α-Pyrone as a marine scaffold for the synthesis of new antileishmanial and antitrypanosomal compounds

Leishmaniasis and Chagas disease are parasitic protozoan infections, widely found in tropical and subtropical regions, affecting the poorest population and causing high mortality and morbidity. Considering the reduced therapeutic arsenal and highly toxic drugs in clinical use, there is an urgent need for the discovery of alternative treatments [1]. Marine natural products have been used as promising scaffolds for the design of new drug candidates, and marine microbial pyrones have been shown growth inhibition of Mycobacterium tuberculosis, Trypanosoma brucei rhodesiense, Leishmania donovani and Plasmodium falciparum [2]. In the present work, three pyrone analogues were synthesized and their in vitro activity was evaluated against Leishmania (L.) infantum intracellular amastigotes and Trypanosoma cruzi trypomastigotes, using light microscopy counting and the MTT assay, respectively. The mammalian toxicity was also evaluated using NCTC cells and the viability was detected by the mitochondrial oxidation of MTT. Among the three synthesized compounds (PYR1 – 3), PYR2 and PYR3 demonstrated antileshmanial activity against the intracellular forms, eliminating 100% of parasites without toxicity to macrophages, and showing IC50 values of 53 and 52µM, respectively (Table 1). PYR2 were also effective to eliminate trypomastigotes of T. cruzi, showing an IC50 value of 73µM. The pyrone derivatives demonstrated moderate toxicity to NCTC cells, showing IC50 values in a range between 195 to 323µM. Despite the toxicity, PYR2 and PYR3 demonstrated selectivity towards the parasites and could be explored for future drug design studies against neglected tropical diseases.

Tab. 1: Antileishmanial, antitrypanosomal and cytotoxicity studies of α-pyrone derivatives. IC₅₀ - 50% inhibitory concentration; CC₅₀ - 50% cytotoxic concentration, n.a. – not active, 95% C.I. – 95% confidence interval.

Acknowledgements: FAPESP 2012/18756 – 1.

Keywords: marine compounds, neglected diseases, Leishmania, Trypanosoma cruzi, therapy

References:

[1] Pinto, E. G., Pimenta, D. C., Jaredd, C., Tempone, A. G. Antimicrobial peptides isolated from Phyllomedusa nordestina (Amphibia) alter the permeability of plasma membrane of Leishmania and Trypanosoma cruzi. Exp Parasit, 2013, 135: 655 – 660.

[2] Giddens, A. C., Nielsen, L., Boshoff, H. I., Tasdemir, D., Perozzo, R., Kaiser, M., Wang, F., Sacchettini, J. C., Copp, B. R. Natural Product Inhibitors of Fatty Acid Biosynthesis: Synthesis of the Marine Microbial Metabolites Pseudopyronines A and B and Evaluation of Their Antiinfective Activities. Tetrahedron, 2008, 64: 1242 – 1249.