Ghilsoo Nam

Syntheses and evaluation of pyrido[2,3-d]pyrimidine-2,4-diones as PDE 4 inhibitors

The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).

Synthesis and structure–activity relationships of quaternary ammonium cephalosporins with 3-pyrazolylpyridinium derivatives

Cephalosporins with 3-pyazolylpyridinium at C-3 position, which is supposed to exhibit synergic activity of ceftazidime and cefoselis, were synthesized and their antibacterial activity against gram-positive and gram-negative was inspected.

Synthesis and Biological Evaluation of Aryloxazole Derivatives as Antimitotic and Vascular-Disrupting Agents for Cancer Therapy

A series of aryloxazole, thiazole, and isoxazole derivatives was synthesized as vascular-targeting anticancer agents. Antiproliferative activity and tumor vascular-disrupting activity of all of the synthesized compounds were tested in vitro using various human cancer cell lines and HUVECs (human umbilical vein endothelial cells). Several compounds with an arylpiperazinyl oxazole core showed excellent cytotoxicity and metabolic stability in vitro. Among this series, two representative compounds (6-48 and 6-51) were selected and tested for the evaluation of anticancer effects in vivo using tumor-bearing mice. Compound 6-48 effectively reduced tumor growth (42.3% reduction in size) at the dose of 100 mg/kg. We believe that compound 6-48 will serve as a good lead compound for antimitotic and vascular-disrupting agents; further investigation to improve the in vivo efficacy of this series is underway.

Synthesis and in vitro antibacterial activity of 3-[N-methyl-N-(3-methyl-1,3-thiazolium-2-yl)amino]methyl cephalosporin derivatives

The new cephalosporins having N-linked quarternary ammonium salt at C-3 position were prepared from the reaction of 2-methylimino-3-methyl-1,3-thiazoline derivatives with cephalosporins. Also antimicrobial activities of those compounds were determined.

Novel 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-one derivatives as potential anti-cancer agents.

A novel series of 3,5,6-trisubstituted pyrazolo[4,3-d]pyrimidin-7-one derivatives, especially 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-ones were synthesized and evaluated for their in vitro anticancer activities against various human cancer cell lines. The inhibitory activities for several kinases have also been tested. The prepared compounds library exhibited significant anticancer activity towards HT-29 colon and DU-145 prostate cancer cell lines. The structure-activity relationships of the 6-N-arylcarboxamidopyrazolo[4,3-d]pyrimidin-7-one scaffold at R(1), R(2) and R(3) have been elucidated. Among the synthesized compounds, 12b was the most active compound with GI(50) value of 0.44microM and 1.07microM against HT-29 and DU-145 cell lines, respectively, and 13a was the most selective compound towards colon cancer cell line.

Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson’s disease

In Parkinsons disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinsons disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinsons disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure-activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.

Monitoring of Intracellular Tau Aggregation Regulated by OGA/OGT Inhibitors

Abnormal phosphorylation of tau has been considered as a key pathogenic mechanism inducing tau aggregation in multiple neurodegenerative disorders, collectively called tauopathies. Recent evidence showed that tau phosphorylation sites are protected with O-linked β-N-acetylglucosamine (O-GlcNAc) in normal brain. In pathological condition, tau is de-glycosylated and becomes a substrate for kinases. Despite the importance of O-GlcNAcylation in tau pathology, O-GlcNAc transferase (OGT), and an enzyme catalyzing O-GlcNAc to tau, has not been carefully investigated in the context of tau aggregation. Here, we investigated intracellular tau aggregation regulated by BZX2, an inhibitor of OGT. Upon the inhibition of OGT, tau phosphorylation increased 2.0-fold at Ser199 and 1.5-fold at Ser396, resulting in increased tau aggregation. Moreover, the BZX2 induced tau aggregation was efficiently reduced by the treatment of Thiamet G, an inhibitor of O-GlcNAcase (OGA). Our results demonstrated the protective role of OGT in tau aggregation and also suggest the counter-regulatory mechanism of OGA and OGT in tau pathology.

Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4-phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model.

New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Ca(v)3.1 (α(1G)) and Ca(v)3.2 (α(1H)) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of α(1G) and α(1H) subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain.

Synthesis and antibacterial activity of new 9-O-arylpropenyloxime ketolides

A novel series of 9-O-arylpropenyloxime ketolide was synthesized and evaluated for their antibacterial activity. This series of ketolide exhibited potent activity against clinically isolated gram-positive strains including Staphylococcus pneumoniae and Straptococcus Pyogenes.

Synthesis and T-type calcium channel-blocking effects of aryl(1,5-disubstituted-pyrazol-3-yl)methyl sulfonamides for neuropathic pain treatment

A novel series of aryl(1,5-disubstituted pyrazol-3-yl)methyl sulfonamide derivatives was designed, synthesized, and evaluated for T-type calcium channel (α1G and α1H) inhibitory activity. We identified several compounds, 9a, 9b, 9g, and 9h that displayed good T-type channel inhibitory potency with low hERG channel and CYP450 inhibition. Among them, 9a and 9b exhibited neuropathic pain alleviation effects in mechanical and cold allodynia induced in the SNL rat model. Compounds 9a and 9b displayed better efficacy than mibefradil and gabapentin against cold allodynia. In particular, compound 9a seemed to be valuable as shown fast acting performance in mechanical neuropathic pain model.