Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners
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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2006 |
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| Erschienen: |
2006 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:58 |
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| Enthalten in: |
The Journal of pharmacy and pharmacology - 58(2006), 8 vom: 28. Aug., Seite 1033-42 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huang, Tien L [VerfasserIn] |
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| Themen: |
673LC5J4LQ |
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| Anmerkungen: |
Date Completed 30.11.2006 Date Revised 10.12.2019 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM164431977 |
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| 100 | 1 | |a Huang, Tien L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Anti-plasmodial and anti-leishmanial activity of conformationally restricted pentamidine congeners |
| 264 | 1 | |c 2006 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
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| 500 | |a Date Completed 30.11.2006 | ||
| 500 | |a Date Revised 10.12.2019 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 7 | |a Antimalarials |2 NLM | |
| 650 | 7 | |a Antiprotozoal Agents |2 NLM | |
| 650 | 7 | |a Pentamidine |2 NLM | |
| 650 | 7 | |a 673LC5J4LQ |2 NLM | |
| 700 | 1 | |a Vanden Eynde, Jean Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Mayence, Annie |e verfasserin |4 aut | |
| 700 | 1 | |a Donkor, Isaac O |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Shabana I |e verfasserin |4 aut | |
| 700 | 1 | |a Tekwani, Babu L |e verfasserin |4 aut | |
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