RESUMEN
Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Aß) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Aß and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC50: 4.16 ± 0.063 µM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Aß aggregation at 0.5, 10 and 20 µM doses. Approximately, 50% of AChE-induced Aß aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.
RESUMEN
BACKGROUND: BACE1 (beta-site amyloid precursor protein (APP) cleaving enzyme) is a key target for Alzheimer's disease research because it catalyses the rate-limiting step in the formation of amyloid protein (Aß). Natural dietary flavonoids have gained a lot of interest as potential Alzheimer's therapy candidates because of their anti-amyloidogenic, antioxidative, and anti-inflammatory properties. More research is needed, however, to learn more about the specific routes through which flavonoids may have neuroprotective benefits in Alzheimer's disease. OBJECTIVE: Here, we report an in silico molecular modeling study for natural compounds, particularly flavonoids, as BACE-1 inhibitors. METHODS: The interactions of flavonoids with the BACE-1 catalytic core were disclosed by demonstrating the predicted docking pose of flavonoids with BACE-1. The stability of flavonoids BACE-1 complex was analyzed by molecular dynamic simulation (standard dynamic cascade). RESULTS: Our findings imply that these flavonoids, which have methoxy group instead of hydroxy may be promising BACE1 inhibitors that could reduce Aß formation in Alzheimer's disease. The molecular docking study revealed that flavonoids e bind with the BACE1's wide active site along with the catalytic residues Asp32 and Asp228. Further molecular dynamic investigation revealed that the average RMSD for all complexes ranged from 2.05 to 2.32 Å, indicating that the molecules were relatively stable during MD simulation. The RMSD analyses demonstrate that the flavonoids were structurally stable during the MD simulation. The RMSF was utilised to study the time-dependent fluctuation of the complexes. The N-terminal (~2.5 Å) fluctuates less than the C-terminal (~6.5 Å). Rutin and Hesperidin were highly stable in the catalytic region as compared to other flavonoids like Rhoifolin, Hesperidin, Methylchalcone, Phlorizin and Naringin. CONCLUSION: We were able to justify the flavonoids' selectivity for BACE-1 and crossing BBB for the treatment of Alzheimer's disease by using a combination of molecular modelling tools.
Asunto(s)
Enfermedad de Alzheimer , Hesperidina , Humanos , Flavonoides/farmacología , Flavonoides/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Simulación de Dinámica MolecularRESUMEN
With the rollout of the world's largest vaccine drive for SARS-CoV-2 by the Government of India on January 16 2021, India had targeted to vaccinate its entire population by the end of 2021. Struggling with vaccine procurement and production earlier, India overcome these hurdles, but the Indian population still did not seem to be mobilizing swiftly toward vaccination centers. The severe second wave has slowed the vaccination pace and was also one of the major contributing factors to vaccine hesitancy. To understand the nature of vaccine hesitancy and its underlying factors, we conducted extensive online and offline surveys in Varanasi and adjoining regions using structured questions. Most respondents were students (0.633). However, respondents from other occupations, such as government officials (0.10), have also participated in the study. Interestingly, most people (0.75) relied on fake news and did not take COVID-19 seriously. Most importantly, we noticed that a substantial proportion of respondents (relative frequency 0.151; mean age 24.8 years) reported that they were still not interested in vaccination. We observed a significant association between vaccine hesitancy and socioeconomic status (χ2 = 307.6, p < 0.001). However, we failed to detect any association between vaccine hesitancy and gender (χ2 = 0.007, p > 0.5). People who have neither been vaccinated nor have ever been infected may become the medium for spreading the virus and creating new variants, which may lead to the vaccine-resistant variant. We expect this extensive survey to help the Government upgrade their vaccination policies for COVID-19 in North India.
