Design, synthesis, and biological evaluation of 1,3-dioxoisoindoline-5-carboxamide derivatives as T-type calcium channel blockers

A small molecule library of 1,3-dioxoisoindoline-5-carboxamides 4 was designed based on the pharmacophore model, synthesized and biologically evaluated as potential T-type calcium channel blockers. The most active compounds 4d and 4n show T-type calcium channel blocking activity with IC50 values of 0.93 and 0.96 microM, respectively.     

Synthesis and SAR studies of a novel series of T-type calcium channel blockers

For the novel, potent, and selective T-type Ca2+ channel blockers, a series of sulfonamido-containing 3,4-dihydroquinazoline derivatives were prepared and evaluated for their blocking actions on T- and N-type Ca2+ channels. Among them, 9c (KYS05064, IC50 = 0.96 +/- 0.22 microM) was found to be as potent as Mibefradil and also showed the highest selectivity for T-type Ca2+ channel with no effect on N-type Ca2+ channel.     

Discovery of potent T-type calcium channel blocker

The intensive SAR study of 3,4-dihydroquinazoline series led to the most potent compound 10 (KYS05090: IC(50)=41+/-1 nM) against T-type calcium channel and its potency is nearly comparable to that of Kurtoxin. As a small organic molecule, this compound showed the highest blocking activity reported to date.     

Hymenobacter negativus sp. nov., bacteria isolated from mountain soil collected in South Korea

Two novel Gram-negative bacterial strains BT442^T and BT584 were isolated from dry soil collected in mountains Busan and Guri, Korea during wintertime. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strains BT442^T and BT584 both belong to a distinct lineage within the genus Hymenobacter (family Hymenobacteraceae, order Cytophagales, class Cytophagia). Strain BT442^T was closely related to Hymenobacter soli PB17^T (98.0% 16S rRNA gene similarity) and Hymenobacter terrae POA9^T (97.6%). No other recognized bacterial species showed more than 97% 16S rRNA gene sequence similarity to strains BT442^T. The genome size of strain BT442^T was 5,143,362 bp. Bacterial growth was observed at 10–30 °C (optimum 25 °C), pH 6.0–8.0 (optimum pH 6.0) in R2A agar and in the presence up to 1% NaCl. The major cellular fatty acids of strains BT442^T and BT584 were iso-C_15:0, anteiso-C_15:0 and summed feature 3 (C_16:1 ω6c / C_16:1 ω7c). In addition, their predominant respiratory quinone was MK-7. The major polar lipids of strains BT442^T and BT584 were identified to be phosphatidylethanolamine, aminophospholipid, and aminolipid. Based on the biochemical, chemotaxonomic, and phylogenetic analyses, strains BT442^T and BT584 are novel bacterial species within the genus Hymenobacter, and the proposed name is Hymenobacter negativus. The strain type of Hymenobacter negativus is BT442^T (=?KCTC 72902^T?=?NBRC XXXX^T).

     

Lead discovery and optimization of T-type calcium channel blockers

A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with alpha1(G) and alpha1(H) clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch-clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC(50) values than Mibefradil.