Journal of Medicinal Chemistry J
@ Copyrzghl 1867 by the American Chemical Society
VOLUME10, NUMBER 6
OCTOBER26, 1967
Analysis of the Structure-Activity Relationship of the Sulfonamide Drugs Vsing Substituent Constants' TOSHIO hJIT.4 Drpnrtiiirnl o,f 1qrcr.itllii~a1Chemzstri/, Kyoto 17niiP r s i l y , Kc/olo, J a p n n AND
CORWIXH . 4 x - s ~ ~
Department of Chemistry, Pomona College, Claremont, Calijornza Recezaed X a y 15, 1967 A recently developed method for the correlation of biological activity and chemical striicture of dissociable c4ornpoiinds under physiological coiiditioits iisiiig t,he Hammett u constant and the hydrophobicity constant A with a correctioii for the effect of dissociat,iori has been applied t o the anal of the hacteriohtat,ic activity and pi.oleitr binding of the srilfotiamide driigs. The hydrophobicity of the driigs is foiitid to play a defiiiite role O I I ihe activity, and the optimal hydrophobic character for the activity is deduced from the relationships. 01her f:ivtors beiiig eqrial, logarithmic plots of the appareiit activity agaiiist the dissociation constant, are rhowi t,o he expressed by t w o .*traight lilies, the intersection of which corresponds sometimes to the maximal activity for N series of srilfaiiilamider. The moat favorable diss;ociat.ioii constant for the maximrim activity and the optimal hydrophobicity for a series of aiilfanilamides have been eiiggested to help in the designing of new srilfonamide driigs.
l l u c h work has been done to elucidate the relation between physicochemical properties and bacteriostatic activity of the hulfonamide drugs. Bell arid RoblinL found that a logarithmic plot of the bacteriostatic activities of a series of sulfonamides against their dissociation constants exhibits a parabolic relationship. Considering that the activity increases with the negative character of the SO1 group, they postulated that the electron-attracting power of the P? substituent should be in an optimal range for the maximal activity so that the ionization constant of the SO?SH group is about 10-6-10-7. An alternative explanation for the parabolic relationship was proposed by Cowles3 who a-mmed that the negative ion which is responsible for the bacteriostatic action penetrates with difficulty to the site of action inside the cell so that there should be an optimal dissociation constant where the balance between the intrinsic activity and the penetration is most favorable to the bacteriostatic process. Seydel and his c o - ~ o r k e r sfrom , ~ a correlation between ir spectra and activity of a number of sulfonamides, emphasized that the amount of negative charge on the aromatic amino group is a significant factor for the activity. I n spite of these efforts and others,j generally consider(1) Studies on Structure-Activity Relationship.
11.
(2) P. H. Bell and R . 0. Roblin, Jr., J . Am. Chem. Soc., 64, 2905 (1942). (8) P. B. Cowles, Yale J . Biol. M e d . , 14, 599 (1942). (4) J. K . Seydel, E. Kriiger-Thiemer, and E. Wempe, 2. .Tntur/orsrh., 16b, 628 (1960). (5) See, e . 0 . . (a) H . G. Ing, "Organic Chemistry, An Advanced Treatise," Vol. 111, H. Gilman. Ed.. John Wiley and Sons, Inc., New York, N. Y., 1953, p 436; (b) IV. A . Sexton, "Chemical Constitution and Biological Activity." :3rd ed, D. Van Nostrand Co., Inc., Princeton, Pi. J., 1963, p 160; (c) G. Zbinden, ";\lolecular Modification in Drug Design," F. IT. Schuler, Ed., .\inerican Chemical Society, Washington, D . C., 1964, p 25.
ing a single physicochemical parameter, the structureactivity studies on the sulfonamides still leave much t o be desired. Recently,6 we have developed a method for the correlation of biological activity and chemical structure using substituent constants such as the Hammett u constant and a hydrophobicity constant T defined as T = log Px - log P H , where P X and P H are the partition coefficients, determined in the system 1-octanol-water, of the substituted and unsubstituted compounds, respectively. The contributions of the electronic and hydrophobic characters of a substituent t o a specific biological activity of a series of substituted compounds can be analyzed simultaneously by eq 1. I n eq 1, P i u log ( l / C )
= aA
+
-b ~ 2
PO
+c
(1)
the equieffective molar concentration, ie., the concentration causing a standard response such as CDio, EDho, minimum inhibitory concentration, etc., and a , b ( 2 0), p, and c are constants which are determined b j the method of least squares. The value of 1/C is proportional to the magnitude of biological activity. We have applied this method7 to compounds which are dissociated under physiological conditions such as a series of substituted phenols. For these compounds, the biological activity can be expressed by either eq 2 or 3 regardless of whether the sites of action are located inside or outside the cell. In eq 2 and 3, [H+]is the h j (6) (a) C. Hansch and T. Fujita, J . A m . Chem. Soc., 8 6 , 1616 (1964); (b) C. Hansch and A. R. Steward, J . .Wed. Chem., 7 , 691 (1964); (e) C. Hansch, E. W.Deutsch, and R. N. Smith, J . A m . Chem. Soc., 87, 2738 (1965): (d) C. Hansch, K. Kiehs. and G. L. Lawrence, ibid., 81, 5770 (1965); (e) I
