Highly potent and selective 4,4'‐biphenyl‐4‐acylate‐4'‐N‐n‐butylcarbamate inhibitors of Pseudomonas species lipase

4,4'‐Biphenyl‐4‐acylate‐4'‐N‐n‐butylcarbamates ( 1–8 ) are synthesized and characterized as highly potent and selective pseudo‐substrate inhibitors of Pseudomonas species lipase. Thus, the n‐butylcarbamate moieties of the inhibitors bind to the first acyl chain binding site (ACS) of the enzyme. Therefore, the ester moieties of the inhibitors may bind to the second ACS of the enzyme, due to the linear 4,4'‐biphenyl moiety of the inhibitors. –logK_i, logk₂, and logk_i values of carbamates 1–8 are multiply linearly correlated with the Taft steric constant (E_S) and the Hansch hydrophobicity constant (π), but not with the Taft substituent constant (σ*). For –logK_i, logk₂, and logk_i correlations, values of δ are 0.8, 0.34, and 1.0, respectively, and values of ψ are 1.0, 0.4, and 1.3, respectively. Positive δ and ψ values for these correlations indicate that the second ACS of the enzyme prefers to bind to small and hydrophobic ester groups of the inhibitors. Among carbamates 1–8 , carbamate 3 , with a K_i value of 2.5 nM, is the most potent inhibitor.