Activities and conformational fitting of 1,4-naphthoquinone derivatives and other cyclic 1,4-diones tested in vitro against Pneumocystis carinii.
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 microg/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 microg/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 A 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 A from position 3, without projecting steric bulk perpendicularly. This structure-activity relationship may prove useful in the rational design of better antipneumocystis agents.
Ball
M D
MD
Dept. of Chemistry, Rose-Hulman Institute of Technology, Terre Haute, Indiana 47803, USA. mark.d.ball@rose-hulman.edu
Bartlett
M S
MS
Shaw
M
M
Smith
J W
JW
Nasr
M
M
Meshnick
S R
SR
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D011010:Pneumocystis / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D009285:Naphthoquinones; C035342:1,4-naphthoquinone