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We report the stereocontrolled synthesis of 1,6-diazecanes via a tandem aza-Prins type reaction of N-acyliminium ions with allylsilanes.

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington’s disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined in silico and in vitro cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD., Graphical Abstract

A concise synthesis of 8-azabicyclo[3.2.1]octanes via sequential oxidative Mannich reactions is described. This approach involves an intermolecular oxidative Mannich coupling reaction between N-aryl pyrrolidines with TMS enol ether and a subsequent intramolecular oxidative Mannich cyclization of the corresponding silyl enol ether. DDQ is used as a key oxidant for both reactions.

The serotonin 2C receptor subtype (5-HT2C) is an excitatory 5-HT receptor widely distributed throughout the central nervous system. As the 5-HT2C receptor displays multiple actions on various neurotransmitter systems including glutamate, dopamine, epinephrine, and γ-aminobutyric acid (GABA), abnormalities of the 5-HT2C receptor are associated with psychiatric diseases such as depression, schizophrenia, drug abuse, and anxiety. Up to date, three kinds of 5-HT2C PET radiotracers such as [11C]N-methylated arylazepine (1), [11C]WAY-163909 (2), and [18F]fluorophenylcyclopropane (3) have been developed, but they may not be suitable for in vivo 5-HT2C imaging study due to their modest specific binding. Herein, the synthesis and in vivo evaluation of 4-(3-[18F]fluorophenethoxy)pyrimidine [18F]4 as a potential PET radiotracer for the 5-HT2C receptor is described. [18F]4 was synthesized by nucleophilic aromatic substitution of diaryliodonium precursor 17a with a 7.8 ± 2.7% (n = 6, decay corrected) radiochemical yie...

A transition-metal-free and regioselective synthesis of a series of 2-amino-4-alkoxypyrimidines is described. The SNAr alkoxylation of 2,4-dichloropyrimidines regioselectively provided 2-chloro-4-alkoxypyrimidines, which were subsequently subject to the second SNAr amination with cyclic amines in the presence of triethylamine at high temperature to afford 2-amino-4-alkoxypyrimidines in good overall yield.

TREK1 (Twik-RElated Potassium (K+ ) channel 1), although a well-characterized target for several neuropsychiatric disorders, underwent very few explorations for prototypic inhibitors. This study aimed to find diverse chemotypes by an in silico means. Homology-built TREK1 on docking with high-affinity quaternary ammonium compounds (QAs) corroborated the previous findings by recreating the binding mode with proximally positioned key residues: Thr157, Thr266, Ile182, Leu189, and Leu304. Physical interactions between TREK1 and known antagonists were modeled to compensate the lack of ligand-bound protein crystal structures. A common feature hypothesis (Hypo1) was deduced from the chemical features of six active compounds. Validated Hypo1 and the most potent compound in the data set were employed as pharmacophore- and similarity-based virtual screening queries, respectively. Thirty-three hit compounds were tested for their ability to block TREK1 currents in HEK-293-transfected cells using whole-cell patch-clamp recording. Eleven candidates displayed dose-dependent inhibition of channel currents; among these, NC30 possessing a 4-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)piperidin-4-ol heterocyclic core was the most potent one with an IC50 of 4.7 μm. These results form a rational basis to design future drugs, and this is the first report of novel TREK1 antagonists delineated by a synergistic application of structure- and ligand-based approaches.

Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity in vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.

A synthetic approach toward the tricyclic 5,7,6-membered ring structure of daphnane-family natural products is described. An intramolecular [4 + 3] cycloaddition reaction of furan with an oxypentadienyl cation constructed the oxa-bridged bicyclic structure in a stereoselective fashion. Structural analysis revealed that the desired exo isomer was predominantly acquired through epimerization. Finally, formation of the five-membered ring was achieved through SmI2-mediated pinacol coupling.

Microtubules are important cellular component that are critical for proper cellular function. Microtubules are synthesized by polymerization of αβ tubulin heterodimers called protofilaments. Microtubule dynamics facilitate proper cell division during mitosis. Disruption of microtubule dynamics by small-molecule agents inhibits mitosis, resulting in apoptotic cell death and preventing cell cycle progression. To identify a novel small molecule that binds the αβ tubulin interface to affect microtubule dynamics, we developed a bioactive conformation alignment pharmacophore (BCAP) model to screen tubulin inhibitors from a huge database. The application of BCAP model generated based on the known αβ-tubulin interface binders enabled us to identify several small-molecules that cause apoptosis in human promyelocytic leukemia (HL-60) cells. Virtual screening combined with an in vitro assay yielded 15 cytotoxic molecules. In particular, ethyl 2-(4-(5-methyl-3-nitro-1H-pyrazol-1-yl)butanamido)-4-phenylthiophene-3-carboxylate (H05) inhibited tubulin polymerization with an IC50 of 17.6 μm concentration. The virtual screening results suggest that the application of an unbiased BCAP pharmacophore greatly eliminates unlikely compounds from a huge database and maximizes screening success. From the limited compounds tested in the tubulin polymerization inhibitor (TPI) assay, compound H05 was discovered as a tubulin inhibitor. This compound requires further structure activity optimization to identify additional potent inhibitors from the same class of molecules.

