A new chemotype with promise against Trypanosoma cruzi

Xiaofang Wang; Monica Cal; Marcel Kaiser; Frederick S Buckner; Galina I Lepesheva; Austin G Sanford; Alexander I Wallick; Paul H Davis; Jonathan L Vennerstrom

doi:10.1016/j.bmcl.2019.126778

A new chemotype with promise against Trypanosoma cruzi

Bioorg Med Chem Lett. 2020 Jan 1;30(1):126778. doi: 10.1016/j.bmcl.2019.126778. Epub 2019 Oct 31.

Authors

Xiaofang Wang¹, Monica Cal², Marcel Kaiser², Frederick S Buckner³, Galina I Lepesheva⁴, Austin G Sanford⁵, Alexander I Wallick⁵, Paul H Davis⁵, Jonathan L Vennerstrom⁶

Affiliations

¹ College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, United States.
² Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; University of Basel, CH-4003 Basel, Switzerland.
³ Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, United States.
⁴ Department of Biochemistry, Vanderbilt University, 2200 Pierce Ave., Nashville, TN, United States.
⁵ Department of Biology, University of Nebraska at Omaha, Omaha, NE, United States.
⁶ College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, United States. Electronic address: jvenners@unmc.edu.

Abstract

Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ≥10. The initial structure-activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi. Compound 2 and its active analogs had low to moderate metabolic stabilities in human and mouse liver microsomes.

Keywords: Chagas disease; SAR; Trypanosoma cruzi.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Chagas Disease / drug therapy*
Humans
Structure-Activity Relationship
Trypanocidal Agents / pharmacology
Trypanocidal Agents / therapeutic use*
Trypanosoma cruzi / drug effects*

Substances

Trypanocidal Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding