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Quantitative structure-selectivity relationships. Comparison of the inhibition of Escherichia coli and bovine liver dihydrofolate reductase by 5-(substituted benzyl)-2,4-diaminopyrimidines
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1980
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E. ColiBioorganic ChemistryAldo-keto ReductaseEscherichia ColiDrug ResistanceMedicinal ChemistryQuantitative Structure-selectivity RelationshipsStructure-function Enzyme KineticsInhibitory ActivityAldehyde DehydrogenaseSubstituted BenzylBiochemistryAntibacterial AgentAntimicrobial CompoundPharmacologyBovine EnzymeNatural SciencesEnzyme CatalysisMedicineQuantitative Structure-activity RelationshipDrug Discovery
A quantitative structure-activity relationship (QSAR) has been formulated for the inhibition of purified E. coli dihydrofolate reductase by 23 5-(substituted benzyl)-2,4-diaminopyrimidines: log 1/C = 1.14MR'3,4,5 + 5.73; r = 0.887; s = 0.285. In this expression, MR'3,4,5 refers to the sum of MR values for X in the 3, 4 and 5 positions of the phenyl moiety. MR' signifies that the effective value of MR is limited to 0.79. Comparison of the QSAR for E. coli enzyme inhibition with that previously obtained for bovine enzyme offers the first general explanation for the great selectivity of the important antibacterial agent trimethoprim. Such QSSR promise to be of value in devising more selective drugs.