Abstract
An enzymatic route for phosphorous-carbon- bond formation is developed by discovering new promiscuous activity of lipase. This biocatalytic transformation of phosphorous-carbon- bond addition leads to biologically and pharmacologically relevant α-acyloxy phosphonates with methyl group in α-position. A series of target compounds were synthesized with yields ranging from 54% to 83% by enzymatic reaction with Candida cylindracea (CcL) lipase via Markovnikov addition of H-phosphites to vinyl esters. We carefully analyzed the best conditions for the given reaction such as the type of enzyme, temperature, and type of solvent. The developed protocol is applicable to a range of H-phosphites and vinyl esters significantly simplifying the preparation of synthetically challenging α-pivaloyloxy phosphonates. Further, the obtained compounds were validated as new potential antimicrobial drugs with characteristic E. coli bacterial strains and DNA modification recognized by the Fpg protein, N-methyl purine glycosylases as new substrates. The impact of the methyl group located in the α-position of the studied α-acyloxy phosphonates on the antimicrobial activity was demonstrated. The pivotal role of this group on inhibitory activity against selected pathogenic E. coli strains was revealed. The observed results are especially important in the case of the increasing resistance of bacteria to various drugs and antibiotics.
Highlights
2-dimethylphosphonoethyl example, 2-dimethylphosphonoethyl acetate which was synthesized via radical addition acetate which was synthesized via radical addition reaction of H-phosphite to vinyl acetate reaction of H-phosphite to vinyl acetate exhibits broad bioactivity, e.g., anti-hypoxic, exhibits broad bioactivity, e.g., anti-hypoxic, soporific, anticonvulsive, and hypothermic soporific, anticonvulsive, and hypothermic (Figure 1) [15]
Some chemical strategies based on addition of H-phosphites towards the synthesis of α-acyloxy phosphonates catalyzed either by sodium ethanolate or K2CO3/18crown-6 ether have been reported [38,39], the biocatalytic synthesis of target α-acyloxy
Α-hydroxy phosphonates have grasped attention towing to their wide range bioactivity. α-hydroxy phosphonates are usually synthesized by the base-catalyzed Pudovik reaction, the addition of dialkyl phosphite to an oxo compound [4,21]
Summary
Α-Hydroxy phosphonates are recognized as a valuable class of substances exhibiting interesting medicinal and agricultural properties [1–4]. Α-Hydroxy phosphonate derivatives are of great importance due to their various biological actions and therapeutic applications such as bactericidal [5], fungicidal [6], antitumor [7], and HIV inhibitory activities [8]. The high interest in this class of compounds has been reflected in numerous publications on their synthesis, modification, and application in medical chemistry [9–14]. It was shown that further functionalization of the hydroxy group has a pivotal impact on the biological. Materials 2022, 15, 1975 publications on their synthesis, modification, and application in ofmedical chemistry [9–14]. It was shown that further functionalization of the hydroxy group has a pivotal impact on the biological activity of the modified α-hydroxy phosphonates. For activity of the modified α-hydroxy phosphonates. 2-dimethylphosphonoethyl example, 2-dimethylphosphonoethyl acetate which was synthesized via radical addition acetate which was synthesized via radical addition reaction of H-phosphite to vinyl acetate reaction of H-phosphite to vinyl acetate exhibits broad bioactivity, e.g., anti-hypoxic, exhibits broad bioactivity, e.g., anti-hypoxic, soporific, anticonvulsive, and hypothermic soporific, anticonvulsive, and hypothermic (Figure 1) [15]
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