Abstract
Dehydroacetic acid is a common pyrone derivative used commercially as an antibacterial and antifungal agent. Based on the synthesis of dehydroacetic acid (1) from N-hydroxysuccinimdyl acetoacetate, a novel series of enamine-based derivatives were synthesised in order to improve the antibacterial activity of dehydroacetic acid. The antibacterial activities of the synthesised analogues were evaluated against Escherichia coli and Staphylococcus aureus. Derivative 4d (N-Ph) was identified as the most potent inhibitor of S. aureus growth. Overall, derivative 4b (N-Me) showed the best broad-spectrum activity with five-fold greater minimum inhibitory concentration and 11-fold greater minimum biocidal concentration against E. coli when compared to dehydroacetic acid, in addition to improved antibacterial activity against S. aureus.
Highlights
There is an urgent need for the development of new antibacterial agents in order to overcome bacterial resistance
We propose that two equivalents of 2 undergo Claisen condensation, followed by intramolecular nucleophilic substitution and subsequent loss of two equivalents of N-hydroxysuccinimide in support of the proposed reaction mechanism (Scheme 2)
A number of (E)-enaminopyran-2,4-diones based on the structure of 1 were prepared and evaluated for antibacterial activity against Gram-positive and Gramnegative bacteria and demonstrate broad-spectrum activities
Summary
There is an urgent need for the development of new antibacterial agents in order to overcome bacterial resistance. Our intention was to synthesise acetoacetamide derivatives (3) by reacting commercially available N-hydroxysuccinimidyl acetoacetate (2) with a range of amines (R = H, Me, Et, Ph and substituted anilines, CH2Ph, CH2CH2Ph, cyclohexyl and CH2C≡CH). These were required as intermediates for a novel class of antiinflammatory agents that target the NLRP3 inflammasome (Baldwin et al 2017). Surprisingly it soon became apparent following characterisation of the products that the desired compounds (3) were not obtained and that the enamine analogues (4) were synthesised, arising from 1. We discuss the novel synthesis of 1 from 2 and
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