On the optimization of hydrophobic and hydrophilic substituent interactions of 2,4-diamino-5-(substituted-benzyl)pyrimidines with dihydrofolate reductase.
J Med Chem
; 34(1): 46-54, 1991 Jan.
Article
en En
| MEDLINE
| ID: mdl-1899453
ABSTRACT
The inhibition constants (Kiapp) were obtained from the action of 68 2,4-diamino-5-(substituted-benzyl)pyrimidines on dihydrofolate reductase from an Escherichia coli strain MB 1428. Subsequently, these results were used to formulate appropriate quantitative structure-activity relationships (QSAR). Once again these equations emphasize the paramount importance of steric/dispersion factors in enhancing antibacterial potency. Hydrophobicity also plays a role, albeit a minor one. Comparisons with the QSAR obtained versus prokaryotic dihydrofolate reductase (DHFR) demonstrate subtle differences in binding behavior between meta and para substituents which may be effectively maximized in the design of more efficacious and selective antibacterial agents. The bacterial and avian QSAR equations can be used to calculate selectivity indices for trimethoprim, tetroxoprim, and two other specially designed 2,4-diamino-5-(substituted-benzyl)pyrimidines.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Diaminas
/
Antagonistas del Ácido Fólico
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1991
Tipo del documento:
Article