N-(5-chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as gamma-secretase inhibitors

A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.     

Novel 5-(benzyloxy)pyridin-2(1H)-one derivatives as potent c-Met inhibitors

A series of novel 5-(benzyloxy)pyridin-2(1H)-ones were designed, synthesized and biologically evaluated for c-Met inhibition. Various amides and benzoimidazoles at C-3 position were investigated. A potent compound 12b with a c-Met IC₅₀ of 12 nM was identified. This compound exhibited potent inhibition of EBC-1 cell associated with c-Met constitutive activation and showed high selectivity for c-Met than other tested 11 kinases. The binding model 12b with c-Met was disclosed by docking analysis.     

Novel 1-(2-pyrimidin-2-yl)piperazine derivatives as selective monoamine oxidase (MAO)-A inhibitors

In the present study, a new series of 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-substituted piperazine-1-carbodithioate derivatives (2a-n) were synthesized and screened for their monoamine oxidase A and B inhibitory activity. The structures of compounds were elucidated using spectroscopic methods and some physicochemical properties of new compounds were predicted using Molinspiration and MolSoft programs. Compounds 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-(4-nitrophenyl)piperazine-1-carbodithioate (2j) and 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-benzhydrylpiperazine-1-carbodithioate (2m) exhibited selective MAO-A inhibitory activity with IC_50?=_?23.10, 24.14?µM, respectively. Some of the biological results were found in accordance with the obtained in silico data based on Lipinski’s fule of five.     

Novel tetrahydro-beta-carboline-1-carboxylic acids as inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)

A structure-activity relationship study was conducted on a series of tetrahydro-beta-carboline-1-carboxylic acid analogs in order to identify the key functionality responsible for activity against the mitogen-activated protein kinase-activated protein kinase 2 enzyme (MK-2). The compounds were further evaluated for their ability to inhibit TNFalpha production in U937 cells and in vivo. These compounds represent a novel structural class of compounds capable of inhibiting MK-2 with remarkable selectivity.     

Novel P450(17alpha) inhibitors: 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androstene derivatives

Twelve 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androsta-5,16-diene derivatives were designed and synthesized from 3 beta-acetoxy-pregna-5,16-dien-20-one (1b) as inhibitors of 17 alpha-hydroxylase-C(17,20)-lyase (P450(17 alpha)). Potent inhibitors of this enzyme could be of value as treatment of prostate cancer. Two substituents (methyl and phenyl) were introduced either at their 4'- or 5'-position in order to investigate their structure-activity relationship. Due to the 16,17-double bond, 17-thiazoles were generally obtained in low yield. The pharmacological results showed that the compounds containing 17-(2'-oxazolyl) (14c) and 17-(2'-thiazolyl) (8c) (41.5%) demonstrated reasonable inhibition against P450(17 alpha). Their 3-acetate (13c and 7c) were less potent than their 3-OH counterparts. The introduction of a phenyl or methyl group generally decreased inhibitory activity. Surprisingly, 17-(5'-methyl-2'-thiazolyl) (12a) was the most potent compound in this series and was almost as potent as L-39, which has good antitumor activity.     

Novel 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase

A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.     

Synthesis,structure and antibacterial activity of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives

A series of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized. The results showed that compounds 9q and 10q can strongly inhibit Staphylococcus aureus DNA gyrase and Bacillus subtilis DNA gyrase (with IC_50s of 0.125 and 0.25 μg/mL against S. aureus DNA gyrase, 0.25 and 0.125 μg/mL against B. subtilis DNA gyrase). On the basis of the biological results, structure–activity relationships were also discussed.     

Novel 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids: discovery and hit-to-lead evolution of a selective CRTh2 receptor antagonist chemotype

Hit-to-lead evolution of 2-(2-((2-(4-chlorophenoxy)ethyl)thio)-1H-benzo[d]imidazol-1-yl)acetic acid (1), discovered in a high-throughput screening campaign as a novel chemotype of CRTh2 receptor antagonist, is presented. SAR development as well as in vitro and in vivo DMPK properties of selected representatives of substituted 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids are discussed.     

Novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors

A series of novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors was prepared via treatment of various diaryl amides with tetrachlorosilane/sodium azide. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles contained a methylsulfonyl or sulfonamide group as COX-2 pharmacophore displayed only low inhibitory potency towards COX-2. Most potent compounds showed IC(50) values of 6 and 7 μM for COX-2. All compounds showed IC(50) values greater 100 μM for COX-1 inhibition.     

Novel poly(ADP-ribose) polymerase-1 inhibitors

Synthesis and activity of a series of 3-aroyl-derived analogs of novel pyrrolocarbazole 1 as poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are disclosed.     

Novel poly(ADP-ribose) polymerase-1 inhibitors

Synthesis and activity of a series of 4-thiazol-yl substituted analogs of novel pyrrolocarbazole 1 as poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been disclosed.     

Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors

Tryptophan hydroxylase (TPH) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. Here we describe the discovery of substituted triazines as a novel class of tryptophan hydroxylase inhibitors. This class of TPH inhibitors can selectively reduce serotonin levels in murine intestine after oral administration without affecting levels in the brain. These TPH inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.     

Enhancement in antimicrobial activity of 2-(phenyl)-3-(2-butyl-4-chloro-1H-imidazolyl)-5-butylate isoxazolidine

The trans rich isomer, 2-(phenyl)-3-(2-butyl-4-chloro-1H-imidazolyl)-5-butylate isoxazolidine A (>96% ee) was synthesized by the condensation of E isomer rich nitrone 4 (>98% ee) with butyl acrylate in an inert solvent. Obtained isoxazolidine was screened for its antifungal activity against Aspergillus niger, Cephalosporium acremonium, Fusarium moniliforme by using Nystatin as positive control. It was also tested for its antibacterial activity against Bacillus subtilis, Escherichia coli, and Staphylococcus aureus by using Streptomycin as positive control. Enhanced antifungal activity was observed in isoxazolidine of >96% ee compared to the isoxazolidine of >69% ee (B), and enhancement was not observed in antibacterial activity.     

Effect of H4R antagonist N-(2-aminoethyl)-5-chloro-1H-indol-2-carboxamides and 5-chloro-2-(piperazin-1-ylmethyl)-1H-benzimidazole on histamine and 4-methylhistamine-induced mast cell response

Context: The histamine plays a decisive role in acute and chronic inflammatory responses and is regulated through its four types of distinct receptors designated from H1 to H4. Recently histamine 4 receptor (H4R) antagonists have been reported to possess various pharmacological effects against various allergic diseases.

Objective: To investigate the inhibitory effect of N-(2-aminoethyl)-5-chloro-1H-indol-2-carboxamide (Compound A) and 5-chloro-2-(piperazin-1-ylmethyl)-1H-benzimidazole (Compound L) on H4R-mediated calcium mobilization, cytokine IL-13 production, ERK1/2, Akt and NF-κB activation in human mastocytoma cells-1 (HMC-1).

Materials and methods: Compounds A and L were synthesized chemically and their inhibitory effect on intracellular calcium release was analyzed by Fluo-4 calcium assay, cytokine measurement through ELISA and activation of signaling molecules by western blot.

Results: Pre-treatment with compounds A and L significantly reduced the H4R-mediated intracellular calcium release. Histamine and 4-methylhistamine (4-MH) induced Th2 cytokine IL-13 production in HMC-1 cells, was inhibited by compound A (77.61%, 74.25% at 1?μM concentration) and compound L (79.63%, 81.70% at 1?μM concentration). Furthermore, histamine induced the phosphorylation of ERK1/2, Akt and NF-κB was suppressed by compounds A and L at varying levels, ERK1/2 (88%, 86%), Akt (88%, 89%) and NF-κB (89%, 87%) in HMC-1 cells.

Discussion and conclusions: Taken together these data demonstrate that compound A and compound L may block H4R-mediated downstream signaling events.     

Lipase-catalyzed irreversible transesterification of 1-(2-furyl)ethanol using isopropenyl acetate

Asymmetric acetylation of racemic 1-(2-furyl)ethanol with the innocuous acyl donor isopropenyl acetate catalyzed by lipases in organic media afforded the chiral alcohol and acetate in high enantiomeric excess (up to 99%). The effect of molecular sieves as well as organic solvents on the kinetic resolution were studied. An effective separation of the enantiomers of both substrate and product was performed using gas chromatography on the chiral stationary phase heptakis-(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin.     

