RESUMO
Alzheimer's disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039 µM, respectively. Both compounds showed very good self-induced Aß aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aß-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites.
Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Animais , Ácido Aspártico Endopeptidases , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ratos , Relação Estrutura-Atividade , Tacrina/química , Tacrina/farmacologiaRESUMO
A novel series of tacrine based cyclopentapyranopyridine- and tetrahydropyranoquinoline-kojic acid derivatives were designed, synthesized, and evaluated as anti-cholinesterase agents. The chemical structures of all target compounds were characterized by 1 H-NMR, 13 C-NMR, and elemental analyses. The synthesized compounds mostly inhibited acetylcholinesterase enzyme (AChE) with IC50 values of 4.18-48.71â µM rather than butyrylcholinesterase enzyme (BChE) with IC50 values of >100â µM. Among them, cyclopentapyranopyridine-kojic acid derivatives showed slightly better AChE inhibitory activity compared to tetrahydropyranoquinoline-kojic acid. The compound 10-amino-2-(hydroxymethyl)-11-(4-isopropylphenyl)-7,8,9,11-tetrahydro-4H-cyclopenta[b]pyrano[2',3' : 5,6]pyrano[3,2-e]pyridin-4-one (6f) bearing 4-isopropylphenyl moiety and cyclopentane ring exhibited the highest anti-AChE activity with IC50 value of 4.18â µM. The kinetic study indicated that the compound 6f acts as a mixed inhibitor and the molecular docking studies also illustrated that the compound 6f binds to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE. The compound 6f showed moderate neuroprotective properties against H2 O2 -induced cytotoxicity in PC12 cells. The theoretical ADME study also predicted good drug-likeness for the compound 6f. Based on these results, the compound 6f seems to be a very promising AChE inhibitor for the treatment of Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Pironas/síntese química , Pironas/química , Pironas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Ratos , Tacrina/análogos & derivados , Tacrina/químicaRESUMO
The complex pathophysiology of Alzheimer's disease (AD) has prompted researchers to develop multitarget-directed molecules to find an effective therapy against the disease. In this context, a novel series of N-(1-benzylpiperidin-4-yl)-5-arylisoxazole-3-carboxamide derivatives were designed, synthesized, and evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro biological evaluation demonstrated that compound 4e was the best AChE (IC50 = 16.07 µM) and BuChE inhibitor (IC50 = 15.16 µM). A kinetic study of 4e was also conducted, which presented a mixed-type inhibition for both enzymes. Molecular docking studies revealed that compound 4e fitted well into the active sites of AChE and BuChE, forming stable and strong interactions with key residues Glu199, Trp84, Asp72, Tyr121, and Phe288 in AChE and His438, Trp82, Ala328, Tyr332, Phe329, Thr120, and Pro285 in BuChE. Besides, the inhibition of BACE1 by 4e and the biometal chelation activity of 4e were measured. The neuroprotective assessment revealed that 4e exhibited 23.2% protection at 50 µM toward amyloid-beta-induced PC12 neuronal cells. Overall, this study exhibited that compound 4e was a promising compound targeting multiple factors associated with AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Isoxazóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Isoxazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Piperidinas/síntese química , Piperidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
In search of safer tacrine analogs, various thieno[2,3-b]pyridine amine derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs). Among the synthesized compounds, compounds 5e and 5d showed the highest activity towards acetylcholinesterase and butyrylcholinesterase, with IC50 values of 1.55 and 0.23 µM, respectively. The most active ChE inhibitors (5e and 5d) were also candidates for further complementary assays, such as kinetic and molecular docking studies as well as studies on inhibitory activity towards amyloid-beta (ßA) aggregation and ß-secretase 1, neuroprotectivity, and cytotoxicity against HepG2 cells. Our results indicated efficient anti-Alzheimer's activity of the synthesized compounds.
Assuntos
Inibidores da Colinesterase/farmacologia , Piridinas/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Butirilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Células Hep G2 , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Piridinas/síntese química , Piridinas/química , Tacrina/síntese química , Tacrina/químicaRESUMO
A novel series of hybrid arylisoxazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman's method. Among synthesized compounds, 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide depicted the most acetylcholinesterase (AChE) inhibitory activity (IC50 =1.23â µm) and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was found to be the most potent butyrylcholinesterase (BChE) inhibitor (IC50 =9.71â µm). 5-(3-Nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was further investigated for its BACE1 inhibitory activity as well as neuroprotectivity and metal chelating ability as important factors involved in onset and progress of Alzheimer's disease. It could inhibit BACE1 by 48.46 % at 50â µm. It also showed 6.4 % protection at 25â µm and satisfactory chelating ability toward Zn2+ , Fe2+ , and Cu2+ ions. Docking studies of 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide confirmed desired interactions with those amino acid residues of the AChE and BChE, respectively.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Cromonas/farmacologia , Desenho de Fármacos , Isoxazóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Isoxazóis/síntese química , Isoxazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Alzheimer's disease (AD) is a well-known neurodegenerative disorder affecting millions of old people worldwide and the corresponding epidemiological data highlights the significance of the disease. As AD is a multifactorial illness, various single-target directed drugs that have reached clinical trials have failed. Therefore, various factors associated with outset of AD have been considered in targeted drug discovery and development. In this work, a wide range of 1,2,3-triazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase inhibitory activity. Among them, N-(1-benzylpiperidin-4-yl)-7-((1-(3,4-dimethylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-oxo-2H-chromene-3-carboxamide (11b) showed the best acetylcholinesterase inhibitory activity (IC50â¯=â¯1.80⯵M), however, it was inactive toward butyrylcholinesterase. It should be noted that compound 11b was evaluated for its BACE1 inhibitory activity and calculated IC50â¯=â¯21.13⯵M confirmed desired inhibitory activity. Also, this compound revealed satisfactory neuroprotective effect against H2O2-induced cell death in PC12 neurons at 50⯵M as well as metal chelating ability toward Fe2+, Cu2+, and Zn2+ ions.