A series of pyrimidine derivatives 4a–i were synthesized and evaluated for their binding affinities towards 5-HT2C receptors. With regard to designed molecules 4a–i, the influence of the size of alkyl ether and the absolute configuration of a stereogenic center on the 5-HT2C binding affinity and selectivity was studied. The most promising diasteromeric mixtures 4d and 4e were selected in the initial radioligand binding assay and they were further synthesized as optically active forms starting from optically active alcohols 5d and 5e, prepared by an enzymatic kinetic resolution. Pyrimidine analogue (R,R)-4e displayed an excellent 5-HT2C binding affinity with good selectivity values against a broad range of other 5-HT receptor subtypes.

The serotonin 2C receptor subtype (5-HT

We have described a highly diastereoselective synthesis of 2,6-disubstituted 4-(dimethoxymethyl)tetrahydropyrans via ­TMSOTf-promoted Prins–pinacol reaction of methylene diol with acetals. This reaction provides an efficient procedure to synthesize functionalized tetrahydropyrans containing an acetal group at the C4 position with all-cis 2,4,6 relative configuration.

We described here the synthesis and biological evaluation of mGluR5 antagonists containing a quinoline ring structure. Using intracellular calcium mobilization assay (FDSS assay), we identified compound 5n, showing high inhibitory activity against mGluR5. In addition, it was found that compound 5n has excellent stability profile. Finally, this compound exhibited favorable analgesic effects in spinal nerve ligation model of neuropathic pain, which is comparable to gabapentin.

Drug selectivity is one of the most critical improvement steps in drug development. The 5-hydroxytryptamine 2 (5-HT2) receptor has 3 subtypes that exhibit different pharmacological functions. Because of their high amino acid sequence similarity, designing small molecules that selectively activate only 1 receptor among the 3 subtypes is difficult. We performed homology modeling of the 5-HT2 receptor subtypes using the β2-adrenergic receptor as a template to identify differences in active sites that may influence 5-HT2 receptor agonist selectivity. A subset of selective 5-HT2 agonists was docked into the modeled protein structures to investigate their interactions with each receptor. Subtype-specific active site residues at positions xl2.54, 5.39, and 5.46 interacted differently with each ligand. Molecular dynamics simulations revealed that position 5.46 of the 5-HT2A receptor interacted more favorably with selective 5-HT2A agonists than with selective 5-HT2B agonists. These computationally obtained insights provided clues to improving agonist selectivity for specific pharmacological action at 5-HT2 receptors.

Agonists of the 5-HT2C receptor have attracted much attention as therapeutic agents for the treatment of obesity. Subtype selectivity against other 5-HT2 receptors is one of the most important prerequisites for reducing side effects. We present the synthesis of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs and their structure–activity relationship studies on 5-HT2A and 5-HT2C receptors. Although the compounds showed nanomolar activity to the 5-HT2C receptor, their selectivity against the 5-HT2A receptor was modest to low. Molecular modeling studies using homology modeling and docking simulation revealed that selectivity originated from subtype specific residues. The observed binding modes and receptor–ligand interactions provided us a clue for optimizing the selectivity against the 5-HT2A receptor.

A concise synthesis of tetrabenazine and dihydrotetrabenazine is described. The key feature of this synthesis is the intramolecular aza-Prins-type cyclization of an amino allylsilane via oxidative C-H activation.

The synthesis and biological evaluation of 1-heteroarylmethyl 1,4-diazepane derivatives as potential T-type calcium channel blockers is described. In this study, we have identified the compound 211 exhibiting the most potent T-type calcium channel blocking activity with IC(50) value of 0.20 mu M, which is superior to that of mibefradil.

Serotonin or 5-hydroxytryptamine subtype 2C (5-HT2C) receptor belongs to class A amine subfamily of Gprotein-coupled receptor (GPCR) super family and its ligands has therapeutic promise as anti-depressant and -obesity agents. So far, bovine rhodopsin from class A opsin subfamily was the mostly used X-ray crystal template to model this receptor. Here, we explained homology model using beta 2 adrenergic receptor (β2AR), the model was energetically minimized and validated by flexible ligand docking with known agonists and antagonists. In the active site Asp134, Ser138 of transmembrane 3 (TM3), Arg195 of extracellular loop 2 (ECL2) and Tyr358 of TM7 were found as important residues to interact with agonists. In addition to these, V208 of ECL2 and N351 of TM7 was found to interact with antagonists. Several conserved residues including Trp324, Phe327 and Phe328 were also found to contribute hydrophobic interaction. The predicted ligand binding mode is in good agreement with published mutagenesis and homology model data. This new template derived homology model can be useful for further virtual screening based lead identification.

A series of isoxazol-indolin-2-one was designed for GSK-3 inhibitors as novel anticancer agents based on their binding mode analysis in GSK-3 crystal structure. Total 21 compounds were synthesized and evaluated for their inhibitory activity against two tumor cell lines (DU145 and HT29). Most of the synthesized compounds were potent with above 80% inhibitory activity at 100 , and several compounds were examined for inhibitory activity against GSK-3. Among them, 15(Z) (=H, =3-Cl-phenyl) was most active with 78% inhibition of tumor cell line (HT29) at 20 and 72% inhibition of GSK-3 at 20 .

