Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids

Bioorg Med Chem Lett. 2017 Feb 15;27(4):755-758. doi: 10.1016/j.bmcl.2017.01.043.

Amber Hackler ¹, Stephen L Patrick ¹, Elizabeth W Kahney ¹, Daniel P Flaherty ², Elizabeth R Sharlow ³, James C Morris ¹, Jennifer E Golden ⁴

Affiliations

1 Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA.
2 KU Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047, USA.
3 Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; Fiske Drug Discovery Laboratory, University of Virginia, Charlottesville, VA 22908, USA.
4 KU Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047, USA. Electronic address: jennifer.golden@wisc.edu.

PMID: 28119024 DOI: 10.1016/j.bmcl.2017.01.043

Abstract

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=0.010μM) while several compounds showed ∼10-fold less potency against Leishmania promastigotes without impacting mammalian cells (EC₅₀>25μM). 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.

Keywords

African sleeping sickness; Antiparasitic; Leishmaniasis; Sulfonamide.

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