Synthesis of novel N-substituted amino acids derivatives bearing 2-hydroxy-5-nitrophenyl moietyas promising metallo- β-lactamases inhibitors

Growing antimicrobial resistant among Gram-negative bacterial pathogens remains one of the major healthcare associated threats worldwide [1]. The emergence of broad-spectrum metallo-β-lactamases (MBL) results in resistance to majority of β-lactam ring containing antibiotics, leading to the treatment failure and death. Therefore, it is important to search for novel inhibitors targeting MBL’s. In this study we report a characterization of synthesis and invitro inhibitory activity of novel amino acid derivatives on NDM-1 and VIM-2 metallo-β- lactamases. […]. Fig. 1. The synthesis of novel amino acid derivatives bearing 2-hydroxy-5-nitrophenyl moiety One of the most convenient methods for the preparation of N-substituted β-amino acids and 1-aryl-5-oxopyrrolidine-3-carboxylic acids is the interaction of primary amines with unsaturated acrylic and itaconic acids. For this purpose starting material was chosen 2-ydroxy-5-nitroaniline (1), which reacted with acrylic acid to form β-amino acid 2. Meanwhile the reaction of 2-hydroxy-5-nitroaniline (1) with it aconic acid gave an intermediate product 3,which is cyclized to the target compound 4 during the reaction. Obtained compounds 2,4 were used for the synthesis of methyl esters 5,6. Reactions carried out in boiling methanol in the presence of a catalytic amount of sulfuric acid. When conducting hydrazinolysis of both esters, it was observed that ester 5 not only forms the acid hydrazide, but also occurs when the nitro group is reduced with the formation of the compound 7. Table 1. The in vitro inhibitory activity of compounds 2, 4-8 on the enzymatic activity of NDM-1 and VIM-2metallo-β-lactamases. […]