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Synthesis and Antitrypanosomal Activity of 1,4-Disubstituted Triazole Compounds Based on a 2-Nitroimidazole Scaffold: a Structure-Activity Relationship Study.
- Source :
-
ChemMedChem [ChemMedChem] 2020 Nov 04; Vol. 15 (21), pp. 2019-2028. Date of Electronic Publication: 2020 Sep 15. - Publication Year :
- 2020
-
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 (IC <subscript>50</subscript> =3.0 μM, SI>65.3), with an IC <subscript>50</subscript> =3.1 μM and SI>64.5. Compound 8 o (3,4-di-OCH <subscript>3</subscript> -Ph) with IC <subscript>50</subscript> = 0.65 μM was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3-NO <subscript>2</subscript> , 4-CH <subscript>3</subscript> -Ph) with IC <subscript>50</subscript> =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.<br /> (© 2020 Wiley-VCH GmbH.)
- Subjects :
- Animals
Cells, Cultured
Macaca mulatta
Molecular Structure
Nitroimidazoles chemistry
Parasitic Sensitivity Tests
Triazoles chemical synthesis
Triazoles chemistry
Trypanocidal Agents chemical synthesis
Trypanocidal Agents chemistry
Nitroimidazoles pharmacology
Triazoles pharmacology
Trypanocidal Agents pharmacology
Trypanosoma cruzi drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 15
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 32729242
- Full Text :
- https://doi.org/10.1002/cmdc.202000460