Structure-activity relationships of analogs of pentamidine against Plasmodium falciparum and Leishmania mexicana amazonensis.
The antiprotozoal compound 1,5-di(4-amidinophenoxy)pentane (pentamidine) and 36 of its analogs were screened for in vitro activity against Leishmania mexicana amazonensis clone 669 C4S (MHOM/BR/73/M2269) and Plasmodium falciparum clones W2 (Indochina III/CDC) and D6 (Sierra Leone I/CDC). Pentamidine and each of the analogs tested exhibited activity in vitro against L. m. amazonensis and P. falciparum. The pentamidine analogs were more effective against the P. falciparum clones than against L. m. amazonensis. P. falciparum was extremely susceptible to these compounds, with 50% inhibitory concentrations as low as 0.03 microM. While none of the analogs exhibited marked improvement in antileishmanial activity compared with pentamidine, 12 of the pentamidine analogs showed activity approximately equal to or greater than that of the parent compound. From the promising activity exhibited by the pentamidine analogs in this in vitro study and their potential for reduced toxicity relative to the parent drug, pentamidine-related compounds hold promise as new agents for the treatment of protozoal infections.
Bell
C A
CA
Department of Parasitology, School of Public Health, University of North Carolina, Chapel Hill 27599.
Hall
J E
JE
Kyle
D E
DE
Grogl
M
M
Ohemeng
K A
KA
Allen
M A
MA
Tidwell
R R
RR
D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D007894:Leishmania mexicana / Q000187:drug effects*; D015767:Mefloquine / Q000494:pharmacology; D010419:Pentamidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D010419:Pentamidine; D002738:Chloroquine; D015767:Mefloquine