- Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism in Vivo
-
Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2O2-induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment. Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. The results of the biological evaluation showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment.
- Dong, Ze-Xi,Shi, Zhi-Hao,Li, Nian-Guang,Zhang, Wei,Gu, Ting,Zhang, Peng-Xuan,Wu, Wen-Yu,Tang, Yu-Ping,Fang, Fang,Xue, Xin,Li, He-Min,Cheng, Hai-Bo,Yang, Jian-Ping,Duan, Jin-Ao
-
p. 946 - 957
(2016/05/24)
-
- Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors
-
At present, inhibitors of α/β-hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 = 44 nM) and showed ~ 230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes.
- Patel, Jayendra Z.,Nevalainen, Tapio J.,Savinainen, Juha R.,Adams, Yahaya,Laitinen, Tuomo,Runyon, Robert S.,Vaara, Miia,Ahenkorah, Stephen,Kaczor, Agnieszka A.,Navia-Paldanius, Dina,Gynther, Mikko,Aaltonen, Niina,Joharapurkar, Amit A.,Jain, Mukul R.,Haka, Abigail S.,Maxfield, Frederick R.,Laitinen, Jarmo T.,Parkkari, Teija
-
p. 253 - 265
(2015/02/05)
-
- Enantioselective synthesis of α-phenyl- and α-(dimethylphenylsilyl)alkylboronic esters by ligand mediated stereoinductive reagent-controlled homologation using configurationally labile carbenoids
-
Chain extension of boronic esters by the action of configurationally labile racemic lithium carbenoids in the presence of scalemic bisoxazoline ligands was explored for the enantioselective synthesis of the two title product classes. Enantioenriched 2° carbinols generated by oxidative work-up (NaOOH) of initial α-phenylalkylboronate products were obtained in 35-83% yield and 70-96% ee by reaction of B-alkyl and B-aryl neopentyl glycol boronates with a combination of O-(α-lithiobenzyl)-N,N-diisopropylcarbamate and ligand 3,3-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl] pentane in toluene solvent (-78 °C to rt) with MgBr2·OEt2 additive. Enantioenriched α-(dimethylsilylphenylsilyl)alkylboronates were obtained in 35-69% yield and 9-57% ee by reaction of B-alkyl pinacol boronates with a combination of lithio(dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate and ligand 2,2-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl]propane in cumene solvent (-45 °C to -95 °C to rt). The stereochemical outcome of the second type of reaction depended on the temperature history of the organolithium·ligand complex indicating that the stereoinduction mechanism in this case involves some aspect of dynamic thermodynamic resolution. This journal is
- Barsamian, Adam L.,Wu, Zhenhua,Blakemore, Paul R.
-
supporting information
p. 3781 - 3786
(2015/03/30)
-
- Synthesis of scutellarein derivatives to increase biological activity and water solubility
-
In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease.
- Shi, Zhi-Hao,Li, Nian-Guang,Shi, Qian-Ping,Zhang, Wei,Dong, Ze-Xi,Tang, Yu-Ping,Zhang, Peng-Xuan,Gu, Ting,Wu, Wen-Yu,Fang, Fang,Xin-Xue,Li, He-Min,Yang, Jian-Ping,Duan, Jin-Ao
-
p. 6875 - 6884
(2015/11/11)
-
- Synthesis of pterostilbene and resveratrol carbamate derivatives as potential dual cholinesterase inhibitors and neuroprotective agents
-
Pterostilbene and resveratrol carbamate derivatives were designed and synthesized by use of a multi-target directed drug-design strategy. Their acetylcholinesterase and butylcholinesterase inhibitory activity and neuroprotective effects against hydrogen peroxide-induced PC12 cell injury were evaluated in vitro. The results indicated that some of the compounds had dual inhibitory potency against acetylcholinesterase and butylcholinesterase, and potential neuroprotective effects, and could be considered as potential multi-target-directed agents.
- Yuan, Wen,Shang, Zhipei,Qiang, Xiaoming,Tan, Zhenghuai,Deng, Yong
-
p. 787 - 800
(2014/02/14)
-
- Development of an improved method for conversion of thiuram disulfides into N,N-dialkylcarbamoyl halides and derivatives
-
A convenient procedure for preparing N,N-disubstituted carbamoyl halides is reported. It consists of two steps: (1) reaction of carbon disulfide and a secondary amine in the presence of a polar organic solvent and oxygen to produce the corresponding tetraalkyl thiuram disulfides and (2) reaction of tetraalkyl thiuram disulfide with a halide in the presence of an aprotic organic solvent to produce the corresponding N,N-disubstituted carbamoyl halide. Copyright Taylor & Francis Group, LLC.
