Selective Activity Against Amastigote Forms of Trypanosoma cruzi and Leishmania infantum of Diastereomeric Dicentrine N-oxides

Author(s)

Tristao, Daniela C. ; Barbosa, Henrique ; Levatti, Erica V. de Castro ; Andrade, Beatriz A. ; Romanelli, Maiara M. ; Antar, Guilherme M. ; Tempone, Andre G. ; Lago, Joao Henrique G.

• Document type: Journal article
• Source: CHEMISTRY & BIODIVERSITY; v. 21, n. 9, p. 6-pg., 2024-08-11.

Abstract

As part of our continuous research for the discovery of bioactive compounds against Trypanosoma cruzi and Leishmania infantum, the alkaloid (6aS)-dicentrine (1) was oxidized to afford (6aS,6S)- (2) and (6aS,6R)- (3) dicentrine-N-oxides. Evaluation of the cytotoxicity against NCTC cells indicated that 2 and 3 are non-toxic (CC50>200 mu M) whereas 1 demonstrated CC50 of 52.0 mu M. Concerning T. cruzi activity against amastigotes, derivatives 2 and 3 exhibited EC50 values of 9.9 mu M (SI>20.2) and 27.5 mu M (SI>7.3), respectively, but 1 is inactive (EC50>100 mu M). Otherwise, when tested against L. infantum amastigotes, 1 and 3 exhibited EC50 values of 10.3 mu M (SI=5.0) and 12.7 mu M (SI>15.7), respectively, being 2 inactive (EC50>100 mu M). Comparing the effects of positive controls benznidazol (EC50=6.5 mu M and SI>30.7) and miltefosine (EC50=10.2 mu M and SI=15.2), it was observed a selective antiparasitic activity to diastereomers 2 and 3 against T. cruzi and L. infantum. Considering stereochemical aspects, it was suggested that the configuration of the new stereocenter formed after oxidation of 1 played an important role in the bioactivity against amastigotes of both tested parasites. (AU)

• FAPESP's process: 21/04464-8 - Microbial and plant prototypes as drug candidates for protozoan neglected diseases and multidrug-resistant bacteria
• Grantee: André Gustavo Tempone Cardoso
• Support Opportunities: Regular Research Grants
• FAPESP's process: 23/12447-1 - Searching for specialized metabolites from Brazilian floristic biodiversity as drug candidates for neglected tropical diseases
• Grantee: João Henrique Ghilardi Lago
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants