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ChemMedChem. 2018 Sep 6;13(17):1751-1754. doi: 10.1002/cmdc.201800404. Epub 2018 Aug 7.

Brain-Penetrant Triazolopyrimidine and Phenylpyrimidine Microtubule Stabilizers as Potential Leads to Treat Human African Trypanosomiasis.

Author information

1
Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
2
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA, 19104-6323, USA.
3
Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA, 19104-6323, USA.

Abstract

In vitro whole-organism screens of Trypanosoma brucei with representative examples of brain-penetrant microtubule (MT)-stabilizing agents identified lethal triazolopyrimidines and phenylpyrimidines with sub-micromolar potency. In mammalian cells, these antiproliferative compounds disrupt MT integrity and decrease total tubulin levels. Their parasiticidal potency, combined with their generally favorable pharmacokinetic properties, which include oral bioavailability and brain penetration, suggest that these compounds are potential leads against human African trypanosomiasis.

KEYWORDS:

Trypanosoma brucei; human African trypanosomiasis; microtubules; phenylpyrimidines; triazolopyrimidines

PMID:
29969537
PMCID:
PMC6286711
DOI:
10.1002/cmdc.201800404
[Indexed for MEDLINE]
Free PMC Article

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