2. Academic Validation
  3. Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei

Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei

  • Bioorg Med Chem Lett. 2023 Feb 1:81:129123. doi: 10.1016/j.bmcl.2023.129123.
Karol R Francisco 1,  Ludovica Monti 2,  Wenqian Yang 2,  Hayoung Park 2,  Lawrence J Liu 2,  Kaitlyn Watkins 2,  Dilini K Amarasinghe 2,  Marianna Nalli 3,  Carlos Roberto Polaquini 4,  Luis O Regasini 4,  Antônio Eduardo Miller Crotti 5,  Romano Silvestri 3,  Lizandra Guidi Magalhães 6,  Conor R Caffrey 2
Affiliations

Affiliations

  • 1 Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: krfranci@ucsd.edu.
  • 2 Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3 Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy.
  • 4 Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University, São José do Rio Preto, SP 15054-000, Brazil.
  • 5 Faculty of Philosophy, Sciences, and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14040-900, Brazil.
  • 6 Research Group on Natural Products, Center for Research in Sciences and Technology, University of Franca, Franca, SP 14404-600, Brazil.
PMID: 36608774 DOI: 10.1016/j.bmcl.2023.129123
Abstract

Trypanosoma brucei is a protozoan Parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC50 values. A structure-activity relationship study including 26 DBA analogs was initiated, and several compounds exhibited EC50 values as low as 200 nM. Cytotoxicity counter screens in HEK293 cells identified several compounds having selectivity indices above 10. These data suggest that DBAs offer starting points for a new small molecule therapy of HAT.

Keywords

Antiparasitic activity; Curcuminoid; Cytotoxicity; Dibenzylideneacetone; Trypanosoma brucei.

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