Search Results (5)

Sirtuin 1 (SIRT1) is an NAD⁺-dependent deacetylase implicated in various physiological and pathological processes, including cardiovascular diseases. The lead compound for SIRT1, resveratrol (1), as well as natural-derived and synthetic SIRT1-activating compounds demonstrated to exert cardioprotective effects. In the present work, we evaluated a small series of diarylimidazoles, of which 4 emerged, in in vitro enzymatic assays, as an activator of SIRT1 endowed with a similar potency compared with that of 1. Therefore, 4 was subjected to pharmacological investigation, where it was proven to reduce myocardial damage induced by ischemia/reperfusion injury in isolated rat hearts, thus demonstrating its cardioprotective properties. An in silico study suggested the binding mode of this derivative within SIRT1 in the presence of the p53-AMC-peptide. These promising results could pave the way to further expand and optimize this chemical class of new SIRT1 activators as potential cardioprotective agents. Full article

Inspired by the vascular-disrupting agent combretastatin A-4 and recently published anticancer active N-heterocyclic carbene (NHC) complexes of Au(I), a series of new iodidogold(I)–NHC complexes was synthesized and characterized. The iodidogold(I) complexes were synthesized by a route involving van Leusen imidazole formation and N-alkylation, followed by complexation with Ag₂O, transmetalation with chloro(dimethylsulfide)gold(I) [Au(DMS)Cl], and anion exchange with KI. The target complexes were characterized by IR spectroscopy, ¹H and ¹³C NMR spectroscopy, and mass spectrometry. The structure of 6c was validated via single-crystal X-ray diffraction. A preliminary anticancer screening of the complexes using two esophageal adenocarcinoma cell lines showed promising nanomolar activities for certain iodidogold(I) complexes accompanied with apoptosis induction, as well as c-Myc and cyclin D1 suppression in esophageal adenocarcinoma cells treated with the most promising derivative 6b. Full article

A series of halogenated 1,5-diarylimidazole compounds were synthesized and their inhibitory effects on LPS-induced PGE₂ production in RAW 264.7 cells were evaluated. A wide variety of 2,4-, 4-, and 2-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles were synthesized for SAR study via two different pathways. Overall, 4-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles, regardless of the species of halogen, exhibited very strong inhibitory activities of PGE₂ production. Among them, 4-chloro-5-(4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole (3, IC₅₀ 3.3 nM ± 2.93), and 4-chloro-5-(4-chlorophenyl)-1-(4-methylsulfonylphenyl)imidazole (13, IC₅₀ 5.3 nM ± 0.23) showed the best results. Full article

The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC₅₀ CK1δ = 4 nM, IC₅₀ CK1ε = 25 nM), 12a (IC₅₀ CK1δ = 19 nM, IC₅₀ CK1ε = 227 nM), and 16b (IC₅₀ CK1δ = 8 nM, IC₅₀ CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC₅₀ = 3.5 µM) and Panc89 (EC₅₀ = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1δ and 11b in p38α. Full article

Self-organizing molecular field analysis (SOMFA), a simple three-dimensionalquantitative structure–activity relationship (3D-QSAR) method is used to study the correlationbetween the molecular properties and the anti-inflammatory biological activities of a new series of1,5-Diarylimidazoles that act as selective COX-2 inhibitors. The statistical results, cross-validated r_CV² (0.507) and non cross-validated r² (0.546), show a satisfied predictive ability. Full article