Synthesis and Antitrypanosomal Activity of 1,4‐Disubstituted Triazole Compounds Based on a 2‐Nitroimidazole Scaffold: a Structure‐Activity Relationship Study

Abstract

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 (IC50=3.0 μM, SI>65.3), with an IC50=3.1 μM and SI>64.5. Compound 8 o (3,4‐di‐OCH3−Ph) with IC50 = 0.65 μM was five‐fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3‐NO2, 4‐CH3−Ph) with IC50=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.

Design and Synthesis of Novel 3-Nitro-1H-1,2,4-triazole-1,2,3-triazole-1,4-disubstituted Analogs as Promising Antitrypanosomatid Agents: Evaluation of In Vitro Activity against Chagas Disease and Leishmaniasis

“…In this area, the 3-nitro-1 H -1,2,4-triazole is a relevant scaffold considering the discovery of new antichagasic agents. − Moreover, studies reported that 3-nitrotriazoles derivatives showed increased potency and lower toxic effects than 2-nitroimidazole. ,, In a previous study, our research group synthesized 22 2-nitroimidazole-triazole compounds derivatives of BZN with potent antitrypanosomal activity in vitro. Bioisosterism between the amide group of the BZN scaffold and the triazole core enhanced the antichagasic activity of this series, pointing out the compound 14 , which was 6-fold more active than BZN (IC 50 = 0.65 μM) . These findings boosted our interest in broadening the structure–activity relationship (SAR) studies with triazole derivatives.…”

“…Remarkably, analog 15ab (R 1 = Ph-4-O-Ph, IC 50 = 0.07 μM) stands out as the most promising compound of this series, demonstrating exceptional antichagasic activity in vitro at submicromolar concentrations. Specifically, this analog showed 88-fold greater activity compared to the reference drug BZN and up to 94-fold more active than the 2-nitroimidazoletriazole derivative with the same substitution pattern, 54 and still 19-fold more active than 15a. Hence, the analog 15ab (R 1 = Ph-4-O-Ph) scored an impressive selectivity index (SI > 714.20) compared to BZN (SI = 8.13) on LLC-MK2 cells.…”

“…For instance, compound 15g with an OCF 3 substituent was found to be 176 times more potent than its 2-nitroimidazole analogue. 54 (2) Compounds with substituents respectively. These results corroborate findings in the literature with the same type of scaffold, indicating the important role of chloro (magic chloro effect) in anti-T. cruzi activity.…”

1,2,3-Triazoles as Biomimetics in Peptide Science

“…The bioisosteric replacement between amide bonds and 1,4-disubstituted 1,2,3-triazole provides new analogues of benznidazole with anti-trypanosomal activity [ 111 ]. These compounds were synthesized by CuAAC and designed as a Craig-plot (two-dimensional plot) and Topliss Scheme (decision-making tree).…”

Neuroprotective Profile of Triazole Grandisin Analogue against Amyloid-Beta Oligomer-Induced Cognitive Impairment

“…Our research group has experience synthesizing small bioactive molecules using different medicinal chemistry approaches, such as bioisosterism and molecular hybridization. − Our synthesis strategy is most often inspired by natural products, such as tetrahydrofuran neolignans, whose privileged scaffold offer versatility for diverse biological applications. ,,− Grandisin (Figure , compound 5 ), a neolignan obtained from Virola surinamensis, a plant commonly found on the banks of the Amazon River, possesses anti-inflammatory and antioxidant properties. Carvalho and colleagues (2010) demonstrated that grandisin reduced inflammation in formalin-induced and croton-oil-induced paw and ear edema, respectively .…”