RESUMO
A quantitative structure-activity relationship (QSAR) has been formulated for quinazolines causing 50% inhibition of liver dihydrofolate reductase. The QSAR for the quinazolines is compared with QSAR for triazine and pyrimidine inhibitors. The three QSAR suggest new possibilities for the design of inhibitors of mammalian dihydrofolate reductase.
Assuntos
Antagonistas do Ácido Fólico , Quinazolinas/farmacologia , Sítios de Ligação , Fígado/enzimologia , Conformação Molecular , Quinazolinas/síntese química , Relação Estrutura-AtividadeRESUMO
Constants for pi and omega ahve been measured for a miscellaneous group of aromatic substituents of interest to medicinal chemists. Swain and Lupton's gamma and kappa values have been calculated from the omego constants. Values for molar refractivity are also given for each of the substituents.
Assuntos
Relação Estrutura-Atividade , Fenômenos Químicos , Química Farmacêutica , Físico-QuímicaRESUMO
A quantitative structure-activity relationship has been formulated for 646 antimalarials acting against P. berghei in mice. The equation developed has 14 terms, 9 of which are indicator variables. The correlation coefficient for the QSAR is 0.898 and the standard deviation is 0.309. The antimalarials are all arylcarbinols of the type X-ArCHOHCH2NR1R2. Sixty different aryl structures, including a variety of heterocyles, are contained in the study. The most important determinate of activity is found to be the electron-withdrawing ability of the substituents X; the hydrophobic character of X and R plays less important roles. Suggestions for more potent analogues are made and the lack of activity of about 100 additional analogues is also considered.
Assuntos
Antimaláricos/farmacologia , Etanolaminas/farmacologia , Animais , Malária/tratamento farmacológico , Camundongos , Modelos Biológicos , Fenantrenos/farmacologia , Plasmodium berghei , Piridinas/farmacologia , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A correlation equation based solely on de novo constants was formulated for 105 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines acting as inhibitors of dihydrofolate reductase. An equation with seven indicator variables gives a correlation with a correlation coefficient of 0.903 and a standard deviation of 0.229. The technique used is a modification of the Free-Wilson approach. The results indicate that correlation equations with fewer parameters than the theoretical required to account for all molecular changes may often be encountered. It is also shown that cross-product terms can be used to establish the significance of cooperative substituent effects.