A lipophilic, selective alpha1 -adrenoceptor agonist: 2-(2-chloro-5-trifluoromethylphenylimino)imida-zolidine (St 587)

A new compound (St 587) is described, which is a selective α₁ -adrenoceptor stimulating agent with lipophilic properties. This combination of characteristics is novel, since all α₁ -adrenoceptor agonists developed so far are hydrophilic. The α-adrenergic effects of 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), a derivative of clonidine, were examined in several animal models. St 587 (1–10,000 μg/kg, i.v.) induced vasoconstriction in pithed, normotensive rats. This peripheral pressor activity was strongly antagonized by prazosin (0.1 mg/kg), but not affected by yohimbine (1 mg/kg). In intact, pentobarbitone-anaesthetized normotensive rats, St 587 (1–3,000 μg/kg, i.v.) evoked transient pressor responses, but a secondary fall in blood pressure and cardiac frequency was not observed. In pitched rats, St 587 (1–1,000 μg/kg) failed to modify the increase in heart rate produced by electrical stimulation of the cardioaccelerator sympathetic nerve fibres. St 587 (300 and 1,000 μg/kg) did not display central hypotensive activity, when injected into the left vertebral artery of anaesthetized cats. In addition, no hypotensive effect was observed when St 587 was administered i.v. to anaesthetized normotensive rats and cats. In mice, St 587 (10–10,000 μg/kg, i.p.) lacked sedative properties, since it did not prolong the hexobarbitone (75 mg/kg, i.p.)-induced loss of the righting reflex. The overall lipophilicity (log P′) of St 587 in the octanol/buffer (pH=7.4) reference system at 37°C amounted to 1.54. The experimental data suggest that St 587 is a lipophillic compound with selective α₁ - agonistic activity. The inability of St 587 to cause hypotension and sedation provides further evidence for the view that α₁ -adrenoceptors in the brain are not involved in the central hypotensive action and the sedation, caused by clonidine and related drugs. These effects are solely mediated by homogenous populations of α₂ -adrenoceptors.     

2(S)-(Cycloalk-1-enecarbonyl)-1-(4-phenyl-butanoyl)pyrrolidines and 2(S)-(aroyl)-1-(4-phenylbutanoyl)pyrrolidines as prolyl oligopeptidase inhibitors

In order to replace the P2-P1 amide group, different 1-cycloalkenyls and 2-aryls were studied in the place of the P1 pyrrolidine group of a 4-phenylbutanoyl-L-Pro-pyrrolidine structure, which is a well-known prolyl oligopeptidase inhibitor SUAM-1221. The 1-cyclopentenyl and the 2-thienyl groups gave novel compounds, which were equipotent with the corresponding pyrrolidine-analog SUAM-1221. It was shown that the P2-P1 amide group of POP inhibitors can be replaced by an alpha,beta-unsaturated carbonyl group or the aryl conjugated carbonyl group.     

Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas as potent inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2)

Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas are described as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). These compounds demonstrate potent in vitro activity against the enzyme with IC₅₀ values as low as 15 nM, and suppress expression of TNFα in THP-1 cells and in vivo in an acute inflammation model in mice. The synthesis, structure–activity relationship (SAR), and biological evaluation of these compounds are discussed.     

An NMR investigation of the conformational equilibria of 2-(2'-pyridyl)ethylphosphonic acid in several solvents

Vicinal proton-proton NMR couplings have been used to investigate whether the position of conformational equilibria is determined by intramolecular N-H hydrogen bonding for 2-(2'-pyridyl)ethylphosphonic acid 1 in its various possible ionization states in water, methanol, ethanol, and dimethyl sulfoxide (DMSO). With 1 in the form of its monoanion and dianion, the trans is favored, with the dianion being more trans than the monoanion for a given solvent, probably as the result of steric effects, possibly enhanced by repulsive electrostatic effects between the negatively charged phosphonic group and the lone pair on the pyridine nitrogen. For 1 and its conjugate acid, the gauche amounts, respectively, to 43% and 45% in water, 66% and 51% in methanol, 66% and 64% in ethanol, and 29% and 49% in DMSO. For these latter two species, electrostatic, steric, and hydrogen bonding-effects are all likely to play a role in determining the conformational equilibria.