Parallel solution-phase synthesis of conformationally restricted congeners of pentamidine and evaluation of their antiplasmodial activities.
Conformationally restricted bisbenzamidines and related congeners have been synthesized and evaluated for activity against two Plasmodium falciparum strains. The most active compounds, bisbenzamidines linked by a 1,4-piperazinediyl core, had IC(50) values between 3 and 18 nM against both chloroquine-susceptible and -resistant parasites and IC(50) values for cytotoxicity greater than 5 microM, using the A549 human lung epithelial cell line. DNA binding affinity, as estimated by DeltaT(m), did not correlate with either antiparasite effects or cytotoxicity. Each of the active bisbenzamidines interfered with the formation of hemozoin in cell-free systems.
Mayence
Annie
A
College of Pharmacy, Division of Basic Pharmaceutical Sciences, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, Louisiana 70125, USA.
Vanden Eynde
Jean Jacques
JJ
Krogstad
Fran M
FM
Krogstad
Donald J
DJ
Cushion
Melanie T
MT
Huang
Tien L
TL
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002474:Cell-Free System; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D006427:Hemin / Q000378:metabolism; D006801:Humans; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
D000962:Antimalarials; D006427:Hemin; D002738:Chloroquine