benzofurans and benzothiazole

Heteroaromatic analogs of DMU-212 (8-15) have been synthesized and evaluated for their anti-cancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran, benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth inhibition in 85% of the cancer cell lines examined, with GI50 values <1 μM. Interestingly, trans-3,4- and trans-3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anti-cancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on tubulin, and that their binding modes are similar to that of DMU-212.

Topics: Antineoplastic Agents; Benzofurans; Benzothiazoles; Binding Sites; Cell Line, Tumor; Cell Survival; Colchicine; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Protein Structure, Tertiary; Resveratrol; Stilbenes; Thiophenes; Tubulin

Based on the structure activity relationship of 2-(4-phenoxybenzoyl)-5-hydroxyindole (1), a novel structural class of Ca²⁺/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 IC₅₀ values of 24 nM and 32 nM, respectively.

Topics: Benzofurans; Benzothiazoles; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Indoles; Protein Binding; Protein Kinase Inhibitors; Structure-Activity Relationship

Starting from benzofuran-2-methanal, 6-substituted benzothiazole-2-amines and malonic esters, sixteen title compounds were designed and synthesized seeking to introduce anti-TMV activity. The structures of the newly synthesized compounds were confirmed by 1H-NMR, 13C-NMR, IR spectra, and MS (HREI) analysis. The bioassays identified some of these new compounds as having moderate to good anti-TMV activity. The compounds 5i and 5m have good antiviral activity against TMV with a curative rate of 52.23% and 54.41%, respectively, at a concentration of 0.5 mg/mL.

Topics: Antiviral Agents; Benzofurans; Benzothiazoles; Malonates; Microbial Sensitivity Tests; Molecular Structure; Tobacco Mosaic Virus

The synthesis and SAR of new β-amyloid binding agents are reported. Evaluation of important properties for achieving good signal-to-background ratio is described. Compounds 27, 33, and 36 displayed desirable lipophilic and pharmacokinetic properties. Compound 27 was further evaluated with autoradiographic studies in vitro on human brain tissue and in vivo in Tg2576 mice. Compound 27 showed an increased signal-to-background ratio compared to flutemetamol 4, indicating its suitability as PET ligand for β-amyloid deposits in AD patients. The preparation of the corresponding (18)F-labeled PET radioligand of compound 27 is presented.

Topics: Alzheimer Disease; Aminopyridines; Amyloid beta-Peptides; Animals; Benzofurans; Benzothiazoles; Benzoxazoles; Brain; Contrast Media; Fluorine Radioisotopes; Humans; Mice; Mice, Transgenic; Positron-Emission Tomography; Radiopharmaceuticals; Structure-Activity Relationship

Several series of benzofurans, benzothiophenes, and benzothiazoles, all featuring the thioamide group, were synthesized and tested as novel K(ATP) channel openers in artificial cell systems: CHO cells transfected with SUR1/Kir6.2, and HEK 293 cells transfected with SUR2B/Kir6.1; these served as model systems for insulin-secreting pancreatic β cells and smooth muscle cells, respectively. All compounds were investigated with respect to their binding affinity for the SUR2B-type K(ATP) channels using [(3)H]P1075 as radioligand. Selected compounds were also tested as agonists in intact cells using DiBAC(4)(3) and DyeB (R7260) as membrane potential dyes. Remarkable affinity for SUR2B/Kir6.1 channels in the single-digit micromolar range was observed. In addition, benzothiazole-derived thioamides with sterically demanding, lipophilic substituents showed >100-fold selectivity in favor of SUR2B/Kir6.1. A one-carbon spacer between the heterocyclic skeleton and the thioamide moiety was observed to be crucial for affinity and selectivity. Two of the most potent and selective compounds were studied by crystal structure analyses.

Topics: Animals; Benzofurans; Benzothiazoles; Binding Sites; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; HEK293 Cells; Humans; KATP Channels; Molecular Conformation; Potassium Channels, Inwardly Rectifying; Structure-Activity Relationship; Thioamides; Thiophenes