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Título : Bis-acridines as lead anti-parasitic agents: structure activity analysis of a discrete compound library in vitro
Autor : Caffrey, Conor R.
Weismann, Jennifer
Swinerton, Ryan K.
Kelly, Ben
Fafarman, Aaron T.
Rodgers, Michael
Beauchene, Jessica
Schreiber, Kimberly
Cohen, Fred E.
McKerrow, James H.
Zhou, Yuan-Min
Doyle, Patricia
Moll, Heidrun
Ponte-Sucre, Alicia
Schirmeister, Tanja
Saravanamuthu, Ahilan
Fairlamb, Alan H.
Steverding, Dietmar
May, Barnaby C. H.
Palabras clave : Leishmania
bis-acridines
antiparasitic agents
Fecha de publicación : 22-Aug-2012
Citación : Antimicrobial Agents and Chemotherapy;51: 2164-72, 2007
Resumen : An extensive analysis of the anti-parasite activity of bis-acridine compounds was undertaken using a focused library of 18 structurally diverse compounds. The compound library was screened for in vitro bioactivity against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Leishmania major, Schistosoma mansoni, Entamoeba histolytica and Trichomonas vaginalis, and for cytotoxicity in two mammalian cell lines. Structure-activity-relationships (SAR) were derived for each target, and demonstrated the influence of the bis-acridine linker and terminal heterocycle on potency and cytotoxicity. Certain bis-acridine compounds were active at nanomolar concentrations against Plasmodium falciparum and Trypanosoma brucei. Low therapeutic indices could be mitigated by structural modification of the linker, such that certain bis-acridine compounds demonstrated equivalent or better therapeutic profiles than existing clinical treatments. No one compound was effective against all parasite targets. New parasite targets were identified including, Schistosoma mansoni, Entamoeba histolytica and Trichomonas vaginalis. A novel class of bis-aza-acridine compounds was effective against a broad range of parasite targets. Our approach illustrates the usefulness of screening focused compound libraries against multiple, related parasite targets.
URI : http://saber.ucv.ve/123456789/1695
ISSN : 1098-6596
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