Antiprotozoal activity of 3'-deoxyinosine. Inverse correlation to cleavage of the glycosidic bond.
Two nucleosides related to the known antiprotozoal agent 1-(beta-D-ribofuranosyl)-1,5-dihydro-4H-pyrazolo-[3,4-d]pyrimidine-4-one (allopurinol riboside, 1) were prepared and evaluated against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma gambiense. 3'-Deoxyinosine (2) exhibited potent antiprotozoal activity against the three protozoal pathogens with minimal toxicity for host cells. It was found to be especially effective against the Columbia strain of T. cruzi reported to be resistant to 1. The antiprotozoal activity of 2 appeared to be inversely related to the rate of cleavage of the glycosidic bond, as shown by metabolic profiles of 2 in the various pathogenic hemoflagellates and host cells. Combining the key structural elements of 1 and 2 led to the synthesis of 1-(3-deoxy-beta-D-erythro-pentofuranosyl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one (3'-deoxy-allopurinol riboside, 3). which was found to be inactive as an antiprotozoal agent.
Moorman
A R
AR
Division of Experimental Therapy, Burroughs Wellcome Co., Research Triangle Park, NC 27709.
LaFon
S W
SW
Nelson
D J
DJ
Carter
H H
HH
Marr
J J
JJ
Berens
R L
RL
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis*; D004305:Dose-Response Relationship, Drug; D007288:Inosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects
D000981:Antiprotozoal Agents; C070014:3'-deoxyinosine; D007288:Inosine