RESUMO
Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), ß secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Aß aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC50 value = 0.486 ± 0.047 µM), BACE-1 inhibition (IC50 value = 0.542 ± 0.099 µM) along with good anti-Aß aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC50 value = 2.000 ± 0.360 µM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Aß-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand-protein confirmation throughout the simulation run.
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Inibidores da Colinesterase , Desenho de Fármacos , Triazinas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Ratos , Relação Estrutura-Atividade , Acetilcolinesterase/metabolismo , Triazinas/química , Triazinas/farmacologia , Triazinas/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Estrutura Molecular , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Simulação de Acoplamento Molecular , Quinases Dyrk , Relação Dose-Resposta a Droga , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Masculino , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Butirilcolinesterase/metabolismoRESUMO
The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and ß-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Aß aggregation inhibition in a self- and AChE-induced Aß aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Aß-induced cognitive deficits in the Aß-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the Aêµ-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Aß and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Inibidores da Colinesterase , Desenho de Fármacos , Quinazolinas , Quinazolinas/farmacologia , Quinazolinas/síntese química , Quinazolinas/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Acetilcolinesterase/metabolismo , Ratos , Relação Estrutura-Atividade , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Dose-Resposta a Droga , Butirilcolinesterase/metabolismo , MasculinoRESUMO
An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives (AV-1 to AV-21) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human ß-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds AV-1, AV-2, and AV-3 from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood-brain barrier permeability via the PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 µM) against differentiated SH-SY5Y cell lines. Compound AV-2 also prevented AChE- and self-induced Aß aggregation in the thioflavin T assay. Additionally, compound AV-2 significantly ameliorated scopolamine and Aß-induced cognitive impairments in the in vivo behavioral Y-maze and Morris water maze studies, respectively. The ex vivo and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound AV-2. Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Aß, BACE-1, APP/Aß, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound AV-2 demonstrated significant oral absorption with good bioavailability. The in silico molecular modeling studies of lead compound AV-2 moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand-protein complexes throughout the 100 ns run. Compound AV-2 can be regarded as the lead candidate and could be explored more for AD therapy.
Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/metabolismo , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Inibidores da Colinesterase/química , Desenho de Fármacos , Peptídeos beta-Amiloides/metabolismo , Simulação de Acoplamento MolecularRESUMO
Alzheimer's disease (AD) is a multifactorial and emerging neurological disorder, which has invoked researchers to develop multitargeted ligands. Herein, hybrid conjugates of 5-phenyl-1,3,4-oxadiazole and piperazines were rationally designed, synthesized, and pharmacologically evaluated against hAChE, hBChE, and hBACE-1 enzymes for the management of AD. Among the series, compound 5AD comprising pyridyl substitution at terminal nitrogen of piperazine contemplated as a paramount lead compound (hAChE, IC50 = 0.103 ± 0.0172 µM, hBChE, IC50 ≥ 10 µM, and hBACE-1, IC50 = 1.342 ± 0.078 µM). Compound 5AD showed mixed-type enzyme inhibition in enzyme kinetic studies against the hAChE enzyme. In addition, compound 5AD revealed a significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE and excellent blood-brain barrier (BBB) permeability in a parallel artificial membrane permeation assay (PAMPA). Besides, 5AD also exhibited anti-Aß aggregation activity in self- and AChE-induced thioflavin T assay. Further, compound 5AD has shown significant improvement in learning and memory (p < 0.001) against the in vivo scopolamine-induced cognitive dysfunction mice model. The ex vivo study implied that after treatment with compound 5AD, there was a decrease in AChE and malonaldehyde (MDA) levels with an increase in catalase (CAT, oxidative biomarkers) in the hippocampal brain homogenate. Hence, compound 5AD could be regarded as a lead compound and further be explored in the treatment of AD.
RESUMO
Light aromatics (benzene, toluene, and xylene, collectively known as BTX) are essential commodity chemicals in the petrochemical industry. The present study examines the aromatization of bioethanol with Cr- and Ga-modified ZSM-5. Both Cr and Ga were incorporated by the ion-exchange method. Cr-modified ZSM-5 outperforms the Ga-modified ZSM-5 and H-ZSM-5 catalysts. Cr-H-ZSM-5 almost doubled the carbon yield of aromatics compared to H-ZSM-5 at an optimum reaction temperature of 450 °C. Cr-H-ZSM-5 produced aromatics with a yield of ~40 %. The effect of dilution in feed on BTX production is also studied. Cr-H-ZSM-5 was found to be more active than H-ZSM-5. Complete ethanol conversion was obtained with both pure and dilute bioethanol. The Bronsted-Lewis acid (BLA) pair formed after metal incorporation is responsible for dehydrogenation followed by aromatization, leading to increased aromatic production.