Biochemical and microbiological evaluation of <i>N</i>-aryl urea derivatives against mycobacteria and mycobacterial hydrolases.
Vartak A, Goins C, de Moura VCN, Schreidah CM, Landgraf AD, Lin B, Du J, Jackson M, Ronning DR, Sucheck SJ.
A focused library of 24 <i>N</i>-aryl urea derivatives was prepared and evaluated against serine esterases of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) Rv3802c and <i>Mtb</i> Ag85C. The members of the library were evaluated for both selectivity and mode of inhibition. Furan-based urea derivative <b>6c</b> was found to be the most potent non-covalent inhibitor of Rv3802c with a <i>K</i> <sub>i</sub> value of 5.2 ± 0.7 μM. On the other hand, triazole-based ureas <b>10a</b> and <b>10b</b> selectively inhibited Ag85C irreversibly with a <i>k</i> <sub>inact</sub>/<i>K</i> <sub>i</sub> value of 2.3 ± 0.3 and 5.5 ± 0.4 × 10<sup>-3</sup> μM<sup>-1</sup> min<sup>-1</sup>, respectively. The library was also evaluated for minimum inhibitory concentration (MIC) against two strains of <i>Mtb</i>, <i>Mycobacterium smegmatis</i>, and <i>Mycobacterium abscessus</i>. Compounds <b>4a</b> and <b>4c</b> were active against <i>Mtb</i> H37Rv mc<sup>2</sup>6206 with MIC values of 3.12 and 1.5 μM, respectively. Closely related <b>4e</b> showed similar activity against <i>Mtb</i> H37Rv mc<sup>2</sup>6206 but also possessed activity against <i>Mtb</i> H37Ra, <i>Mycobacterium smegmatis</i> and <i>Mycobacterium abscessus</i>. Compounds <b>4a</b>, <b>4c</b>, and <b>4e</b> 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.