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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 of Trypanosoma cruzi. Compound 8 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 (IC 50 =3.0 μM, SI>65.3), with an IC 50 =3.1 μM and SI>64.5. Compound 8 o (3,4-di-OCH 3 -Ph) with IC 50 = 0.65 μM was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3-NO 2 , 4-CH 3 -Ph) with IC 50 =1.2 μM 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 σ+) at position 3, and electron-donating groups (Hammett σ-) at position 4, as observed in 8 o and 8 v. Further research might explore in vivo antitrypanosomal activity of promising analogues 8 a, 8 o, and 8 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., (© 2020 Wiley-VCH GmbH.)