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Abstract: A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT6 antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT6 receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (K i =12.3nM) for 5-HT6 receptor with good selectivity over other serotonin and dopamine (D1–D4) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC50 =0.61μM). [Copyright &y& Elsevier]

Due to the large size and high flexibility of the catalytic active site of BACE1 enzyme, the development of nonpeptide inhibitors with optimal pharmacological properties is still highly demanding. In this work, we have discovered 2-aminobenzimidazole-containg ether scaffolds having potent and selective inhibitory potentials against BACE1 enzyme. We have synthesized novel 29 compounds and optimization of aryl linker region resulted in highly potent BACE1 inhibitory activities with EC 50 values of 0.05–2.71 μM. The aryloxy-phenyl analogs 20j showed the EC 50 value as low as 0.07 μM in the enzyme assay, whereas, the benzyloxyphenyl dervative 24b was comparatively less effective in the enzyme assay. But interestingly the latter was more effective in the cell assay (EC 50 value 1.2 μM). While comparing synthesized derivatives in the cell assay using PC12-APP SW cell, compound 27f appeared as the most potent BACE1 inhibitor having EC 50 value 0.7 μM. This scaffold also showed high selectivity over BACE2 enzyme and cathepsin D. Furthermore, the research findings were bolstered through the incorporation of molecular docking, molecular dynamics, and DFT studies. We firmly believe that these discoveries will pave the way for the development of a novel class of small-molecule selective BACE1 inhibitors. [Display omitted] • 29 Novel diaryl ether-benzimidazole derivatives exhibit potent BACE1 inhibition. • Some compounds showed the EC 50 value as low as 0.07 μM in the enzyme assay. • Compound 27f most potent BACE1 inhibitor having EC 50 value 0.7 μM in cell assay. • Some derivatives showed SI greater than 15 in BACE2 and cathepsin D inhibitory assays. • The interactions of lead compounds with BACE1 were elucidated by in silico models. [ABSTRACT FROM AUTHOR]

Recovery of mitochondrial dysfunction has gained increasing attention as an alternative therapeutic strategy for Alzheimer's disease (AD). Recent studies suggested that the 18 kDa mitochondrial translocator protein (TSPO) has the potential to serve as a drug target for the treatment of AD. In this study, we generated a structure-based pharmacophore model and virtually screened a commercial library, identifying SVH07 as a virtual hit, which contained a tricyclic core structure, thieno[2′,3’:4,5]pyrrolo[1,2- d ][1,2,4]triazine group. A series of SVH07 analogues were synthesized and their effects on the mitochondrial membrane potential and ATP production were determined by using neuronal cells under Aβ-induced toxicity. Among these analogues, compound 26 significantly recovered mitochondrial membrane depolarization and ATP production. In vitro binding assays indicated that SVH07 and 26 showed high affinities to TSPO with the IC 50 values in a nanomolar range. We believe that compound 26 is a promising lead compound for the development of TSPO-targeted mitochondrial functional modulators with therapeutic potential in AD. [ABSTRACT FROM AUTHOR]

Synthesis, SAR study and BACE1 inhibitory activity of (3 S ,4 S )-4-aminopyrrolidine-3-ol derivatives ( 2 ) were described. The compound 7c exhibited more inhibition activity than 11a (IC 50 : 0.05 μM vs 0.12 μM, respectively), but the latter was more effective in cell-based assay (IC 50 : 1.7 μM vs 40% inhibition by 7c @ 10 μM) due to the relatively higher cell permeability. Most of the compounds showed high selectivity over BACE2 and cathepsin D. This work will provide useful information for further structural modifications to develop potent BACE1 inhibitors in cell. [ABSTRACT FROM AUTHOR]