SÍNTESE DE ANÁLOGOS 3-NITRO-1H-1,2,4-TRIAZOL PARA SUBSTITUÍDOS BIOISOSTÉRICOS DO BENZNIDAZOL VIA REAÇÃO DE MITSUNOBU

Abstract

Chagas disease, or American trypanosomiasis, caused by Trypanosoma cruzi, is a neglected disease that affects mainly Latin American countries. Currently, chemotherapeutic treatment is restricted to two nitro-heterocyclic drugs: benznidazole and nifurtimox, which are effective mainly in the acute phase of the disease. In Brazil, however, only benznidazole is approved by Anvisa for therapeutic use. Considering the problems associated with resistance to benznidazole, its toxicity, and its limited efficacy in the chronic phase of the disease, medicinal chemistry seeks, through bioisosterism, to design new bioactive antitrypanosomal molecules. One of the molecular classes used in this search is the triazoles, known for their chemical, synthetic, and biological diversity, and capable of bioisosterically replacing the amide group of benznidazole while maintaining its chemical and electronic properties. In addition, the maintenance of the nitro group may favor the biological activity of the proposed analogues. Thus, the aim of this work was to synthesize eight para-substituted 3-nitro-1H-1,2,4-triazole compounds with different substitution patterns through the Mitsunobu reaction. As results, all starting materials were synthesized: 3-nitro-1,2,4-triazole, responsible for maintaining the bioisosterism with benznidazole, and the benzyl alcohols, which provide chemical variability to the proposed compounds. Eight para substituted analogues were also synthesized, with yields ranging from 47% to 95%. Their structures were confirmed by Proton Nuclear Magnetic Resonance (^1H NMR) spectroscopy.