Evaluation of Antioxidant and Antitrypanosomal Properties of a Selected Series of Synthetic 3‐Carboxamidocoumarins

Abstract

Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted 3‐carboxamidocoumarins exerting both antioxidant and trypanocidal activities are described. Among the compounds synthesized, compound 3 (N‐(4‐hydroxyphenyl)coumarin‐3‐carboxamide) showed the most interesting antioxidant profile, presenting 53.2 % superoxide radical scavenging and the highest ORAC‐FL value (ORAC‐FL=1.87) of the series. In the trypanocidal study, compounds 9 (N‐(quinolin‐6‐yl)coumarin‐3‐carboxamide) and 10 (N‐(quinolin‐3‐yl)coumarin‐3‐carboxamide) presented high activity in epimastigote stage and low activity in trypomastigote stage, as well as low cytotoxic effects. Additionally, these compounds decreased mitochondrial transmembrane potential in epimastigote Dm28c. Based on these results, compounds 9 and 10 proved to be good candidates for further studies. Interestingly, the current study revealed that small structural changes in this scaffold allow modulating both activities, suggesting that these molecules present the desirable properties for the development of promising classes of antichagasic compounds.

Evaluation of Trypanocidal and Antioxidant Activities of a Selected Series of 3-amidocoumarins

“…Based on the ORAC-FL values (Table 1), the antioxidant profile of the studied molecules can be organized as: 3 > 7 > 5 > 6 ≈ 8 ≈ 4 ≈ 9 > 2 ≈ 1. ORAC-FL indexes described here are similar to those previously determined for coumarins presenting the same structural patterns [4,15]. However, in general these values are lower than the determined for 3-aryl-4-hydroxycoumarins [14].…”

“…All compounds showed higher trypanocidal activity against both cellular forms of the parasite (% cell viability, Table 2) than the previously described 2-chloro-N-(coumarin-3-yl)acetamide [4]. In addition, these compounds showed similar activity to a previously studied series of 3carboxamidocumarins [15]. Based on this data, the design of the new molecules can be considered a step forward in the use of 3-substituted coumarins as multi-target compounds against T. cruzi.…”

“…In order to obtain information about the trypanocidal mechanism of action of a series of 3-carboxamidocoumarins, we studied the parasite mitochondrial membrane potential [15]. The generation of oxidative stress in the parasite can be responsible for the mitochondrial dysfunction, essential for the survival of parasite and the regulation of processes related to energy balance and modulation of apoptosis [16].…”

Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi

“…For example, Munoz et al described the syntheses of 3-carboxyamidocoumarins and evaluation in vitro of antitrypanosomal activity of these compounds against epimastigotes and trypomastigotes of T. cruzi (Muñoz et al, 2016). In the same year, Vazquez-Rodriguez et al described the synthesis of new coumarin-chalcone hybrids and evaluated their antitrypanosomal activity against epimastigotes, trypomastigotes, and amastigotes of T. cruzi (Vazquez-Rodriguez et al, 2016).…”

QSAR study of synthetic 3-arylcoumarins: <em>in silico</em> clastogenic prediction

“…The antioxidant activity has been extensively studied in the last years, and has been reported for natural and synthetic coumarins. Recently, our research group has experimentally studied the antioxidant activity of several synthetic coumarins [6][7][8][9][10][11]. This activity is of great interest in the treatment of chronic diseases [12].…”