Asunto(s)
COVID-19 , Vacunas , Humanos , Adulto Joven , Adulto , SARS-CoV-2 , Vacilación a la Vacunación , COVID-19/epidemiología , COVID-19/prevención & control , Aceptación de la Atención de SaludRESUMEN
A novel series of 5,6-diphenyl-1,2,4-triazine-3-thiol derivatives were designed, synthesized, and screened for their inhibitory potential against COX-2 and 5-LOX enzymes. The compounds from the series have shown moderate to excellent inhibitory potential against both targets. Compound 6k showed the inhibitions against COX-2 (IC50 = 0.33 ± 0.02 µM) and 5-LOX inhibition (IC50 = 4.90 ± 0.22 µM) which was better than the standard celecoxib (IC50 = 1.81 ± 0.13 µM) for COX-2 and zileuton (IC50 = 15.04 ± 0.18 µM) for 5-LOX respectively. Further investigation on the selected derivative 6k in rat paw edema models revealed significant anti-inflammatory efficacy. Compound 6k has also shown negligible ulcerogenic liability as compared to indomethacin. Moreover, in vivo biochemical analysis also established the compound's antioxidant properties. Compounds 6c and 6k were also observed to be devoid of cardiotoxicity post-myocardial infarction in rats. The molecular docking and dynamics simulation studies of the most active derivative 6k affirmed their consentient binding interactions with COX-2 specific ravine and cleft of 5-LOX.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Lipooxigenasa , Ratas , Animales , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Lipooxigenasa/química , Araquidonato 5-Lipooxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Cardiotoxicidad , Compuestos de Sulfhidrilo/farmacología , Antiinflamatorios no Esteroideos/farmacología , Edema/inducido químicamente , Edema/tratamiento farmacológico , Relación Estructura-Actividad , Estructura MolecularRESUMEN
Fungal infections in humans are responsible for mild to severe infections resulting in systemic effects that cause a large amount of mortality. Invasive fungal infections are having similar symptomatic effects to those of COVID-19. The COVID-19 patients are immunocompromised in nature and have a high probability of developing severe fungal infections, resulting in the development of further complications. The existing antifungal therapy has associated problems related to the development of drug resistance, being sub-potent in nature, and the presence of undesirable toxic effects. The fungal dihydrofolate reductase is an essential enzyme involved in the absorption of dietary folic acid and its conversion into tetrahydrofolate, which is a coenzyme required for the biosynthesis of the fungal nucleotides. Thus, in the current study, an attempt has been made to identify potential folate inhibitors of Candida albicans by a computational drug repurposing approach. Based upon the molecular docking simulation-based virtual screening followed by the molecular dynamic simulation of the macromolecular complex, benzbromarone has been identified as a potential anti-folate agent for the development of a novel therapy for the treatment of candidiasis.
Asunto(s)
COVID-19 , Antagonistas del Ácido Fólico , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Benzbromarona/farmacología , Candida albicans , Reposicionamiento de Medicamentos , Antagonistas del Ácido Fólico/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento MolecularRESUMEN
As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer's disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule SD-30, having hydrogen bond donor (HBD) at para-position, showed maximum AChE inhibition potential (IC50 13.86 ± 0.163 µM) in the indene series. Further, the SD-30 showed maximum BuChE inhibition potential (IC50 = 48.55 ± 0.136 µM) with a selectivity ratio of 3.50 and reasonable antioxidant properties compared to ascorbic acid (using DPPH assay). SD-30 (at a dose level: of 10 µM, 20 µM) effectively inhibited AChE-induced Aß aggregation and showed no significant toxicity up to 30 mM against SH-SY5Y cell lines.
RESUMEN
Novel N-Benzylpyrrolidine hybrids were designed, synthesized, and tested against multiple in-vitro and in-vivo parameters. Among all the synthesized molecules, 8f and 12f showed extensive inhibition against beta-secretase-1 (hBACE-1), human acetylcholinesterase (hAChE) & human butyrylcholinesterase (hBuChE). These molecules are also endowed with significant AChE-peripheral anionic site (PAS) binding capability, blood-brain barrier permeability, potential disassembly of Aß aggregates along with neuroprotection ability on SHSY-5Y cell lines. Results of the Y-Maze and Morris water maze test concluded that compounds 8f and 12f ameliorated cognitive dysfunction induced by scopolamine and Aß. The ex-vivo activity was executed on rat's brain homogenate indicating a reduction in AChE level and oxidative stress. The pharmacokinetic investigation ascertained considerable oral absorption profile of the lead 12f. The results of the in silico docking studies and molecular dynamics simulations demonstrated stable interactions of compounds 8f and 12f with the target residues of hAChE, hBuChE and hBACE-1.