2. Academic Validation
  3. Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds

Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds

  • Eur J Med Chem. 2018 Feb 10:145:191-205. doi: 10.1016/j.ejmech.2017.12.051.
Geraldo Célio Brandão 1,  Franciele C Rocha Missias 2,  Lucas Miquéias Arantes 3,  Luciana Ferreira Soares 3,  Kuldeep K Roy 4,  Robert J Doerksen 5,  Alaide Braga de Oliveira 3,  Guilherme Rocha Pereira 6
Affiliations

Affiliations

  • 1 Departamento de Farmácia, Escola de Farmácia, UFOP, Campus Morro do Cruzeiro, s/n, Balxita, CEP 35400-000, Ouro Preto, MG, Brazil.
  • 2 Pontifícia Universidade Católica de Minas Gerais, PUC Minas, Departamento de Física e Química, Instituto de Ciências Exatas e Informática ICEI, Av. Dom José Gaspar, 500 Prédio 34 Coração Eucarístico, CEP 30535.901, Belo Horizonte, MG, Brazil.
  • 3 Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, UFMG, Av. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
  • 4 Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA; National Institute of Pharmaceutical Education and Research, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, WB, India.
  • 5 Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA.
  • 6 Pontifícia Universidade Católica de Minas Gerais, PUC Minas, Departamento de Física e Química, Instituto de Ciências Exatas e Informática ICEI, Av. Dom José Gaspar, 500 Prédio 34 Coração Eucarístico, CEP 30535.901, Belo Horizonte, MG, Brazil; Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, UFMG, Av. Antônio Carlos, 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil. Electronic address: gpereira@pucminas.br.
PMID: 29324340 DOI: 10.1016/j.ejmech.2017.12.051
Abstract

Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) Click Chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 μM) and selectivity index (SI) values in the range of 4.5-197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial Enzyme of the Parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between -9.375 and -14.55 units, compared to -9.137 for lapachol and -12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives.

Keywords

Atovaquone; Chloroquine; Copper-catalyzed cycloaddition; Dihydroorotate dehydrogenase (DHODH); Malaria; Plasmodium falciparum; Triazole.

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