- Adeppa,Rupainwar,Misra, Krishna
-
experimental part
p. 285 - 290
(2011/03/20)
-
- Antimalarial and antitrypanosomal activity of a series of amide and sulfonamide derivatives of a 2,5-diaminobenzophenone
-
Here, we describe a series of readily obtainable benzophenone derivatives with antimalarial and antitrypanosomal activity. The most active compounds display submicromolar activity against Plasmodium falciparum. Micromolar activity is obtained against Trypanosoma brucei. Main problem of the compounds is low selectivity. However, there are indications that separation of antimalarial and cytotoxic activity might by possible. In addition, some compounds inhibit human ABC transporter with nanomolar activity.
- Altenkaemper, Mirko,Bechem, Benjamin,Perruchon, Johann,Heinrich, Swetlana,Maedel, Andrea,Ortmann, Regina,Dahse, Hans-Martin,Freunscht, Ellen,Wang, Yulin,Rath, Jennifer,Stich, August,Hitzler, Manuela,Chiba, Peter,Lanzer, Michael,Schlitzer, Martin
-
experimental part
p. 7690 - 7697
(2010/03/24)
-
- CCR5 ANTAGONISTS AS THERAPEUTIC AGENTS
-
The present invention relates to compounds of formula (I) or pharmaceutically acceptable derivatives thereof, useful in the treatment or prophylaxis of CCR5-related diseases and disorders, for example, in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
- -
-
-
- Importance of the lipophilic group in carbamates having histamine H3- receptor antagonist activity
-
In order to evaluate changes in the lipophilic part of designed carbamates concerning their potential histamine H3-receptor antagonist properties a new series of O-[3-(1H-imidazol-4-yl)propanol]carbamates was derived containing N-mono- or dialkenyl, alkynyl, cycloalkyl, or double- branched alkyl substituents. The compounds were tested in vitro for their H3-receptor antagonist activity on synaptosomes of rat cerebral cortex and shared moderate to high antagonist activity in vitro. In this series 3-(1H- imidazol-4-yl)propyl N-(4-pentenyl)carbamate (4) was the most potent compound in vitro (K(i) = 6.3 nM). H3-receptor antagonist activity in the central nervous system (CNS) was detected for most compounds in the in vivo H3- receptor assay based upon measurement of brain N(τ)-methylhistamine levels after p.o. administration to mice. The most effective carbamate in vivo, 3- (1H-imidazol-4-yl)propyl N-(allyl)carbamate (3), showed higher CNS potency (ED50 = 0.48 mg/kg p.o.) than the reference antagonist thioperamide. For some novel carbamates their histamine H1- and H2-receptor activities were determined on isolated organs of guinea-pig thereby demonstrating their high H3-receptor selectivity.
- Kiec-Kononowicz,Wiecek,Sasse,Ligneau,Elz,Ganellin,Schwartz,Stark,Schunack
-
p. 349 - 355
(2007/10/03)
-
- Process for the preparation of 1-4-disubstituted-5 (4H)-tetrazolinones
-
1,4-Disubstituted-5(4H)-tetrazolinones of the formula (I) STR1 wherein R1, R2 and R3 have the meanings given in the specification), which are known to be useful as herbicides, can be obtained in very good yields by reacting the corresponding 1-substituted-5(4H)-tetrazolinones with the corresponding carbamoyl chlorides in the presence of 4-dimethylaminopyridine.
- -
-
-
- The Anomalous Reactions of Some Fluoronitrobenzenes with Some N,N-Dialkylamines
-
The reactions of 1-fluoro-2,4,- and -2,6-dinitrobenzene with certain N,N-dilkylamines in dimethyl sulfoxide solution in the presence of potassium carbonate give the corresponding dinitrophenyl N,N-dialkylcarbamates as well as corresponding N,N-dialkyldinitroanilines.The extent of carbamate formation is governed by steric factors.The corresponding reactions of 1-fluoro-4-nitrobenzene with diisopropylamine and di-s-butylamine give poor yields of the corresponding 4-nitrophenyl N,N-dialkylcarbamates but none of the corresponding N,N-dialkyl-4-nitroanilines; in these reactions, the major product is 4,4'-dinitrodiphenyl ether.The 1H and 13C n.m.r. spectra of the 2,4- and 2,6-dinitrophenyl N,N-dialkylcarbamates reveal that their aliphatic protons and carbon atoms are magnetically non-equivalent.
