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2006-08-01 - Article/Dans un journal avec peer-review - Anglais - 10 page(s)

Huang T.L., Vanden Eynde Jean-Jacques , Mayence A., Donkor I.O., Khan S.I., Tekwani B.L., "Antiplasmodial and Antileishmanial Activities of Conformationnally Restricted Pentamidine Congeners" in Journal of Pharmacy & Pharmacology, 58, 8, 1033 – 1042

  • Edition : Pharmaceutical Press, London (United Kingdom)
  • Codes CREF : Chimie organique (DI1313)
  • Unités de recherche UMONS : Chimie organique (S836)
Texte intégral :

Abstract(s) :

(Anglais) 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.

Identifiants :
  • DOI : 10.1211/jpp.58.8.0003