title: Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners.
abstract: A library of 52 pentamidine congeners in which the flexible pentyldioxy linker in pentamidine was replaced with various restricted linkers was tested for in-vitro activity against two Plasmodium falciparum strains and Leishmania donovani. The tested compounds were generally more effective against P. falciparum than L. donovani. The most active compounds against the chloroquine-sensitive (D6, Sierra Leone) and -resistant (W2, Indochina) strains of P. falciparum were bisbenzamidines linked with a 1,4-piperazinediyl or 1, 4-homopiperazinediyl moiety, with IC50 values (50% inhibitory concentration, inhibiting parasite growth by 50% in relation to drug-free control) as low as 7 nM based on the parasite lactate dehydrogenase assay. Seven piperazine-linked bisbenzamidines substituted at the amidinium nitrogens with a linear alkyl group of 3-6 carbons (22, 25, 27, 31) or cycloalkyl group of 4, 6 or 7 carbons (26, 32, 34) were more potent (IC50<40 nM) than chloroquine or pentamidine as anti-plasmodial agents. The most active anti-leishmanial agents were 4,4'-[1,4-phenylenebis(methyleneoxy)]bisbenzenecarboximidamide (2, IC50 approximately 0.290 microM) and 1,4-bis[4-(1H-benzimidazol-2-yl)phenyl] piperazine (44, IC50 approximately 0.410 microM), which were 10- and 7-fold more potent than pentamidine (IC50 approximately 2.90 microM). Several of the more active anti-plasmodial agents (e.g. 2, 31, 33, 36-38) were also potent anti-leishmanial agents, indicating broad antiprotozoal properties. However, a number of analogues that showed potent anti-plasmodial activity (1, 18, 21, 22, 25-28, 32, 43, 45) were not significantly active against the Leishmania parasite. This indicates differential modes of anti-plasmodial and anti-leishmanial actions for this class of compounds. These compounds provide important structure-activity relationship data for the design of improved chemotherapeutic agents against parasitic infections.
authors.affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, 70125, USA. thuang@xula.edu
authors.forename: Tien L
authors.initials: TL
authors.lastname: Huang
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Vanden Eynde
authors.forename: Annie
authors.initials: A
authors.lastname: Mayence
authors.forename: Isaac O
authors.initials: IO
authors.lastname: Donkor
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D007893:Leishmania donovani / Q000187:drug effects*; D008968:Molecular Conformation; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D000981:Antiprotozoal Agents; D010419:Pentamidine