Abstract:
: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.
journal_name
Medchemcommjournal_title
MedChemCommauthors
Vartak A,Goins C,de Moura VCN,Schreidah CM,Landgraf AD,Lin B,Du J,Jackson M,Ronning DR,Sucheck SJdoi
10.1039/c9md00122ksubject
Has Abstractpub_date
2019-06-04 00:00:00pages
1197-1204issue
7eissn
2040-2503issn
2040-2511pii
c9md00122kjournal_volume
10pub_type
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