New 2- arylazoimidazoles derivatives as inhibitors of Trypanosoma cruzi growth: synthesis and biological evaluation

BLANCO M; LORENZO M; BALCAZAR DE; LÓPEZ J; GARCÍA VIOR C; CARRILLO C; SALERNO A

Atenas

Conferencia; 5° BBBB International Conference; 2013

EUFEPS (Estonian and the Finnish - Baltic; Hungarian - Balaton; Slovenian ? Bled & and the Turkish Pharmaceutical Association - Bosphorus)

Chagas disease is an insidious, potentially fatal parasitic disease that is widespread in Latin America affecting 10-14 millon or more. People with Chagas disease (American Trypanosomiasis) may develop progressive and potentially lethal heart conditions. The current standard therapy nifurtimox or benznidazole is, at best, only minimally effective in chronic Chagas disease and it is associated with significant side effects. The development of new compounds is a clear need for a safe and effective drug for the treatment of chronic Chagas disease. Imidazoles, in general, are very promising trypanocidal drugs, but most of them are soluble only in organic solvents which, in most cases, are not allowed in pharmaceutical formulations. Since imidazoles are highly hydrophobic, which make it difficult to administer them parenterally in physiological media, delivery strategies have been developed to increase their solubility and improved their bioavailability. Purpose: In the search for new trypanocidal agents, in this work, we synthesized and evaluate the trypanocidal activity of a new series of 2-arylazoimidazoles derivatives 1 (benznidazole analogues) through inhibition of T. cruzi epimastigote growth. Material and Methods: The compounds 1 were prepared using 2-arylazoimidazoles 2 as commom starring material, potassium carbonate and the corresponding chloroamide 3 in DMF at room temperature. All derivatives were purified and characterized by spectroscopic methods (mass spectrometry, 1H and 13C NMR). Activity assays in vitro against noninfective T cruzi epimastigote forms were performed using a CL-Brener clone and different concentrations (1, 5, 10 and 15M) of compounds 1. Nanocarriers, such as liposomes and polymeric micelles are widely used as carrier systems for water-insoluble drugs in pharmaceutics. According to this, the incorporation of 2-arylazoimidazole derivatives 1 into Phospholipon 90 NG liposome and Tetronic 1107 polymeric micelles are carrying out. Results: The modification that were done on the benznidazole structure are shown in the Scheme: variations in the length of side chain, inclusion of a hydrophilic amino substituent (morpholino moiety), and lipophilic amino-substituents with different volumes (dibenzylamino, diethylamino, pirrolidino, piperidino) on the carboxamide moiety. Conclusions: All synthesized compounds were active against T. cruzi. In general, the most active compounds are those derived from carboxamides having piperidino moiety. The results presented indicate that 2-arylazoimidazoles 1 could be a lead compound for the design of new drugs for Chagas disease.