Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents

[Display omitted] Arylimidamide (AIA) compounds containing two pyridylimidamide terminal groups (bis-AIAs) possess outstanding in vitro antileishmanial activity, and the frontrunner bis-AIA DB766 (2,5-bis[2-(2-isopropoxy)-4-(2-pyridylimino)aminophenyl]furan) is active in visceral leishmaniasis model...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2016-05, Vol.26 (10), p.2551-2556
Hauptverfasser: Zhu, Xiaohua, Farahat, Abdelbasset A., Mattamana, Meena, Joice, April, Pandharkar, Trupti, Holt, Elizabeth, Banerjee, Moloy, Gragg, Jamie L., Hu, Laixing, Kumar, Arvind, Yang, Sihyung, Wang, Michael Zhuo, Boykin, David W., Werbovetz, Karl A.
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Sprache:eng
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Zusammenfassung:[Display omitted] Arylimidamide (AIA) compounds containing two pyridylimidamide terminal groups (bis-AIAs) possess outstanding in vitro antileishmanial activity, and the frontrunner bis-AIA DB766 (2,5-bis[2-(2-isopropoxy)-4-(2-pyridylimino)aminophenyl]furan) is active in visceral leishmaniasis models when given orally. Eighteen compounds containing a single pyridylimidamide terminal group (mono-AIAs) were synthesized and evaluated for their antileishmanial potential. Six of these compounds exhibited sub-micromolar potency against both intracellular Leishmania donovani and Leishmania amazonensis amastigotes, and three of these compounds also displayed selectivity indexes of 25 or greater for the parasites compared to a J774 macrophage cell line. When given orally at a dose of 100mg/kg/day for five days, compound 1b (N-(3-isopropoxy-4-(5-phenylfuran-2-yl)phenyl)picolinimidamide methanesulfonate) reduced liver parasitemia by 46% in L. donovani-infected mice. Mono-AIAs are thus a new class of candidate molecules for antileishmanial drug development.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.03.082