In vitro and in vivo trypanocidal activities of 8‐methoxy‐3‐(4‐nitrobenzoyl)‐6‐propyl‐2H‐cromen‐2‐one, a new synthetic coumarin of low cytotoxicity against mammalian cells

Abstract

Natural and synthetic coumarins have been described as prototypes of new drug candidates against Chagas' disease. During a typical screening with new compounds, we observed the potential of a new synthetic nitrobenzoylcoumarin (1) as trypanocidal against Trypanosoma cruzi epimastigotas. Then, we decided to prepare and evaluate a set of analogues from 1 to check the major structural requirements for trypanocidal activity. The structural variations were conducted in six different sites on the original compound and the best derivative (3) presented activity (IC 28 ± 3 μM) similar to that of benznidazole (IC 25 ± 10 μM). The enhancement of trypanocidal activity was conditioned to a change in the side chain at C6 (allyl to n-propyl group) and the preservation of coumarin nucleus and the nitrobenzoyl group at C3. Exposure of 3 to H9C2 cells showed low toxicity (CC > 200 μM) and its activity on T. cruzi amastigotes (IC 13 ± 0.3 μM) encouraged us to perform an evaluation of its potential when given orally to mice infected with trypomastigote forms. Derivative 3 was able to reduce parasitemia when compared to the group of untreated animals. Taken together, these results show the potential therapeutic application of the synthetic coumarins.

Allelochemical Activity of Eugenol-Derived Coumarins on Lactuca sativa L.

“…The coumarins A1, A3, A5, and A6 are described here for the first time. The coumarins A2 and A4 have been reported elsewhere [24,25], but as part of studies for other purposes.…”

Indirubin derivatives are potent and selective anti-Trypanosoma cruzi agents

“…Those compounds display lower EC 50 values (EC 50 Try: 0.25-1.30 μΜ, EC 50 Ama: 0.22-1.51 μΜ) than the standard drug benznidazole (EC 50 of 11.4 and 13.4 µM for trypomastigotes and intracellular amastigotes upon 24 h and 6 h of treatment, respectively) in vitro, which implies that they are potent inhibitors of the T. cruzi growth. In the literature, benznidazole is reported to inhibit T. cruzi amastigotes in vitro with EC 50 values ranging from 1-15 μΜ, this variation being the result of the use of different host cell types, strains of parasites used and time of exposure to test compounds [33][34][35]. Compounds 10, 11 and 17 are 3'substituted-6BIO analogues and were identified as most potent inhibitors of Leishmania and T. brucei parasites, as well as of their parasitic kinase-targets (GKS-3s, CRK3) [22,23], while compound 32 is a 7substituted indirubin.…”

Computer‐Guided Trypanocidal Activity of Natural Lactones Produced by Endophytic Fungus of Euphorbia umbellata

“…Natural lactones ( 1 – 3 ) and benznidazole (reference drug; Sigma‐Aldrich) were tested at the same concentrations (200–1.56 μg mL −1 ) in triplicate, for both the trypanocidal and cytotoxicity assays, as previously described [69] . All trypanocidal and cytotoxic results were expressed as the average of two independent assays and used for calculating the correspondent inhibitory concentrations.…”

“…[44] In Vitro Trypanocidal and Cytotoxic Assays Natural lactones (1 -3) and benznidazole (reference drug; Sigma-Aldrich) were tested at the same concentrations (200 -1.56 μg mL À 1 ) in triplicate, for both the trypanocidal and cytotoxicity assays, as previously described. [69] All trypanocidal and cytotoxic results were expressed as the average of two independent assays and used for calculating the correspondent inhibitory concentrations. The concentrations required to inhibit 50 % of the epimastigotes or trypomastigotes (IC 50 ) and 50 % of Vero cells (CC 50 ), along with the selectivity index (SI, CC 50 /IC 50 ) values, were calculated with the CompuSyn software (Figures S17, S18, and S19 in Supporting Information).…”