2. Academic Validation
  3. Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids

Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids

  • Eur J Med Chem. 2020 Sep 1;201:112418. doi: 10.1016/j.ejmech.2020.112418.
Fábio S Fernandes 1,  Hugo Santos 1,  Samia R Lima 1,  Caroline Conti 1,  Manoel T Rodrigues Jr 1,  Lucas A Zeoly 1,  Leonardo L G Ferreira 2,  Renata Krogh 2,  Adriano D Andricopulo 3,  Fernando Coelho 4
Affiliations

Affiliations

  • 1 Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas, PO Box 6154, 13083-970, Campinas, SP, Brazil.
  • 2 Laboratory of Medicinal and Computational Chemistry, Institute of Physics of Sao Carlos, University of Sao Paulo, Avenida Joao Dagnone, 1100, 13563-120, Sao Carlos, SP, Brazil.
  • 3 Laboratory of Medicinal and Computational Chemistry, Institute of Physics of Sao Carlos, University of Sao Paulo, Avenida Joao Dagnone, 1100, 13563-120, Sao Carlos, SP, Brazil. Electronic address: [email protected].
  • 4 Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas, PO Box 6154, 13083-970, Campinas, SP, Brazil. Electronic address: [email protected].
PMID: 32590115 DOI: 10.1016/j.ejmech.2020.112418
Abstract

A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Trypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC50 values of 3.89, 2.38, 2.50 and 2.85 μM, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC50 values of 6.20, 2.20, 2.30 and 2.20 μM, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery.

Keywords

Grubbs catalyst; Heterocycles; Leishmaniasis; Morita-Baylis-Hillman; Olefin metathesis; Organocatalysis; Trypanosomiasis.

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