Insights into the Pharmacological Activity of the Imidazo−Pyrazole Scaffold

Abstract

In previous studies, we synthesized different imidazo−pyrazoles 1 and 2 with interesting anticancer, anti‐angiogenic and anti‐inflammatory activities. To further extend the structure‐activity relationships of imidazo−pyrazole scaffold and to identify novel antiproliferative/anti‐inflammatory agents potentially active with multi‐target mechanisms, a library of compounds 3–5 has been designed and synthesized. The chemical modifications characterizing the novel derivatives include: i) decoration of the catechol ring with groups with different electronic, steric and lipophilic properties (compounds 3); ii) insertion of a methyl group on C‐6 of imidazo−pyrazole scaffold (compounds 4); iii) shift of the acylhydrazonic substituent from position 7 to 6 of the imidazo−pyrazole substructure (compounds 5). All synthesized compounds were tested against a panel of cancer and normal cell lines. Derivatives 3 a, 3 e, 4 c, 5 g and 5 h showed IC50 values in the low micromolar range against selected tumor cell lines and proved to have antioxidant properties, being able to inhibit ROS production in human platelet. In silico calculation predicted favourable drug‐like and pharmacokinetic properties for the most promising compounds. Furthermore, molecular docking and molecular dynamic simulations suggested the ability of most active derivative 3 e to interact with colchicine binding site in the polymeric tubulin α/tubulin β/stathmin4 complex.

A Proteomics Approach Identifies RREB1 as a Crucial Molecular Target of Imidazo–Pyrazole Treatment in SKMEL-28 Melanoma Cells

“…To investigate certain features of the imidazo–pyrazole compound, known as 3e , a differential proteomics approach utilizing the SKMEL-28 cell line treated with the compound was performed. Our proteomic analysis substantiates previous observations regarding the antiproliferative, antiaggregant, and antioxidant properties of imidazo–pyrazole 3e [ 10 ]. Indeed, enriched GO analysis of significantly deregulated proteins in melanoma cells in vitro suggests that pathways involving growth factor beta receptor signaling pathway, membrane organization, epithelial cell migration, regulation of epithelial to mesenchymal transition, and endocytosis are profoundly affected by imidazo–pyrazole 3e compound at different times ( Figure 2 ).…”

“…In this paper, we realized a differential proteomic study on the cutaneous melanoma cell line SKMEL-28. The cells were treated with DMSO, the 3e solvent, or with the promising imidazo–pyrazole compound 3e , using a 3.08 μM concentration corresponding to its IC50 value [ 10 ].…”

“…In particular, ( E )- N’ -(4-((4-chlorobenzyl)oxy)-3-methoxybenzylidene)-2-phenyl-2,3-dihydro-1 H -imidazo[ 1,2-b ]pyrazole-7-carbohydrazide, compound 3e ( Figure S1 ), showed relevant antiproliferative activity against the skin melanoma cell line SKMEL-28 (IC 50 = 3.08 ± 0.10 μM). In contrast, it exhibited growth inhibition against the normal embryonic fibroblast cell line GM 6114, which is comparable to the approved anticancer drugs Cis-Pt [ 10 ].…”

Exploring the latest trends in chemistry, structure, coordination, and diverse applications of 1-acyl-3-substituted thioureas: a comprehensive review

“…64). 121 Naphthoquinone thiazole hybrids synthesized by Efeoglu et al were screened for their anti-inammatory potential. All compounds showed anti-inammatory activity and among the series compounds (138a and 138b) were found more effective, these compounds act by lowering the production of inammatory cytokines (IL-6 and TNF-a) in LPS-stimulated cells.…”

Imidazopyridine Family: Versatile and Promising Heterocyclic Skeletons for Different Applications

“…They have also been the subject of investigation as receptor agonists. The imidazopyridine nucleus, in particular the imidazo[1,2- a ]pyridines, is also present in several commercially available drugs, as reported in Figure 2 , such as zolpidem, alpidem, saripidem, necopidem, olprinone, miroprofene, zolimidine, and many others [ 28 , 66 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ].…”