2. Academic Validation
  3. Series of Alkynyl-Substituted Thienopyrimidines as Inhibitors of Protozoan Parasite Proliferation

Series of Alkynyl-Substituted Thienopyrimidines as Inhibitors of Protozoan Parasite Proliferation

  • ACS Med Chem Lett. 2018 Sep 4;9(10):996-1001. doi: 10.1021/acsmedchemlett.8b00245.
Jennifer L Woodring 1,  Ranjan Behera 2,  Amrita Sharma 2,  Justin Wiedeman 2,  Gautam Patel 1,  Baljinder Singh 1,  Paul Guyett 2,  Emanuele Amata 1,  Jessey Erath 3 4,  Norma Roncal 5,  Erica Penn 5,  Susan E Leed 5,  Ana Rodriguez 3 4,  Richard J Sciotti 5,  Kojo Mensa-Wilmot 2,  Michael P Pollastri 1
Affiliations

Affiliations

  • 1 Department of Chemistry & Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
  • 2 Department of Cellular Biology, Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, United States.
  • 3 Department of Microbiology, New York University School of Medicine, 430 E. 29th Street New York, New York 10010, United States.
  • 4 Anti-Infectives Screening Core, New York University School of Medicine, New York, New York 10010, United States.
  • 5 Experimental Therapeutics, Walter Reed Army Institute of Research, 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
PMID: 30344906 DOI: 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.

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