A focused library of 24 -aryl urea derivatives was prepared and evaluated against serine esterases of () Rv3802c and Ag85C. The members of the library were evaluated for both selectivity and mode of inhibition. Furan-based urea derivative was found to be the most potent non-covalent inhibitor of Rv3802c with a value of 5.2 ± 0.7 μM. On the other hand, triazole-based ureas and selectively inhibited Ag85C irreversibly with a / value of 2.3 ± 0.3 and 5.5 ± 0.4 × 10 μM min, respectively. The library was also evaluated for minimum inhibitory concentration (MIC) against two strains of , , and . Compounds and were active against H37Rv mc6206 with MIC values of 3.12 and 1.5 μM, respectively. Closely related showed similar activity against H37Rv mc6206 but also possessed activity against H37Ra, and . Compounds , , and all contained a common 1-(cyclohexylmethyl)-3-phenylurea motif. In summary, we identified a selective non-covalent inhibitor of Rv3802c and covalently irreversible inhibitors of Ag85C as well as the 1-(cyclohexylmethyl)-3-phenylurea motif which showed activity against a variety of mycobacteria.
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