Optimization of Aminoimidazole Derivatives as Src Family Kinase Inhibitors

Abstract

Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. We previously reported a small library of 4-aminoimidazole and 2-aminothiazole derivatives active as Src family kinase (SFK) inhibitors. Starting from these results, we decided to perform an optimization study applying a mix and match strategy to identify a more potent generation of 4-aminoimidazoles. Firstly, a computational study has been performed, then compounds showing the best predicted docking scores were synthesized and screened in a cell-free assay for their SFK inhibitory activity. All the new chemical entities showed IC50s in the nanomolar range, with 2–130 fold increased activities compared to the previously reported inhibitors. Finally, the most active compounds have been tested on three cancer cell lines characterized by Src hyperactivation. Compounds 4k and 4l showed an interesting antiproliferative activity on SH-SY5Y neuroblastoma (NB) cell line. In this assay, the compounds resulted more potent than dasatinib, a tyrosine kinase inhibitor approved for the treatment of leukemias and in clinical trials for NB.

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…Francini et al described the synthesis of new aminoimidazole anticancer candidates that inhibit SFKs [ 64 ]. The target compounds were screened against K562, U87 (glioblastoma multiforme (GBM)), and SH-SY5Y (neuroblastoma) cancer cell lines.…”

Formation and Intramolecular Capture of α-Imino Gold Carbenoids in the Au(I)-Catalyzed [3 + 2] Reaction of Anthranils, 1,2,4-Oxadiazoles, and 4,5-Dihydro-1,2,4-Oxadiazoles with Ynamides

“…It is noteworthy that several synthetic methods are available for Nor Csubstituted imidazoles, [23] but only a few methods have been reported for the preparation of aminoimidazoles and derivatives [24][25][26][27]. Moreover, although 4-aminoimidazole derivatives present an interesting biological activity profile [28][29][30][31], existing synthetic methods for their preparation are limited [21,22,32]. As a continuation of our efforts to gain a deeper insight into the intricacies of goldmediated transformations [3,33,[34][35][36][37][38][39][40][41][42][43][44][45] and particularly reaction mechanisms including gold carbenes [13,[16][17][18][19][20][21][22]46], here we carried out a thorough investigation of the reaction mechanism of the Au(I)-catalyzed [3 + 2] reaction of the mild nitrogen nucleophiles anthranil, 1,2,4-oxadiazole, and 4,5-dihydro-1,2,4-oxadiazole with ynamides.…”

Synthesis and anti‐proliferative activity studies of 2‐(2‐(trifluoromethyl)‐6‐(substituted)imidazo[1,2‐b]pyridazin‐3‐yl)‐N‐(substituted)acetamide derivatives

“…For normal functioning of cells in the human kinome, there are 518 kinases that are involved in different phases of life and all are associated with each other . Different kinases were responsible for different functioning of cells; some kinases are TOR signaling, which are responsible for cell growth, and some are protein tyrosine kinase inhibitors . The imbalance in the kinases occurs in several diseases like cancer, neurodegenerative disorders, and inflammation.…”

“…[1] Different kinases were responsible for different functioning of cells; some kinases are TOR signaling, which are responsible for cell growth, [2,3] and some are protein tyrosine kinase inhibitors. [4] The imbalance in the kinases occurs in several diseases like cancer, neurodegenerative disorders, and inflammation. By considering the importance of kinases, we need to develop new kinase inhibitors with diversified activity.…”