In the present work, the MeOH extract from roots of Porcelia ponderosa R.E. Fries (Annonaceae) was subjected to several chromatographic techniques to afford three chemically related amides: N-trans-p-coumaroyltyramine (1), N-trans-caffeoyltyramine (2), and N-trans-feruloyltyramine (3). Isolated compounds were characterized by NMR and MS spectral analysis. This is the first report of compounds 1-3 in P. ponderosa, while 1 is a previously unreported metabolite from the Porcelia genus. Previous studies reported the effects of amides 1-3 on the inhibition of sterol 14-α-demethylase (CYP51), a key enzyme in the life cycle of Trypanosoma cruzi, using an in silico approach. However, no experimental evidence was conducted to prove their effects against the parasite. Based on these data and isolation of amides 1-3 from roots of P. ponderosa, these compounds were tested in vitro against the intracellular amastigotes of T. cruzi. Compounds 1 and 2, containing p-coumaroyl and caffeic moieties, displayed potent activity with EC50 values of 6.3 ± 1.2 and 3.4 ± 0.6 µM, respectively, a similar efficacy observed to the standard drug benznidazole (EC50 of 5.5 ± 2.2 µM). Otherwise, compound 3, with a feruloyl moiety, showed moderate activity (EC50 of 14.0 ± 0.3 µM). These results indicated that p-coumaric and caffeoyl moieties play an important role in the potency against amastigotes of T. cruzi. Otherwise, simplified derivatives of 1-3 such as p-coumaric, caffeic and ferulic acids as well as tyramine, showed to be inactive against amastigotes (EC50 > 150 µM) reinforcing the importance of condensation of these free acids and tyramine for the efficacy of amides 1-3. Considering the cytotoxicity against murine fibroblasts, compounds 1-3 displayed CC50 values higher than 200 µM, and SI values higher than 31.7, 55.6, and 14.3, respectively. These findings highlight a safe profile and the antiparasitic potential of amides 1 and 2, which could be used as promising hit compounds for the design of new drug candidates for Chagas disease.
Santos et al. (Sun,) studied this question.