Open AccessDiaryl Ureas as an Antiprotozoal Chemotype
Author(s) -
Derek A. Leas,
Austin G Sanford,
Jianbo Wu,
Monica Cal,
Marcel Kaiser,
Sergio Wittlin,
Ryan M. Hemsley,
Elyssa B Darner,
LeeAnna Lui,
Paul H. Davis,
Jonathan L. Vennerstrom
Publication year - 2021
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.1c00135
Subject(s) - antiprotozoal , antiparasitic , plasmodium falciparum , trypanosoma brucei rhodesiense , trypanosoma brucei , trypanosoma cruzi , adme , chemotype , leishmania donovani , potency , antiparasitic agent , leishmania infantum , biology , pharmacology , toxoplasma gondii , in vitro , biochemistry , chemistry , parasite hosting , malaria , leishmaniasis , visceral leishmaniasis , immunology , medicine , pathology , gene , world wide web , computer science , essential oil , food science , antibody
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 LogD 7.4 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.