Diaryl Ureas as an Antiprotozoal Chemotype

Derek A. Leas, Austin G. Sanford, Jianbo Wu, Monica Cal, Marcel Kaiser, Sergio Wittlin, Ryan M. Hemsley, Elyssa B. Darner, Leeanna M. Lui, Paul H. Davis, Jonathan L. Vennerstrom

Research output: Contribution to journalArticlepeer-review

Abstract

We now describe the physicochemical profiling, in vitro ADME, and antiparasitic activity of eight N,N′-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD7.4 values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 μg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no N,N′-diarylurea had submicromolar potency against Trypanosoma cruzi, two had submicromolar potencies against Toxoplasma gondii and Trypanosoma brucei rhodesiense, and five had submicromolar potencies against Leishmania donovani. Plasmodium falciparum appeared to be the most susceptible to growth inhibition by this compound series. Most of the N,N′-diarylureas had antiprotozoal selectivities ≥10. One N,N′-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.

Original languageEnglish (US)
Pages (from-to)1578-1583
Number of pages6
JournalACS infectious diseases
Volume7
Issue number6
DOIs
StatePublished - Jun 11 2021

Keywords

  • N, N′-diarylurea
  • antiprotozoal
  • chemotype

ASJC Scopus subject areas

  • Infectious Diseases

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