Banca de DEFESA: LUCAS DE OLIVEIRA PIRES

Planning, Synthesis and Evaluation of Biological Properties of Cinnamic Amides and its Prenylated Derivatives

O-prenylation; COX-2; Trypanosoma cruzi; Sporothrix brasiliensis.

A great diversity of cinnamic acids and its derivatives are naturally found as a product from the special metabolism of plants, and several biological properties are described in the literature and can be associated to the presence of these derivatives and several natural products. The aim of this work is to describe the planning, synthesis and biological evaluation of cinnamic acid amides against different biological targets with clinical relevance. Series I and II are composed by amides derived from caffeic acid and their respective O-prenylated analogues, planned as potential COX-2 inhibitors and evaluated against breast cancer cells for antiproliferative activity. Series III and IV are composed by anilides prepared using different cinnamic acids, used to obtain their respective lactamas. Series I – IV were then evaluated against T. cruzi for antiparasitic activity and S. brasiliensis for antifungal activity, as well as cytotoxicity evaluated using LLC-MK2 cells. Among the tested compounds, it is possible to highlight the derivative 3d (caffeic acid hexylamide) due to its inhibition of COX-2 activity (IC₅₀ = 6,3 µM) and antiproliferative activity (IC₅₀ = 62,91 µM), as well as the activity against amastigotes of T. cruzi (IC₅₀ = 27,26 µM) and growth inhibition of S. brasiliensis (CIM = 1,25 µM), with moderate cytotoxic (IC₅₀ = 156,10 µM). Among the different biological evaluations, the O-prenylated analogues from Series II were more active and their respective amide from Series I only for antiparasitic activity, in which the derivatives 3cP (caffeic acid pentylamide O-prenylated) and 3dP (caffeic acid hexylamide O-prenylated) showed the best results against T. cruzi amastigotes (IC₅₀ = 7,54 e 13,28 µM, respectively), while the O-prenylation of amides didn’t modulate the biological aspect of the structure in a positive way in comparison to the compounds from Series I. The compounds from Series III and IV of anilides and their respective lactamas didn’t show biological activity against T. cruzi or S. brasiliensis. The studied compounds from this work showed the potential of cinnamic acid derivatives against different targets, and the O-prenylation reaction can be considered as an important tool in the investigation of new compounds with promising antiparasitic activity