2. Academic Validation
  3. Synthesis, Structure-Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines

Synthesis, Structure-Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines

  • J Med Chem. 2020 Oct 22;63(20):11756-11785. doi: 10.1021/acs.jmedchem.0c00858.
Guang Huang 1,  Claribel Murillo Solano 2,  Joel Melendez 2,  Justin Shaw 2,  Jennifer Collins 2,  Robert Banks 3,  Arash Keshavarzi Arshadi 2,  Rachasak Boonhok 4 5,  Hui Min 4,  Jun Miao 4,  Debopam Chakrabarti 2,  Yu Yuan 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Central Florida, Orlando, Florida 32816, United States.
  • 2 Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, United States.
  • 3 Research Program Services, University of Central Florida, Orlando, Florida 32816, United States.
  • 4 Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • 5 Department of Medical Technology, School of Allied Health Science, Walailak University, Nakhon Si Thammarat 80160, Thailand.
PMID: 32959656 DOI: 10.1021/acs.jmedchem.0c00858
Abstract

There is an urgent need to develop new efficacious antimalarials to address the emerging drug-resistant clinical cases. Our previous phenotypic screening identified styrylquinoline UCF501 as a promising antimalarial compound. To optimize UCF501, we herein report a detailed structure-activity relationship study of 2-arylvinylquinolines, leading to the discovery of potent, low nanomolar antiplasmodial compounds against a Plasmodium falciparum CQ-resistant Dd2 strain, with excellent selectivity profiles (resistance index < 1 and selectivity index > 200). Several metabolically stable 2-arylvinylquinolines are identified as fast-acting agents that kill asexual blood-stage parasites at the trophozoite phase, and the most promising compound 24 also demonstrates transmission blocking potential. Additionally, the monophosphate salt of 24 exhibits excellent in vivo antimalarial efficacy in the murine model without noticeable toxicity. Thus, the 2-arylvinylquinolines represent a promising class of antimalarial drug leads.

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