The application of natural product inspired synthesis has identified novel antibacterial tetramic acids which exhibit wide ranging antibacterial activity, and which provide potential lead structures for antibacterial drug discovery. Their phenotypic activity appears to correlate with action at two enzymes, UPPS and RNAP, which operate in independent metabolic pathways. SAR maps and identification of their relevant binding sites by molecular modelling has been achieved, and characterisation of the most active compounds suggests that these systems offer potential for topical antibiotics but that for oral and injectable use further optimisation is required.

The synthesis of 3-acyltetramic acids, the substructure of bioactive natural products, via O-acylation of tetramic acids with carboxylic acids followed by acyl migration, has been investigated. This acylation sequence is mediated by N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) and is very sensitive to the nature of the nitrogen substituent (R(1)), the nature of the carboxylic acid (R(2)CO(2)H), and the amount of DMAP. Acylation of N-acyl tetramic acids with an alkyl carboxylic acid using 1.3 equiv of DMAP (with 1.1 equiv of DCC) unexpectedly gave the 3-acyltetramic acid directly as a result of acyl migration induced by excess amounts of DMAP. On the other hand, N-unsubstituted, N-alkyl, and N-acyl tetramic acids with alkyl and aromatic carboxylic acids gave the O-acyl tetramic acids by using only 0.1 equiv of DMAP (with 1.1 equiv of DCC); these could be further rearranged to the acyl product by treatment with excess DMAP. The tautomeric equilibrium of these 3-acyltetramic acids in solution was found to strongly depend on the nitrogen substituent group (R(1)) rather than the 3-acyl group.

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SummaryA chemical library of carboxamide-substituted tetramates designed by analogy with antibacterial natural products, a method for their rapid construction, and the evaluation of their antibacterial activity is reported.