TY - JOUR
T1 - Biochemical and microbiological evaluation of
T2 - N-aryl urea derivatives against mycobacteria and mycobacterial hydrolases
AU - Vartak, Abhishek
AU - Goins, Christopher
AU - De Moura, Vinicius Calado Nogueira
AU - Schreidah, Celine M.
AU - Landgraf, Alexander D.
AU - Lin, Boren
AU - Du, Jianyang
AU - Jackson, Mary
AU - Ronning, Donald R.
AU - Sucheck, Steven J.
N1 - Funding Information:
This work was supported by the National Institutes of Health Grant AI105084 to SJS and DRR and Grant AI135313 to SJS.
Publisher Copyright:
© 2019 The Royal Society of Chemistry.
PY - 2019
Y1 - 2019
N2 - A focused library of 24 N-aryl urea derivatives was prepared and evaluated against serine esterases of Mycobacterium tuberculosis (Mtb) Rv3802c and Mtb Ag85C. The members of the library were evaluated for both selectivity and mode of inhibition. Furan-based urea derivative 6c was found to be the most potent non-covalent inhibitor of Rv3802c with a Ki value of 5.2 ± 0.7 μM. On the other hand, triazole-based ureas 10a and 10b selectively inhibited Ag85C irreversibly with a kinact/Ki value of 2.3 ± 0.3 and 5.5 ± 0.4 × 10-3 μM-1 min-1, respectively. The library was also evaluated for minimum inhibitory concentration (MIC) against two strains of Mtb, Mycobacterium smegmatis, and Mycobacterium abscessus. Compounds 4a and 4c were active against Mtb H37Rv mc26206 with MIC values of 3.12 and 1.5 μM, respectively. Closely related 4e showed similar activity against Mtb H37Rv mc26206 but also possessed activity against Mtb H37Ra, Mycobacterium smegmatis and Mycobacterium abscessus. Compounds 4a, 4c, and 4e 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.
AB - A focused library of 24 N-aryl urea derivatives was prepared and evaluated against serine esterases of Mycobacterium tuberculosis (Mtb) Rv3802c and Mtb Ag85C. The members of the library were evaluated for both selectivity and mode of inhibition. Furan-based urea derivative 6c was found to be the most potent non-covalent inhibitor of Rv3802c with a Ki value of 5.2 ± 0.7 μM. On the other hand, triazole-based ureas 10a and 10b selectively inhibited Ag85C irreversibly with a kinact/Ki value of 2.3 ± 0.3 and 5.5 ± 0.4 × 10-3 μM-1 min-1, respectively. The library was also evaluated for minimum inhibitory concentration (MIC) against two strains of Mtb, Mycobacterium smegmatis, and Mycobacterium abscessus. Compounds 4a and 4c were active against Mtb H37Rv mc26206 with MIC values of 3.12 and 1.5 μM, respectively. Closely related 4e showed similar activity against Mtb H37Rv mc26206 but also possessed activity against Mtb H37Ra, Mycobacterium smegmatis and Mycobacterium abscessus. Compounds 4a, 4c, and 4e 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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U2 - 10.1039/c9md00122k
DO - 10.1039/c9md00122k
M3 - Article
C2 - 31741730
AN - SCOPUS:85069430733
SN - 2040-2503
VL - 10
SP - 1197
EP - 1204
JO - MedChemComm
JF - MedChemComm
IS - 7
ER -