Synthesis and antitrypanosomal activity of novel 1,4-dissubstituted-triazole compounds based on 2-nitroimidazole scaffold: a structure-activity relationship (SAR) study.

Chagas disease affects 6-8 million people worldwide, remaining a public health concern. Toxicity, several adverse effects and inefficiency in the chronic stage of the disease are the major challenges regarding the available treatment protocols. This work involved the synthesis of twenty-two 1,4-disubstituted-1,2,3-triazole analogues of benznidazole (BZN), by using a click chemistry strategy. Analogues were obtained in moderate to good yields (40-97 %). Antitrypanosomal activity was evaluated against the amastigote forms ofTrypanosoma cruzi. Compound8 a(4-(2-nitro-1H-imidazol-1-yl)methyl)-1-phenyl-1H-1,2,3-triazole) without substituents on phenyl ring showed similar biological activity to BZN (IC50=3.0 mu M, SI>65.3), with an IC50=3.1 mu M and SI>64.5. Compound8 o(3,4-di-OCH3-Ph) with IC50= 0.65 mu M was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound8 v(3-NO2, 4-CH3-Ph) with IC50=1.2 mu M and relevant SI>166.7, also exhibited higher activity than BZN. SAR analysis exhibited a pattern regarding antitrypanosomal activity relative to BZN, in compounds with electron-withdrawing groups (Hammett sigma+) at position 3, and electron-donating groups (Hammett sigma-) at position 4, as observed in8 oand8 v. Further research might explore in vivo antitrypanosomal activity of promising analogues8 a,8 o, and8 v. Overall, this study indicates that approaches such as the bioisosteric replacement of amide group by 1,2,3-triazole ring, the use of click chemistry as a synthesis strategy, and design tools like Craig-plot and Topliss tree are promising alternatives to drug discovery.