A quantitative structure-activity relationship analysis of some 4-aminodiphenyl sulfone antibacterial agents using linear free energy and molecular modeling methods

A set of 36 congeneric 4-aminodiphenyl sulfones with measured inhibition potencies of dihydropteroate synthase were studied by using both linear free energy and molecular modeling methods. The goals of the investigation were to identify the "active" conformation for these compounds as inhi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1987-05, Vol.30 (5), p.900-906
Main Authors: Lopez de Compadre, Rosa L, Pearlstein, R. A, Hopfinger, A. J, Seydel, J. K
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents
Biological and medical sciences
Chemical Phenomena
Chemistry, Physical
General pharmacology
Medical sciences
Molecular Conformation
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Structure-Activity Relationship
Sulfones
Thermodynamics
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Summary:A set of 36 congeneric 4-aminodiphenyl sulfones with measured inhibition potencies of dihydropteroate synthase were studied by using both linear free energy and molecular modeling methods. The goals of the investigation were to identify the "active" conformation for these compounds as inhibitors and, correspondingly, to contruct a quantitative structure-activity relationship (QSAR). These molecules are quite flexible and possess multiple conformational energy minima. Application of molecular shape analysis (MSA), using all intramolecular energy minima as part of the analysis, was not successful in generating a QSAR. However, the calculated intramolecular conformational entropy of these compounds was found to correlate with inhibition potency leading to a highly significant QSAR. Inhibition potency increases as entropy decreases. A decrease in entropy enhances the population of specific, symmetry-related minimum-energy conformations. In this indirect way, it was possible to postulate an "active" conformation. This investigation illustrates that specific knowledge of the "active" shape of a molecule may not provide the information needed to quantitatively explain the observed structure-activity relationship.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00388a026