A new series of quinolotacrine hybrids including cyclopenta- and cyclohexa-quinolotacrine derivatives were designed, synthesized, and assessed as anti-cholinesterase (ChE) agents. The designed derivatives indicated higher inhibitory effect on the acetylcholinesterase (AChE) with IC50 values of 0.285–100 µM compared to butyrylcholinesterase (BChE) with IC50 values of?>?100 µM. Of these compounds, cyclohexa-quinolotacrine hybrids displayed a little better anti-AChE activity than cyclopenta-quinolotacrine hybrids. Compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6m) including 3-hydroxyphenyl and cyclohexane ring moieties exhibited the best AChE inhibitory activity with IC50 value of 0.285 µM. The kinetic and molecular docking studies indicated that compound 6m occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE as a mixed inhibitor. Using neuroprotective assay against H2O2-induced cell death in PC12 cells, the compound 6h illustrated significant protection among the assessed compounds. In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these quinolotacrine hybrids can be very encouraging AChE inhibitors to treat Alzheimer’s disease.
Graphic abstract
A novel series of quinolotacrine hybrids were designed, synthesized, and evaluated against AChE and BChE enzymes as potential agents for the treatment of AD. The hybrids showed good to significant inhibitory activity against AChE (0.285–100 μM) compared to butyrylcholinesterase (BChE) with IC50 values of?>?100 μM. Among them, compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c′] diquinolin-6-one (6 m) bearing 3-hydroxyphenyl moiety and cyclohexane ring exhibited the highest anti-AChE activity with IC50 value of 0.285 μM. The kinetic and molecular docking studies illustrated that compound 6 m is a mixed inhibitor and binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.
A dynamical theory is studied in which a scalar field ϕ in Einstein-Minkowski space is coupled to the four-velocityNμ of a preferred inertial observer in that space. As a consistent requirement on this coupling we study a principle of duality
invariance of the dynamical mass term of ϕ at some universal length in the small-distance regime. In the large-distance regime
duality breaking can be introduced by giving a background value to ϕ and a background direction toNμ. It is shown that, in an appropriate approximation, duality breaking can be related to the emergence of a characteristic
phase in which the condensation of the ground state allows massive excitations with a characteristic scale of squared mass
which agrees with the present observational bound for the cosmological constant. 相似文献
This paper develops a mathematical model for project time compression problems in CPM/PERT type networks. It is noted this
formulation of the problem will be an adequate approximation for solving the time compression problem with any continuous
and non-increasing time-cost curve. The kind of this model is Mixed Integer Linear Program (MILP) with zero-one variables,
and the Benders' decomposition procedure for analyzing this model has been developed. Then this paper proposes a new approach
based on the surrogating method for solving these problems. In addition, the required computer programs have been prepared
by the author to execute the algorithm. An illustrative example solved by the new algorithm, and two methods are compared
by several numerical examples. Computational experience with these data shows the superiority of the new approach. 相似文献
Summary. Benzyltriphenylphosphonium peroxymonosulfate in the presence of catalytic amounts of bismuth chloride was found to be an
efficient and mild reagent for the oxidative cleavage of oximes and semicarbazones to the corresponding carbonyl compounds
under microwave irradiation.
Corresponding author. E-mail: haji@cc.iut.ac.ir
Received March 4, 2002; accepted (revised) April 8, 2002 相似文献
Regioselective oxidative bromination of electron-rich aromatic rings has been studied using potassium bromide as a bromine source in the presence of benzyltriphenylphosphonium peroxymonosulfate as oxidant under nearly neutral reaction conditions. In most cases we obtained monobrominated derivatives regioselectively and in good to high yields without the aid of strong acids. 相似文献
Dehydrogenation of ethyl 3‐methyl‐4‐oxo‐4,5,6,7‐tetrahydrobenzofuran‐2‐carboxylate 1 with 2,2′‐azobi‐sisobutyronitrile and N‐bromosuccinimide gave ethyl 4‐hydroxy‐3‐methylbenzofuran‐2‐carboxylate 3 . Reaction of compounds 3–4 with hydrazine hydrate afforded the corresponding hydrazides 5a‐b . The reaction of 5a‐b with aldehydes yielded substituted hydrazones 6a‐l . Compounds 7a‐d were prepared from compounds 6a‐d and bromine in acetic acid. Lead tetraacetate oxidation of compounds 6e‐l afforded substituted oxadiazoles 8e‐l . Selenium dioxide oxidation of 4‐oxo‐4,5,6,7‐tetrahydrobenzofuran semicarbazones 9, 14a and 4‐oxo‐4,5,6,7‐tetrahydrobenzothiophene 14b gave the tricyclic 1,2,3‐selenadiazoles 10, 15a and 15b respectively. Reaction of semicarbazones 9, 14a and 14b with thionyl chloride afforded the corresponding 1,2,3‐thiadiazoles 12, 16a and 16b respectively. 相似文献
Construction of C–C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C–C bonds in a tricomponent process.α-Branched carboxylic acids and other carbonyls are readily accessed by a metal- and base-free deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls via boron enolates, resulting in a tricomponent coupling with unconventional electrophiles.相似文献
Oxathioacetalization of carbonyl compounds and transoxathioacetalization of O,O-acetals/ketals are reported under nearly neutral conditions promoted by iron(III) trifluoroacetate [Fe(CF3CO2)3] or trifluoromethanesulfonate [Fe(CF3SO3)3] as recyclable and highly efficient Lewis acid catalysts. 相似文献
The new analogues of nifedipine, in which 2-nitrophenyl group at position 4 is replaced by phenylisoxazolyl substituent, were synthesized. The symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates were prepared by classical Hantzsch condensation, and the asymmetrical analogues were synthesized using a procedure reported by Dagnino that involved the condensation of alkyl acetoacetate with alkyl 3-aminocrotonate and 5-phenylisoxazole-3-carboxaldehyde. The structure of all compounds was confirmed by IR, 1H NMR and Mass spectra. In vitro calcium channel antagonist activities were evaluated as calcium channel antagonists using the high K+ concentration of guinea-pig ileum longitudinal smooth muscle (GPILSM) assay. These compounds exhibited moderate calcium antagonist activity (IC50 = 10?7 to 10?5 M range) relative to the reference drug nifedipine (IC50 = 1.10 ± 0.40 × 10?8 M). 相似文献