Synthesis of Novel Benzo-Fused Heteroaryl Derivatives as Ca²⁺/Calmodulin-Dependent Protein Kinase II Inhibitors

Abstract

Based on the structure activity relationship of 2-(4-phenoxybenzoyl)-5-hydroxyindole (1), a novel structural class of Ca 2 /calmodulin-dependent protein kinase II (CaMKII) inhibitors were synthesized. We show in this study that the acidic proton at the N(1)-position of the indole moiety is not essential for CaMKII inhibitory activity. Among the synthesized compounds, we found the benzofuran and benzothiazole derivative as promising scaffolds for the developement of potent CaMKII inhibitors. In particular, compounds 8 and 14 inhibited CaMKII with IC 50 values of 24 nM and 32 nM, respectively.

New synthesis of 2-aroylbenzothiazoles via metal-free domino transformations of anilines, acetophenones, and elemental sulfur

“…[1][2][3] Among these structures, 2-aroylbenzothiazoles have attracted signicant attention owing to their pharmaceutical and medicinal applications. [4][5][6] Accordingly, several methods have been investigated for the synthesis of 2-aroylbenzothiazoles, including (i) transitional metalcatalyzed sp 2 C-H bond functionalization of benzothiazoles, and (ii) cyclization with or without sulfuration of orthosubstituted anilines. Some examples could be listed, as Feng and Song previously reported a copper-catalyzed acylation of benzothiazoles with aryl methyl ketones to afford 2-aroylbenzothiazoles.…”

A Novel PIFA/KOH Promoted Approach to Synthesize C2-arylacylated Benzothiazoles as Potential Drug Scaffolds

“…For instance, as shown in Figure 1 , 6-hydroxybenzothiophene ketone A exhibits potential for the treatment of breast cancer, endometriotic tissues, and other diseases by functioning as an inhibitor of 17b-hydroxysteroid dehydrogenase Type 1 (17b-HSD1) [ 12 , 13 , 14 ]. C2-arylacylated benzothiazole B act as a novel structural class of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) inhibitors with the potential to be developed as anti-inflammatory agents [ 15 ]; 2-Benzothiazolyl-phenylmethanone C were found to be potent fatty acid amide hydrolase (FAAH) inhibitors with beneficial effects for disorders such as pain and inflammation [ 16 ]. As a potent inhibitor of antiapoptotic Bcl-2 proteins, acylpyrogallol D inhibited growth and induced apoptosis in human breast and prostate cancer cell lines [ 17 ].…”

Iodine- and TBHP-Promoted Acylation of Benzothiazoles under Metal-Free Conditions

“…Some benzothiazoles can be used as labeling reagents to aid in the diagnosis of Alzheimer's disease (AD) at an early-to-moderate stage and to monitor the efficiency of treatment. 2 In addition, other studies have revealed that several benzothiazoles can serve as promising scaffolds for potent CaMKII 3 and 17-HSD1…”