Planejamento e síntese de sistemas heterocíclicos com potencial atividade tripanocida

Abstract

Chagas Disease (CD) is a neglected tropical disease caused by the protozoan Trypanosoma cruzi, transmitted by triatomine insects. It is estimated that 6 million people are currently infected worldwide. Chemotherapy is based on two drugs, benznidazole and nifurtimox, which have limited efficacy and several side effects. Therefore, there is an imminent demand for the development of new compounds that are more active against T. cruzi. Over the years, especially compounds containing heterocyclic nuclei, have shown a wide spectrum of biological activities, including antiprotozoal, with emphasis on the pyrazole, imidazoline, pyrimidine, tetrahydropyrimidine, thiazole and coumarin nuclei, which were synthesized in this research project. In this study, 40 new compounds designated series 1(a-k), 2(a-k), 3(a,c-f,h-j) and 4(a-j) were designed, synthesized and evaluated their for trypanocidal activity, based on previously promising compounds synthesized by our research group. All final compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (HRMS) analyses. The yields of products 1(a-k) ranged from 28% to 77%. In series 2(a-k), derivatives were obtained in 27-91% yields. Derivatives 3(a,c-f,h-j) were isolated in yields ranging from 24-94%, while compounds 4(a-j) were synthesized in yields varying from 36-94%. In silico analyzes showed that all compounds obey Lipinski's rules, and presented a high probability of good oral bioavailability. The present study describes the biological activity of the final compounds 1(a-k), 2(a-k) and 3(a,c-f,g-j). In vitro phenotypic screening showed that among all compounds of series 1(a-k), 1h derivative displayed the highest biological activity (IC50 = 28.57 ± 4.70 μM) gainst trypomastigote forms, and all compounds displayed IC50 > 67 μM against amastigote forms. Among derivatives 2(a-k), compound 2g stood out as it exhibited the most promising results against both forms of the parasite, with an IC50 value equal to 11.66 ± 1.38 μM. The compounds of series 3(a,c-f,g-j) were tested against amastigote forms and demonstrated low efficacy (IC50 > 47 μM). In relation to compounds 4(a-j), 4f derivative has been the most active against both forms of T. cruzi, however trials are still ongoing. All compounds from series 1, 2, 3 and 4 did not show cytotoxicity (CC50 > 100 μM). The compound named MSD24 was synthesized on a larger scale and is currently undergoing in vivo testing. This work highlights the importance of searching for new drug candidates for the treatment of CD.