. 2022 May 27;15(11):3846.
doi: 10.3390/ma15113846.

Relationship between Structure and Antibacterial Activity of α-Aminophosphonate Derivatives Obtained via Lipase-Catalyzed Kabachnik-Fields Reaction

Dominik Koszelewski  1 , Paweł Kowalczyk  2 , Paweł Śmigielski  1 , Jan Samsonowicz-Górski  1 , Karol Kramkowski  3 , Aleksandra Wypych  4 , Mateusz Szymczak  5 , Ryszard Ostaszewski  2
Affiliations

Relationship between Structure and Antibacterial Activity of α-Aminophosphonate Derivatives Obtained via Lipase-Catalyzed Kabachnik-Fields Reaction

Dominik Koszelewski et al. Materials (Basel). .

Abstract

We reported a new method dealing with the synthesis of novel pharmacologically relevant α-aminophosphonate derivatives via a lipase-catalyzed Kabachnik−Fields reaction with yields of up to 93%. The advantages of this protocol are excellent yields, mild reaction conditions, low costs, and sustainability. The developed protocol is applicable to a range of H-phosphites and organic amines, providing a wide substrate scope. A new class of α-aminophosphonate analogues possessing P-chiral centers was also synthesized. The synthesized compounds were characterized on the basis of their antimicrobial activities against E. coli. The impact of the various alkoxy groups on antimicrobial activity was demonstrated. The crucial role of the substituents, located at the aromatic rings in the phenylethyloxy and benzyloxy groups, on the inhibitory action against selected pathogenic E. coli strains was revealed. The observed results are especially important because of increasing resistance of bacteria to various drugs and antibiotics.

Keywords: Kabachnik−Fields reaction; antimicrobial activity; α-aminophosphonates.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 6
Figure 6
Percentage of plasmid DNA recognized by the Fpg enzymes (y-axis) with model bacterial, K12, and R2–R4 strains (x-axis). All analyzed compounds numbered were statistically significant at <0.05 (see Table 2).
Figure 7
Figure 7
Examples of MIC with model bacterial strains K12, R2, R3, and R4 for studying the antibiotics ciprofloxacin (cipro), bleomycin (bleo), and cloxacillin (clox). The x-axis features antibiotics used sequentially. The y-axis features the MIC value in µg/mL−1.
Figure 1
Figure 1
Biologically active antimicrobial α-aminophosphonate derivatives.
Figure 2
Figure 2
α-Aminophosphonates 1–16 obtained via an enzyme-catalyzed Kabachnik–Fields reaction. Yields in brackets provided for isolated products 1–16.
Scheme 1
Scheme 1
Enzyme-catalyzed synthesis of α-aminophosphonates 1–16.
Scheme 2
Scheme 2
Plausible mechanism of the porcine pancreas lipase-catalyzed Kabachnik−Fields reaction.
Figure 3
Figure 3
Minimum inhibitory concentration (MIC) of the phosphonate derivatives in model bacterial strains. The x-axis features compounds 1–16 used sequentially. The y-axis shows the MIC value in µg/mL−1. Investigated strains of E. coli K12 as the control (blue), R2 strains (orange), R3 strains (grey), and R4 strains (yellow). The order in which the compounds were applied to the plate is shown in Supplementary Materials Figure S1.
Figure 4
Figure 4
Minimum bactericidal concentration (MBC) of the phosphonate derivatives. The x-axis features compounds 1–16 used sequentially. The y-axis shows the MIC value in µg/mL−1. Investigated strains of E. coli K12 as control (blue), R2 strains (orange), R3 strains (grey), and R4 strains (yellow). The order in which the compounds were applied to the plate is shown in Supplementary Materials Figure S1.
Figure 5
Figure 5
The ratio of MBC/MIC of the phosphonate derivatives. The x-axis features compounds 1–16 used sequentially. The y-axis shows the MIC value in µg/mL−1. Investigated strains of E. coli K12 as control (blue), R2 strains (orange), R3 strains (grey), and R4 strains (yellow). The order in which the compounds were applied to the plate is shown in Supplementary Materials Figure S1.
Figure 8
Figure 8
Percentage of bacterial DNA recognized by the Fpg enzymes in model bacterial strains after ciprofloxacin, bleomycin, and cloxacillin treatment. The compounds were statistically significant at p < 0.05.
See this image and copyright information in PMC

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