Yong Seo Cho

New serotonin 5-HT(6) ligands from common feature pharmacophore hypotheses.

Serotonin 5-HT6 receptor antagonists are thought to play an important role in the treatment of psychiatry, Alzheimers disease, and probably obesity. To find novel and potent 5-HT6 antagonists and to provide a new idea for drug design, we used a ligand-based pharmacophore to perform the virtual screening of a commercially available database. A three-dimensional common feature pharmacophore model was developed by using the HipHop program provided in Catalyst software and was used as a query for screening the database. A recursive partitioning (RP) model which can separate active and inactive compounds was used as a filtering system. Finally a sequential virtual screening procedure (SQSP) was conducted, wherein both the common feature pharmacophore and the RP model were used in succession to improve the results. Some of the hits were selected based on druglikeness, ADME properties, structural diversity, and synthetic accessibility for real biological evaluation. The best hit compound showed a significant IC50 value of 9.6 nM and can be used as a lead for further drug development.

5- and 6-Exocyclic Products, cis-2,3,5-Trisubstituted Tetrahydrofurans, and cis-2,3,6-Trisubstituted Tetrahydropyrans via Prins-Type Cyclization

Exocyclic products having cis-2,5 and cis-2,6 substitution were synthesized from terminally substituted alkynyl alcohols with various aldehydes via Prins-type cyclization in good yields. It is of interest that synthesized 5- and 6-exocyclic vinyl cations generated as a result of Prins-type cyclization could be trapped as a vinyl triflate in CH2Cl2 to give 3-furanylidenes and 3-pyranylidenes. Those 3-furanylidenes and 3-pyranylidenes underwent hydrolysis to give the corresponding 3-acyl-substituted products having all-cis-configured isomers, such as 2,3,5-trisubstituted tetrahydrofurans and 2,3,6-trisubstituted tetrahydropyrans.

Stereocontrolled Synthesis of Oxaspirobicycles via Prins-Pinacol Annulation

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.

Synthesis and in vitro activity of new oxazolidinone antibacterial agents having substituted isoxazoles.

Two series of oxazolidinone derivatives having substituted isoxazoles were synthesized and tested for antibacterial activities against several Gram-positive strains including the resistant strains of Staphylococcus and Enterococcus, such as MRSA, CRSA, MSSA and VRE. Some of them showed in vitro activities (MIC) comparable or superior to the reference compound vancomycin.

IKKβ inhibitors identification part I: Homology model assisted structure based virtual screening

Control of NF-kappaB release through the inhibition of IKKbeta has been identified as a potential target for the treatment of inflammatory and autoimmune diseases. We have employed structure based virtual screening scheme to identify lead like molecule from ChemDiv database. Homology models of IKKbeta enzyme were developed based on the crystal structures of four kinases. The efficiency of the homology model has been validated at different levels. Docking of known inhibitors library revealed the possible binding mode of inhibitors. Besides, the docking sequence analyses results indicate the responsibility of Glu172 in selectivity. Structure based virtual screening of ChemDiv database has yielded 277 hits. Top scoring 75 compounds were selected and purchased for the IKKbeta enzyme inhibition test. From the combined approach of virtual screening followed by biological screening, we have identified six novel compounds that can work against IKKbeta, in which 1 compound had highest inhibition rate 82.09% at 10 microM and IC(50) 1.76 microM and 5 compounds had 25.35-48.80% inhibition.

Indium and zinc mediated Barbier type reactions: Allylation and propargylation reactions of 6-oxopenicillanate and 7-oxocephalosporanate

Abstract Allylation and propargylation of compounds, 6-oxopenicillanate 1 and 7-oxocephalosporanate 2 , were accomplished by reacting the corresponding bromides in the presence of indium or zinc. Both indium and zinc gave alkylated products in moderate yields under mild conditions. Indium mediated Barbier reactions in aqueous THF exhibited slightly higher stereoselectivity than zinc mediated reactions in anhydrous THF.

Indium-mediated diastereoselective allylation reactions: preparation of tert-α-hydroxy acids

Indium-mediated allylation reactions of α-ketoimides derived from Oppolzers sultam were accomplished in aqueous THF in good yields and excellent diastereomeric excesses. It could be a useful method for the preparation of enantiopure t-α-hydroxy acids. When the substituent of α-ketoimides was changed from phenyl to thiophenyl or furyl group, diastereoselectivity decreased in comparison to N-phenyl derivatives, but changing solvent to aqueous ethanol provided improved levels of diastereoselectivity.

Indium mediated allylation and propargylation reactions of dimethyl acetals and ketals

Abstract Indium mediated allylation and propargylation reactions of acetals and ketals with various allyl or propargyl bromides in aqueous media successfully provided the corresponding homoallylic or homopropargylic (and allenylic) alcohol, respectively, in moderate to good yields. Highly chemoselective allylation is also described. The ketal and aryl acetal could be selectively allylated over the aliphatic one in 80–84% yields.

A Concise Synthesis of Tetrabenazine: An Intramolecular Aza-Prins-Type Cyclization via Oxidative C–H Activation∥

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.

3D QSAR studies on new oxazolidinone antibacterial agents by comparative molecular field analysis

Three-dimensional QSAR studies for two series of new oxazolidinone antibacterial agents were conducted using the comparative molecular field analysis (CoMFA). In vitro activities (MICs) of the compounds against methicillin-resistant Staphylococcus aureus 88 (MRSA 88) exhibited a strong correlation with their steric, electrostatic factors and lipophilicities.