Series of Alkynyl-Substituted Thienopyrimidines as Inhibitors of Protozoan Parasite Proliferation
- 4 September 2018
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Medicinal Chemistry Letters
- Vol. 9 (10), 996-1001
- https://doi.org/10.1021/acsmedchemlett.8b00245
Abstract
Discovery of new chemotherapeutic lead agents can be accelerated by optimizing chemotypes proven to be effective in other diseases to act against parasites. One such medicinal chemistry campaign has focused on optimizing the anilinoquinazoline drug lapatinib (1) and the alkynyl thieno[3,2-d]pyrimidine hit GW837016X (NEU-391, 3) into leads for antitrypanosome drugs. We now report the structure–activity relationship studies of 3 and its analogs against Trypanosoma brucei, which causes human African trypanosomiasis (HAT). The series was also tested against Trypanosoma cruzi, Leishmania major, and Plasmodium falciparum. In each case, potent antiparasitic hits with acceptable toxicity margins over mammalian HepG2 and NIH3T3 cell lines were identified. In a mouse model of HAT, 3 extended life of treated mice by 50%, compared to untreated controls. At the cellular level, 3 inhibited mitosis and cytokinesis in T. brucei. Thus, the alkynylthieno[3,2-d]pyrimidine chemotype is an advanced hit worthy of further optimization as a potential chemotherapeutic agent for HAT.Keywords
Funding Information
- National Institute of Allergy and Infectious Diseases (R01 AI124046, R56 AI099476)
This publication has 30 references indexed in Scilit:
- A fixable probe for visualizing flagella and plasma membranes of the African trypanosomePLOS ONE, 2018
- AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African TrypanosomePublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2017
- Repurposing strategies for tropical disease drug discoveryBioorganic & Medicinal Chemistry Letters, 2016
- Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malariaMedChemComm, 2014
- Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening CampaignPLoS Neglected Tropical Diseases, 2014
- Repurposing human Aurora kinase inhibitors as leads for anti-protozoan drug discoveryMedChemComm, 2014
- Kinase Scaffold Repurposing for Neglected Disease Drug Discovery: Discovery of an Efficacious, Lapatanib-Derived Lead Compound for TrypanosomiasisJournal of Medicinal Chemistry, 2013
- The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposingEuropean Journal of Medicinal Chemistry, 2013
- The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug RepurposingPLoS Neglected Tropical Diseases, 2011
- Cytokinesis in trypanosomatidsCurrent Opinion in Microbiology, 2007