- Gale, Douglas J.,Rosevear, Judi,Wilshire, John F. K.
-
p. 997 - 1008
(2007/10/02)
-
- Process for the preparation of carbamoyl chlorides derived from secondary amines
-
Carbamoyl chlorides derived from secondary aliphatic amines having alkyl groups which are branched in the 1-position are prepared by passing phosgene at an elevated temperature into the corresponding, initially taken--if appropriate dissolved in an inert solvent--secondary aliphatic amines having alkyl groups which are branched in the 1-position. The reaction products are intermediates in various specialized fields, particularly in the plant protection sector.
- -
-
-
- A CONVENIENT PREPARATION OF CERTAIN N,N-DIALKYLCARBAMOYL CHLORIDES
-
Certain N,N-dialkylcarbamoyl chlorides (2) were prepared in moderate yields by the reaction of ethyl N,N-dialkylcarbamates (1) with phosphoryl chloride in boiling acetonitrile.
- Hoshino, Osamu,Saito, Keiji,Ishizaki, Miyuki,Umezawa, Bunsuke
-
p. 1887 - 1892
(2007/10/02)
-
- Dualistic Behaviour of Carbamoyl Isothiocyanates, II. Determination of their Equilibrium with Thiocarbamoyl Isocyanates
-
Various carbamoyl isothiocyanates, in part new, were prepared.The equilibrium R2N-CO-NCS R2N-CS-NCO was proven at elevated temperatures, its equilibrium constants were determined at various temperatures in different solvents by IR spectroscopy.The equilibrium shows considerable dependence on the constitution, mainly on the steric effects of R.
- Goerdeler, Joachim,Bartsch, Hans-Juergen
-
p. 2294 - 2299
(2007/10/02)
-
- Metallated Nitrogen Derivatives of Carbonic Acid in Organic Synthesis, XXVII. - Homoaldol Reaction, VII. Lithiation of Acyclic 2-Alkenyl N,N-Dialkylcarbamates. - Silylation and γ-Selective α-Hydroxyalkylation of Homoenolate Reagents
-
2-Alkenyl N,N-dialkylcarbamates 20 are deprotonated by n-butyllithium/TMEDA to form lithium compounds 21 which are versatile homoenolate reagents.The diisopropylcarbamoyl group is not attacked by butyllithium below -70 deg C.Due to the high kinetic acidity of the α-protons in 20, 1-oxyallyl anions 21, bearing up to two alkyl groups in any given distribution are accessible. - The reaction of 21 with chlorotrimethylsilane gives silanes 28 and/or 29.The regiochemistry of the silylation is mainly controlled by the position of methyl groups present in 21. - The addition of aldehydes or ketones 14 to 21 proceeds with high γ-selectivity yielding 4-hydroxyenol carbamates 30, which are methanolized in the presence of catalytic amounts of mercuric salts to afford 2-methoxytetrahydrofuranes (γ-lactol ethers) 33.Subsequent oxidation of 33 yields γ-lactones 34.Alternatively, O-acetyl derivatives 32 are hydrolyzed to afford γ-acetoxyalkanals or -alkanones 36.Alltogether, the method provides a general and flexible way for realization of homoaldol reactions. - (2E)- and (2Z)-butenyllithium compounds 21g and h are configuratively stable at the reaction conditions, which is an important requirement for accomplishment of syn- and anti-diastereoselective homoaldol reactions. - S-(2-alkenyl) N,N-dimethylthiocarbamates 12 are similarly deprotonated and hydroxyalkylated, but hydrolysis of enol thiocarbamates 15 to prepare homoaldols is not feasible.
- Hoppe, Dieter,Hanko, Rudolf,Broenneke, Alfons,Lichtenberg, Florian,Huelsen, Ede van
-
p. 2822 - 2851
(2007/10/02)
-