Cafestol and kahweol: coffee diterpenes with trypanocidal activity and cardioprotective effects

Chagas disease (CD), caused by Trypanosoma cruzi, remains a major public health challenge in Latin America, affecting more than 7 million people worldwide and approximately 100 million individuals at risk of infection. Current chemotherapy relies exclusively on benznidazole and nifurtimox, which present significant limitations, such as prolonged treatment regimens, severe side effects, and limited efficacy during the chronic phase of the disease. These drawbacks highlight the urgent need for novel therapeutic alternatives. In this context, natural products, particularly diterpenes, have attracted considerable attention due to their broad spectrum of biological activities, including antioxidant, anti-inflammatory, and antimicrobial effects. Cafestol (CF) and kahweol (KW), ent-kaurane diterpenes found in Coffea arabica L., are recognized for their cardioprotective effects; however, their potential cardioprotective properties remain unexplored in the context of neglected diseases. This study aimed to evaluate the potential of CF and KW as trypanocidal agents and modulators of parasite-induced cardiac damage.

To investigate the trypanocidal potential of CF and KW, both compounds were tested individually and in combination (1:1) against two T. cruzi strains representing distinct discrete typing units (DTUs), Y and Tulahuen. Their activity was evaluated against bloodstream trypomastigotes, the infective stage, and intracellular amastigotes, the replicative stage in the mammalian host. An in vitro infection model using cardiac cells as host cells was also employed, allowing the investigation of the ability of these diterpenes to mitigate parasite-induced cellular damage.

The results demonstrated that the combination of CF and KW enhanced trypanocidal activity against both T. cruzi strains tested. The CF+KW mixture showed significantly greater activity than the individual compounds against intracellular amastigotes of the Tulahuen strain (IC₅₀ = 9.6 µg/mL) and bloodstream trypomastigotes of the Y strain (IC₅₀ = 10.4 µg/mL). Against intracellular amastigotes of the Y strain, the combination remained active after 48 h of treatment (IC₅₀ = 13.3 µg/mL).

Moreover, the CF and KW combination demonstrated superior efficacy in preserving sarcomere integrity in infected cardiac cells compared with the individual compounds. Based on these findings and considering their pharmacological potential, CF and KW represent promising candidates for the development of new therapeutic strategies.