Chagas’ disease (American Trypanosomiasis) is a zoonosis caused by the protozoan Trypanosoma cruzi. This parasitic infection is recognized by WHO as one of the thirteen most neglected diseases in the World. There are only two drugs for the treatment of chagasic patients: the nitro-heterocyclic derivatives benznidazole and nifurtimox. However, none of them meets the criteria (i.e. parasitical cure both in acute as well as in chronic phase of the infection and reduced side effects) required to be an optimal drug to treat this illness. Ouassi reported in 1986 that the presence of a fibronectin receptor (FNR) on the parasite`s cell membrane can recognize the peptidic sequence RGDS. Despite the importance of this finding for the development of more selective drugs for the treatment of Chagas’ disease, this information has never been exploited so far. Herein, we have taken the approach of combining the chemical structure of benznidazole and peptide RGDS in a single molecule to achieve our goal in obtaining active and more selective molecules against T. cruzi. Through the molecular planning showed in Figure 1 we were able to synthesize four acyclic and one cyclic peptide-benznidazole conjugates. All the conjugates were prepared in solid phase employing Fmoc/tBu approach using 2-chlorotrityl chloride resin as a solid support. The steps of coupling and deprotection were confirmed by Kaiser Test. The final molecules were detached from the resin using TFA 1% in DCM and the deprotection of the side chains were achieved by using TIPS/H2O 2.5% in TFA. The six new benznidazole-RGDS conjugates were characterized by HRMS and their purities were assessed by RP-HPLC. The citotoxicity of the five new conjugates were assessed on human monocytes cell line in concentrations up to 150 μM showing no toxic effects. A class of novel conjugates was designed and synthesized by combining benznidazole and RGDS fragment via linker. The approach developed herein is being used in the synthesis of a new series of small molecules-RGDS conjugates. The biological assays against T. cruzi trypomatigotes are underway.

Design and synthesis of new peptide-benznidazole conjugates targeting Trypanosoma cruzi fibronectin receptor

255th National Meeting (2018)

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