Effect of the Alkyl Side Chain of Antitrypanosomal Cinnamate, p-Coumarate, and Ferulate n-Alkyl Esters Using Multivariate Analysis and Computer-Aided Drug Design

In the present work, three series of cinnamic (1), p-coumaric (2) and ferulic (3) esters containing different side-chains such as ethyl (1a-3a), n-propyl (1b-3b), n-butyl (1c-3c), n-pentyl (1d-3d), n-hexyl (1e-3e), and n-heptyl (1f-3f) were prepared, tested for activity against trypomastigote forms of the parasite Trypanosoma cruzi and toxicity against NCTC cells. Obtained results indicated that the presence of p-coumaric or ferulic moieties associated with C4-C7 linear side-chains play an important role in the bioactivity against T. cruzi since compounds 2c-2f and 3d-3f were found to be the most active derivatives with a half maximal effective concentration (EC50) value ranging from 12.8 to 1.7 µM, superior to that determined for the positive control benznidazole (EC50 = 16.4 µM). Additionally, machine learning and multivariate statistical analyses identified molecular features correlated with biological activity, emphasizing the importance of side-chain length and lipophilicity, highlighting the significance of the molecular structure of phenylpropanoid derivatives in the activity against T. cruzi.