2. Academic Validation
  3. Semisynthesis, cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives

Semisynthesis, cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives

  • Bioorg Med Chem Lett. 2018 Feb 1;28(3):265-272. doi: 10.1016/j.bmcl.2017.12.060.
Simone Tasca Cargnin 1,  Andressa Finkler Staudt 1,  Patrícia Medeiros 2,  Daniel de Medeiros Sol Sol 2,  Ana Paula de Azevedo Dos Santos 2,  Fernando Berton Zanchi 3,  Grace Gosmann 4,  Antonio Puyet 5,  Carolina Bioni Garcia Teles 6,  Simone Baggio Gnoatto 7
Affiliations

Affiliations

  • 1 Laboratório de Fitoquímica e Síntese Orgânica, Faculdade de Fármacia, UFRGS, Porto Alegre, RS, Brazil.
  • 2 Plataforma de Bioensaios de Malária e Leishmaniose, FIOCRUZ, Porto Velho, RO, Brazil.
  • 3 Laboratório de Bioestatística e Bioinformática, FIOCRUZ, Porto Velho, RO, Brazil. Electronic address: fbzanchi@fiocruz.br.
  • 4 Laboratório de Fitoquímica e Síntese Orgânica, Faculdade de Fármacia, UFRGS, Porto Alegre, RS, Brazil. Electronic address: grace.gosmann@ufrgs.br.
  • 5 Departamento de Bioquímica y Biología Molecular IV, Universidad Complutense de Madrid, Spain. Electronic address: apuyet@ucm.es.
  • 6 Plataforma de Bioensaios de Malária e Leishmaniose, FIOCRUZ, Porto Velho, RO, Brazil. Electronic address: carolinateles@fiocruz.br.
  • 7 Laboratório de Fitoquímica e Síntese Orgânica, Faculdade de Fármacia, UFRGS, Porto Alegre, RS, Brazil. Electronic address: simone.gnoatto@ufrgs.br.
PMID: 29326018 DOI: 10.1016/j.bmcl.2017.12.060
Abstract

In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC50 = 3.4 µM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC50 > 400 µM), showing selectivity towards parasites (selectivity index > 117.47). In combination with artemisinin, compound 7b showed an additive effect (CI = 1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of -7.02 kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC50 = 93 µM) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3β-butanoyl betulinic acid on Plasmodium may be related to Other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources.

Keywords

Antimalarial; Betulinic acid; Plasmodium falciparum; Semisynthesis; Ursolic acid.

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