Abstract
We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aminoquinolines / chemical synthesis*
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Aminoquinolines / pharmacology*
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / pharmacology*
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Antifungal Agents / chemical synthesis
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Antifungal Agents / pharmacology
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Antimalarials / chemical synthesis*
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Antimalarials / pharmacology*
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Antiparasitic Agents / chemical synthesis*
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Antiparasitic Agents / pharmacology*
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Bacteria / drug effects
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Chlorocebus aethiops
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Erythrocytes / drug effects
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Erythrocytes / metabolism
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Erythrocytes / parasitology
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Fungi / drug effects
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Humans
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Indicators and Reagents
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L-Lactate Dehydrogenase / metabolism
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Leishmania donovani / drug effects
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Magnetic Resonance Spectroscopy
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Methemoglobin / metabolism*
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Methicillin Resistance
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Mice
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Microbial Sensitivity Tests
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Plasmodium berghei / drug effects
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Plasmodium falciparum / drug effects
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Structure-Activity Relationship
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Vero Cells / drug effects
Substances
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Aminoquinolines
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Anti-Bacterial Agents
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Antifungal Agents
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Antimalarials
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Antineoplastic Agents
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Antiparasitic Agents
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Indicators and Reagents
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Methemoglobin
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L-Lactate Dehydrogenase
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8-aminoquinoline