title: Parallel solution-phase synthesis of conformationally restricted congeners of pentamidine and evaluation of their antiplasmodial activities.
abstract: 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.
authors.affiliation: College of Pharmacy, Division of Basic Pharmaceutical Sciences, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, Louisiana 70125, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Mayence
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Vanden Eynde
authors.forename: Fran M
authors.initials: FM
authors.lastname: Krogstad
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Krogstad
authors.forename: Melanie T
authors.initials: MT
authors.lastname: Cushion
authors.forename: Tien L
authors.initials: TL
authors.lastname: Huang
mesh_terms: 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
chemical_list: D000962:Antimalarials; D006427:Hemin; D002738:Chloroquine