Affiliation:
1. Dept. of Chemistry, Rose-Hulman Institute of Technology, Terre Haute, Indiana 478031;
2. Dept. of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 462022;
3. Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208923; and
4. Dept. of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan 481094
Abstract
ABSTRACT
Atovaquone is a chemotherapeutic agent used to treat pneumonia caused by
Pneumocystis carinii
in some immunocompromised patients. A set of cyclic 1,4-diones were tested in vitro for ability to inhibit growth of
P. carinii
, including 22 variously substituted 1,4-naphthoquinones, one bis-1,4-naphthoquinone, and three other quinones. For comparison, the antipneumocystic primaquine and its 5-hydroxy-6-desmethyl metabolite were also tested. At 1.0 μg/ml, seven compounds inhibited growth by at least 39%, with atovaquone at 92%; of these seven, five are 2-hydroxy-1,4-naphthoquinones, while one is a 2-chloro- and another is a 2-methyl-1,4-naphthoquinone. At 0.1 μg/ml, however, the most active compound tested was the primaquine metabolite, which inhibited growth by more than 42% at this concentration. To ascertain a structure-activity relationship, all 1,4-naphthoquinones were compared conformationally by means of computer-based molecular modeling (Spartan) incorporating the Sybyl force field. Without exception, for all 21 monomers tested, the substituent at position 3 of the 1,4-naphthoquinone favored activity most strongly when it simultaneously occupied (i) space centered at about 3 Å from position 3, without projecting steric bulk from the area encompassed by atovaquone's cyclohexyl ring, and (ii) roughly planar space at about 7.3 Å from position 3, without projecting steric bulk perpendicularly. This structure-activity relationship may prove useful in the rational design of better antipneumocystis agents.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
15 articles.
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