Sars for the antiparasitic plant metabolite pulchrol. 3. combinations of new substituents in a/b-rings and a/c-rings

Paola Terrazas, Efrain Salamanca, Marcelo Dávila, Sophie Manner, Alberto Gimenez, Olov Sterner

Research output: Contribution to journalArticlepeer-review

Abstract

The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess antiparasitic activity towards Try-panosoma cruzi, Leishmania braziliensis and L. amazonensis, which are protozoa responsible for Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SARs studies, based on the pulchrol scaffold, showed which effects exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent than pulchrol and the current drugs used to treat leishmaniasis and Chagas disease (miltefosine and benznidazole, respectively), in vitro. Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro towards T. cruzi epimastigotes, L. braziliensis promastigotes, and L. amazonensis promastigotes. Some compounds had higher antiparasitic activity than the parental compound pulchrol, and in some cases even benznidazole and miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A-and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which indeed was shown to be potent towards all the parasites.

Original languageEnglish
Article number3944
JournalMolecules
Volume26
Issue number13
DOIs
StatePublished - 1 Jul 2021

Bibliographical note

Funding Information:
Funding: This research was funded by the Swedish International Development Agency (SIDA, grant No 2017-258), and a Ph.D. scholarships for P.T. from SIDA is gratefully acknowledge.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Cannabinol
  • Leishmania amazonensis
  • Leishmania braziliensis
  • Pulchral
  • Pulchrol
  • SARs
  • Trypanosoma cruzi

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