Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids

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• 作者：Amber Hackler^a ; ¹ ; Stephen L. Patrick^a ; ² ; Elizabeth W. Kahney^a ; ³ ; Daniel P. Flaherty^b ; ⁴ ; Elizabeth R. Sharlow^c ; ^d ; James C. Morris^a ; ; Jennifer E. Golden^b ; ^{jennifer.golden@wisc.edu}
• 关键词：Antiparasitic ; African sleeping sickness ; Leishmaniasis ; Sulfonamide
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：27
• 期：4
• 页码：755-758
• 全文大小：444 K
• 卷排序：27

文摘

A sulfonamidebenzamide series was assessed for anti-kinetoplastid parasite activity based on structural similarity to the antiparasitic drug, nifurtimox. Through structure-activity optimization, derivatives with limited mammalian cell toxicity and increased potency toward African trypanosomes and Leishmania promastigotes were developed. Compound 22 had the best potency against the trypanosome (EC50 = 0.010 μM) while several compounds showed ∼10-fold less potency against Leishmania promastigotes without impacting mammalian cells (EC50 > 25 μM). While the chemotype originated from an unrelated optimization program aimed at selectively activating an apoptotic pathway in mammalian cancer cells, our preliminary results suggest that a distinct mechanism of action from that observed in mammalian cells is responsible for the promising activity observed in parasites.