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Antimicrobial Agents and Chemotherapy, June 1998, p. 1454-1458, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Quantitative Structure-Activity Relationship Studies of a Series of Sulfa Drugs as Inhibitors of Pneumocystis carinii Dihydropteroate Synthetase

Theresa Johnson,1 Ikhlas A. Khan,2,3 Mitchell A. Avery,1,2,3,* Juliana Grant,4 and Steven R. Meshnick4,*

Department of Medicinal Chemistry,1 Research Institute of Pharmaceutical Sciences,2 and National Center for the Development of Natural Products,3 University of Mississippi, University, Mississippi 38677, and Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 481094

Received 29 December 1997/Returned for modification 5 February 1998/Accepted 14 March 1998

Sulfone and sulfanilamide sulfa drugs have been shown to inhibit dihydropteroate synthetase (DHPS) isolated from Pneumocystis carinii. In order to develop a pharmacophoric model for this inhibition, quantitative structure-activity relationships (QSAR) for sulfa drugs active against DHPS have been studied. Accurate 50% inhibitory concentrations were collected for 44 analogs, and other parameters, such as partition coefficients and molar refractivity, were calculated. Conventional multiple regression analysis of these data did not provide acceptable QSAR. However, three-dimensional QSAR provided by comparative molecular field analysis did give excellent results. Upon removal of poorly correlated analogs, a data set of 36 analogs, all having a common NHSO2 group, provided a cross-validated r2 value of 0.699 and conventional r2 value of 0.964. The resulting pharmacophore model should be useful for understanding and predicting the binding of DHPS by new sulfa drugs.

* Corresponding author. Mailing address for Mitchell A. Avery: Department of Medicinal Chemistry, 421 Fraser Hall, School of Pharmacy, University of Mississippi, University, MS 38677. Phone: (601) 232-5880. Fax: (601) 232-5638. E-mail: mavery{at}olemiss.edu. Mailing address for Steven R. Meshnick: Department of Epidemiology, School of Public Health, University of Michigan, 109 Observatory St., Ann Arbor, MI 48109. Phone: (734) 747-2406. Fax: (734) 764-3192. E-mail: meshnick{at}umich.edu.

Antimicrobial Agents and Chemotherapy, June 1998, p. 1454-1458, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.




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