Planejamento, síntese e avaliação da atividade antitripanossoma de novos nitro-1,2,4-triazóis via reações de cicloadição [3+2]

Abstract

Design, Synthesis, and Assessment of the antitrypanosomal activity of new nitro- 1,2,4 triazoles via cycloaddition reactions [3+2] Chagas disease or American trypanosomiasis (Trypanosoma cruzi) is a neglected disease that affects Latin America and some developed countries. With the accelerated and progressive growth in the incidence of cases, this disease can be characterized as a serious epidemiological problem. Currently, chemotherapy is restricted to only two nitro-heterocycle drugs, benznidazole and nifurtimox, which are effective in the acute phase of the disease. Benznidazole, however, is the only drug released by Anvisa for its treatment in Brazil. Considering problems of resistance to benznidazole, toxicity, and effectiveness of the same only in the acute phase, new drug candidates need to be developed. Thus, this work aims to synthesize an unprecedented series of nitrotriazole analogues with different substitution patterns, to evaluate the antitrypanosomal biological activity and the mutagenic potential of the most active compounds. Strategies from classical medicinal chemistry, such as bioisosterism, molecular hybridization, and the concept of Click chemistry were used for analog synthesis and structural design. Here, 28 analogues were synthesized with excellent yields (60-96%), and characterized by data analysis from Nuclear Magnetic Resonance techniques (1H NMR and 13C NMR) and Mass Spectrometry. The structural planning of these new analogues was optimized by analyzing the structure-activity relationship, resulting in more active compounds. Of these, analog 15g (R1= 4-OCF3-Ph, IC50 = 0.09 µM, SI = > 555.5) exhibited an outstanding antichagasic activity (Trypanosoma cruzi, Tulahuen LacZ strain) 68-fold more active than benznidazole (BZN, IC50 = 6.15 µM, SI = > 8.13) with relevant selectivity index, and suitable LipE = 5.31. 15g was considered an appropriate substrate for the type I nitro reductases (TcNTR I), contributing to a likely potential mechanism of action for antichagasic activity. Thus, these new 3-Nitro-1H-1,2,4-triazole compounds represent a new and interesting class of bioactive compounds with excellent antitrypanosomal and non-mutagenic activity, essential for developing new safe and effective drugs for the Chagas disease.

Keywords: Chagas disease; Bioisosterism; molecular hybridization; Click Chemistry.