Conformationally-constrained indeno[2,1-c]quinolines--a new class of anti-mycobacterial agents.
Org Biomol Chem
; 8(9): 2180-97, 2010 May 07.
Article
en En
| MEDLINE
| ID: mdl-20401395
ABSTRACT
The design, synthesis and anti-mycobacterial activities of 23 conformationally-constrained indeno[2,1-c]quinolines against Mycobacterium tuberculosis H37Rv is reported. Based on a structural comparison with the anti-TB TMC207 we have devised a synthetic methodology for making new conformationally-constrained indeno[2,1-c]quinoline analogs (Fig. 1), by retaining the biologically significant quinoline and the phenyl rings in the SW and NW hemispheres, respectively. This new class of conformationally-constrained compounds has been designed such that their conformational flexibility across C4-C2' is diminished to nil by covalently locking the C4 center of the quinoline moiety in the SW hemisphere with the C2' center of the phenyl ring in the NW hemisphere, thereby decreasing the entropic penalty for their complex formation within the target protein, which will in turn give improved free-energy of stabilization of the complex. The efficacies of these anti-TB compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of a single-dose on day one. Compounds 11, 13, 16, 24, 30, 32 and 34 showed 85-99% growth inhibition of Mycobacterium tuberculosis. Compounds 13 and 34 however have inhibited the mycobacterial growth more effectively than others in the series, with minimum inhibitory concentrations (MIC) of 0.39 microg mL(-1) (1 microM) and 0.78 microg mL(-1) (2 microM) respectively.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinolinas
/
Indenos
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Mycobacterium tuberculosis
/
Antituberculosos
Límite:
Humans
Idioma:
En
Revista:
Org Biomol Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2010
Tipo del documento:
Article
País de afiliación:
India