Design and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors

Tyrosinase is a key enzyme during the production of melanins in plants and animals. A class of novel N-aryl-N′-substituted phenylthiourea derivatives (3a–i, 6a–k) were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed some 4,5,6,7-tetrahydro-2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (3a–i) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid was replaced with 2-(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (6a–k) against tyrosinase was improved obviously; especially, the inhibitory activity of compound 6h (IC₅₀ = 6.13 μM) is significantly higher than kojic acid (IC₅₀ = 33.3 μM). Moreover, the analysis on inhibition mechanism revealed that compound 6h might plays the role as a noncompetitive inhibitor.     

Thiophene bioisosteres of GluN2B selective NMDA receptor antagonists: Synthesis and pharmacological evaluation of [7]annuleno[b]thiophen-6-amines

Thiophene bioisosteres of potent GluN2B receptor negative allosteric modulators were prepared and evaluated pharmacologically. The five-step synthesis of 4,5,7,8-tetrahydro[7]annuleno[b]thiophen-6-one (10) was considerably improved by carboxylation of thiophene-3-carboxylic acid (8) in the first reaction step. Reductive amination and alkylation led to three homologous series of secondary and tertiary phenylalkylamines 5, 11 and 12. Metalation, reaction with 1-formylpiperidine and subsequent reduction provided hydroxymethyl derivatives 15 and 16, which had been designed as bioisosteres of phenols. 2-Bromo derivatives 18 were obtained by bromination of ketone 10 with NBS and subsequent reductive amination. High GluN2B affinity was achieved with [7]annuleno[b]thiophenes bearing a 3-phenylpropylamino or 4-phenylbutylamino moiety (e.g. 5c: K_i = 5.9 nM; 11d: K_i = 9.0 nM). Tertiary ethylamines 12 showed lower GluN2B affinity than tertiary methylamines 11 or secondary amines 5 (e.g. 5c: K_i = 5.9 nM; 11c: K_i = 6.0; 12c: K_i = 51 nM). A Br-atom or a hydroxymethyl moiety in 2-position were less tolerated by the GluN2B receptor. Very similar relationships between the structure and GluN2B affinity and structure and σ affinity, in particular σ₂ affinity, were detected. A slight preference for the ifenprodil binding site of GluN2B receptors over σ₁ and σ₂ receptors was found for methylamines 11c (≈2-fold) and 11d (≈1.5–2-fold) as well as for bromo derivative 18c (≈3-fold).     

Synthesis and receptor binding studies of some new arylcarboxamide derivatives as sigma-1 ligands

We describe here the synthesis and the binding interaction with σ₁ and σ₂ receptors of a series of new arylcarboxamide derivatives variously substituted on the aromatic portions. Maintaining a partial scaffold of a series of compounds previously synthesized by us, we evaluate the effect of the substitution on σ binding. The synthesized compounds have been tested to estimate their affinity and selectivity toward σ₁ and σ₂ receptors. Two out of 16 derivatives showed an interesting σ₁ affinity (21.2 and 13.6 nM—compounds 2m and 2p) and a good selectivity (K_i(σ₂)/K_i(σ₁) >140 and >40, respectively).     

吩噻嗪衍生物在体内外对肠道细菌的作用

本工作测试了７种吩噻嗪衍生物在体外对５株好氧或兼性厌氧菌和８９株厌氧菌的最小抑菌浓度,结果表明,吩噻嗪衍生物对细菌（尤其是球菌和厌氧菌）具有一定的抑制作用,但携带可拮抗艰难梭菌肠道定植屏障菌群的悉生小鼠接受２周或４周的Ｃｈｌｏｒｐｒｏｍａｚｉｎｅ（０．２ｍｇ／小鼠／天）并不会使菌群屏障遭破坏。     

Synthesis of poly-O-sulfated glycosides of 2,5-anhydro-D-mannitol

2,5-Anhydro-3-O-beta-D-glucopyranosyl-; -3-O-alpha-L-idopyranosyl-; -3-O-alpha-D-arabinopyranosyl-; -3-O-alpha-L-arabinopyranosyl-; -3-O-beta-D-maltopyranosyl-; -3-O-beta-D-gentiobiopyranosyl-; -1,6-di-O-beta-D-glucopyranosyl-; -1,6-di-O-alpha-L-idopyranosyl-; -1-O-beta-D-maltopyranosyl-; -1,3,6-tri-O-beta-D-glucopyranosyl-; -1,6-di-O-beta-maltopyranosyl- and -1,6-di-O-beta-D-gentiobiopyranosyl-2,5-anhydro-D-mannitol as well as their poly-O-sulfated derivatives were synthesized. The IP3-IC50 values of their sodium and/or potassium salts were determined for structure-activity studies aiming at the synthesis of new, orally active antiasthmatic compounds.     

Pharmacophore-based discovery of triaryl-substituted imidazole as new telomeric G-quadruplex ligand

Discovery of potent and selective ligands for telomeric G-quadruplex DNA is a challenging work. Through a combination approach of pharmacophore model construction, model validation, database virtual screening, chemical synthesis and interaction evaluation, we discovered and confirmed triaryl-substituted imidazole TSIZ01 to be a new telomeric G-quadruplex ligand with potent binding and stabilizing activity to G-quadruplex DNA, as well as a 8.7-fold selectivity towards telomeric G-quadruplex DNA over duplex DNA.     

Seven furanoeremophilanes from three Senecio species

The investigation of two further Senecio species and the re-investigation of S. inaequidens afforded, in addition to known compounds, seven new furanoeremophilane derivatives. Six of these are closely related to cacalol, a sesquiterpene type which predominates in the species investigated.     

Studies on the isolation of penicillin acylase from Escherichia coli by aqueous two-phase partitioning

A method of enzyme release and aqueous two-phase extraction is described for the separation of penicillin acylase from Escherichia coli cells. Butyl acetate, 12% (v/v), treatment combined with freeze-thawing gives up to 70% enzyme release. For polyethylene glycol (PEG) + phosphate two-phase extraction systems the enzyme purity and yield were rather low. Modified PEG, including PEG-ampicillin, PEG-aniline, PEG-phosphate, and PEG-trimethylamine, were synthesized and used in aqueous two-phase systems; PEG-trimethylamine is the most satisfactory. A system containing 12% (w/w) PEG4000, 8% (w/w) of which is PEG-trimethylamine, with 0.7M potasium phosphate at pH 7.2, resulted in the enzyme selective partition being greatly enhanced by charge directed effects. Possible mechanisms for the separation process are discussed. (c) 1992 John Wiley & Sons, Inc.     

1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

A series of 1,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase. A variety of flexible and restricted basic amine side chain substitutions was explored at the 1-position of the indole ring, while keeping the amidine group fixed at the 5-position. Compounds having N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)- (12, (R)-12, (S)-12 and 13) and N-(1-(1-methylazepan-4-yl)- side chains (14, 15, (-)-15 and (+)-15) showed increased inhibitory activity for the human nNOS isoform and selectivity over eNOS and iNOS isoforms. The most potent compound of the series for human nNOS (IC(50)=0.02 μM) (S)-12 showed very good selectivity over the eNOS (eNOS/nNOS=96-fold) and iNOS (iNOS/nNOS=850-fold) isoforms.