[en] 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 ~ 0.290 µM) and 1,4-bis[4-(1H-benzimidazol-2-yl)phenyl] piperazine (44, IC50~0.410 µM), which were 10- and 7-fold more potent than pentamidine (IC50 ~ 2.90 µM). 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.
Disciplines :
Chemistry
Author, co-author :
Huang, T.L.
Vanden Eynde, Jean-Jacques ; Université de Mons > Faculté des Sciences > Synthèse et spectrométrie de masse organiques
Mayence, A.
Donkor, I.O.
Khan, S.I.
Tekwani, B.L.
Language :
English
Title :
Antiplasmodial and Antileishmanial Activities of Conformationnally Restricted Pentamidine Congeners
Publication date :
01 August 2006
Journal title :
Journal of Pharmacy and Pharmacology
ISSN :
0022-3573
Publisher :
Wiley, London, United Kingdom
Volume :
58
Issue :
8
Pages :
1033 - 1042
Peer reviewed :
Peer Reviewed verified by ORBi
Research unit :
S836 - Synthèse et spectrométrie de masse organiques
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