An efficient synthesis of 3,4-dimethylidene oxacycles including oxolanes and oxepanes through Prins-type cyclization of hydroxy(allenylmethyl)silanes is described. We have shown that 2-substituted tetrahydrofuran derivatives could be produced by using this strategy although the 5-endo-trig cyclization mode is stereoelectronically disfavored. We also applied our method to the stereoselective synthesis of 2,7-cis-3,4-dimethylidene oxepanes, which were used for constructing more complex ring systems, such as polyether bicycles or tricycles.

Structure based drug design (SBDD) was used to discover heat shock protein 90 (HSP90) inhibitors useful in the treatment of cancer. By using the crystal structure of HSP90-ligand complex (1uyi), a docking model was prepared and was validated by external dataset containing known HSP90 inhibitors. This validated model was then used to virtually screen commercial databases, selected hits of which were bought and sent for real biological evaluation. Further as an alternative method, pharmacophores were generated using crystal structure conformations of ligands in HSP90 complexes (1uyi and 2bz5) and where used for virtual screening. Both cases yielded several hits containing novel scaffolds, particularly compound KHSP8 showed an IC(50) value of 0.902 μM in case of colon cancer (HT29), which is comparable to doxorubicin (0.828 μM). These compounds were being now used as leads for constructing small molecular libraries to get compounds with favourable pharmacokinetics and drug like properties.

Human ether-a-go-go related gene (hERG) potassium channel blockade, an undesirable side effect which might cause sudden cardiac death, is one of the major concerns facing the pharmaceutical industry. The purpose of this study is to develop an in silico QSAR model which uncovers the structural parameters of T-type calcium channel blockers to reduce hERG blockade. Comparative molecular similarity indices analysis (CoMSIA) was conducted on a series of piperazine and benzimidazole derivatives bearing methyl 5-(ethyl(methyl)amino)-2-isopropyl-2-phenylpentanoate moieties, which was synthesized by our group. Three different alignment methods were applied to obtain a reliable model: ligand based alignment, pharmacophore based alignment, and receptor guided alignment. The CoMSIA model with receptor guided alignment yielded the best results : = 0.955, = 0.781, = 0.758. The generated CoMSIA contour maps using electrostatic, hydrophobic, H-bond donor, and acceptor fields explain well the structural requirements for hERG nonblockers and also correlate with the lipophilic potential map of the hERG channel pore.

We have developed a facile synthesis of 3,3-diphenylpropanamides using Meldrum’s acid derivatives as amide coupling components. The in vitro biological evaluation of the title compounds led to the identification of compound 1h, which has good inhibitory activity against T-type calcium channel (IC50 = 0.83 μM).

Growing resistance of prevalent antitubercular (antiTB) agents in clinical isolates of Mycobacterium tuberculosis (MTB) provoked an urgent need to discover novel antiTB agents. Enoyl acyl carrier protein (ACP) reductase (InhA) from Mtb is a well known and thoroughly studied as antitubucular therapy target. Here we have reported the discovery of potent antiTB agents through ligand and structure based approaches using computational tools. Initially compounds with more than 0.500 Tanimoto similarity coefficient index using functional class fingerprints (FCFP_4) to the reference chemotype were mined from the chemdiv database. Further, the molecular docking was performed to select the compounds on the basis of their binding energies, binding modes, and tendencies to form reasonable interactions with InhA (PDB ID = 2NSD) protein. Eighty compounds were evaluated for antitubercular activity against H37RV M. tuberculosis strain, out of which one compound showed MIC of 5.70 μM and another showed MIC of 13.85 μM. We believe that these two new scaffolds might be the good starting point from hit to lead optimization for new antitubercular agents.

T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives substituted with arylpiperazinylalkylamines. The oxazoles were synthesized in a convenient convergent synthetic method, and biologically evaluated against alpha(1G) (Ca(V)3.1) T-type calcium channel. Among total 41 oxazole compounds synthesized, the most active one was the compound 10-35 with an IC(50) value of 0.65 microM, which is comparable with that of mibefradil.

We have synthesized and biologically evaluated 1,4-diazepane derivatives as T-type calcium channel blockers. In this study, we discovered compound 4s, a potential T-type calcium channel blocker with good selectivity over hERG and N-type calcium channels. In addition, it exhibited favorable pharmacokinetic characteristics for further investigation of T-type calcium channel related diseases.

which are more selectively bound to the targets such as serotonin transporter and/or norepinephrine transporter resulting in reduced side effects. However, all antidepressants in clinical use show limited efficacy, slow onset of action, and variable degree of side effects such as changes in sexual performance.

We have developed the stereoselective synthesis of 2-oxaspiro[m,n]alkane derivatives using the Prins-pinacol annulation of alkene diols with a wide range of aliphatic or aromatic aldehydes and ketones. This approach was further applied for the synthesis of oxatricyclic ring system.