Leads for antitubercular compounds from kinase inhibitor library screens.
Tuberculosis (Edinb)
; 90(6): 354-60, 2010 Nov.
Article
in En
| MEDLINE
| ID: mdl-20934382
ABSTRACT
Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find antimycobacterial scaffolds, we screened a kinase inhibitor library of more than 12,000 compounds using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and a target-based assay with the protein kinase PknA. Seventeen "hits" came from the whole cell-based screening approach, from which three displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10µM and were non-mutagenic and non-cytotoxic. Two of these hits were specific for M. tuberculosis versus C. glutamicum and none of them was found to inhibit the essential serine/threonine protein kinases, PknA and PknB present in both bacteria. One of the most active hits, VI-18469, had a benzoquinoxaline pharmacophore while another, VI-9376, is structurally related to a new class of antimycobacterial agents, the benzothiazinones (BTZ). Like the BTZ, VI-9376 was shown to act on the essential enzyme decaprenylphosphoryl-ß-D-ribose 2'-epimerase, DprE1, required for arabinan synthesis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tuberculosis
/
Protein Serine-Threonine Kinases
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Protein Kinase Inhibitors
/
Mycobacterium tuberculosis
/
Antitubercular Agents
Limits:
Humans
Language:
En
Journal:
Tuberculosis (Edinb)
Year:
2010
Document type:
Article
Affiliation country:
Switzerland