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Fármacos Neuroprotectores/farmacología , Oxadiazoles/farmacología , Pirrolidinas/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Oxadiazoles/síntesis química , Oxadiazoles/química , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Multitarget molecular hybrids of N-benzyl pyrrolidine derivatives were designed, synthesized, and biologically evaluated for the treatment of Alzheimer's disease (AD). Among the synthesized compounds, 4k and 4o showed balanced enzyme inhibitions against cholinesterases (AChE and BChE) and BACE-1. Both leads showed considerable PAS-AChE binding capability, excellent brain permeation, potential disassembly of Aß aggregates, and neuroprotective activity against Aß-induced stress. Compounds 4k and 4o also ameliorated cognitive dysfunction against the scopolamine-induced amnesia model in the Y-maze test. The ex vivo study signified attenuated brain AChE activity and antioxidant potential of compounds 4k and 4o. Furthermore, compound 4o also showed improvement in Aß-induced cognitive dysfunction by the Morris water maze test with excellent oral absorption characteristics ascertained by the pharmacokinetic study. In silico molecular docking and dynamics simulation studies of leads suggested their consensual binding affinity toward PAS-AChE in addition to aspartate dyad of BACE-1.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Fármacos Neuroprotectores/farmacología , Pirrolidinas/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Butirilcolinesterasa/metabolismo , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Ratas Wistar , Escopolamina , Relación Estructura-ActividadRESUMEN
The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). In the present study, virtual screening and molecular docking are performed to identify the potential hits. Docking-post processing (DPP) and pose filtration protocols against AChE and BChE resulted in three hits (AW00308, HTS04089, and JFD03947). Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and molecular dynamics simulation analysis affirmed the stability and binding pattern of the docked complex JFD03947, which was further synthesized and evaluated for in vitro cholinesterase inhibition (AChE, IC50 = 0.062 µM; BChE, IC50 = 1.482 µM) activity. The enzyme kinetics study of the JFD03947 against hAChE and hBChE suggested a mixed type of inhibition. The results of thioflavin T-assay also elicited anti-Aß aggregation activity by JFD03947. Further, biological evaluation of identified compound JFD03947 also showed neuroprotective ability against the SH-SY5Y neuroblastoma cell lines.
Asunto(s)
Acetilcolinesterasa/química , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Butirilcolinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Biología Computacional/métodos , Diseño de Fármacos , Dominio Catalítico , Inhibidores de la Colinesterasa/química , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Agregado de ProteínasRESUMEN
Thirty ferulic acid-based 1,3,4-oxadiazole molecular hybrids were designed, synthesized, and screened them for multifunctional inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and beta-secretase-1 (BACE-1). Compound 6j was the most potent inhibitor of AChE (IC50 = 0.068 µM). It also showed equipotent inhibition of BChE and BACE-1 with IC50 values of 0.218 µM and 0.255 µM, respectively. Compound 6k possessed the most significant inhibition of BChE and BACE-1 with IC50 values, 0.163 µM and 0.211 µM, respectively. Compounds 6j and 6k elicited significant displacement of propidium iodide from PAS-AChE, excellent BBB permeability in PAMPA assay, and anti-Aß aggregatory activity in self- and AChE-induced experiments with neuroprotective activity towards neuroblastoma SH-SY5Y cells. The in vivo behavioral studies suggested amelioration of cognitive dysfunction by 6j and 6k in the Y maze test. The ex vivo study signified brain AChE inhibition and antioxidant activity from these compounds. Moreover, 6j showed improvement in learning and memory behavior in the Aß-induced ICV rat model by Morris water maze test with excellent oral absorption characteristics ascertained by pharmacokinetic studies.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Ácidos Cumáricos/farmacología , Diseño de Fármacos , Fármacos Neuroprotectores/farmacología , Oxadiazoles/farmacología , Acetilcolinesterasa/metabolismo , Administración Oral , Enfermedad de Alzheimer/metabolismo , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Amnesia/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Butirilcolinesterasa/metabolismo , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Ácidos Cumáricos/síntesis química , Ácidos Cumáricos/química , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Oxadiazoles/química , Agregado de Proteínas/efectos de los fármacos , Ratas , Ratas Wistar , Escopolamina , Relación Estructura-ActividadRESUMEN
The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50â¯=â¯0.054⯵M), butyrylcholinesterase (hBChE, IC50â¯=â¯0.787⯵M) and beta-secretase-1 (hBACE-1, IC50â¯=â¯0.098⯵M). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Kiâ¯=â¯0.030⯵M). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Aß aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Aß-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Fármacos Neuroprotectores/química , Oxadiazoles/química , Piperazinas/química , Piridinas/química , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/psicología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Antioxidantes/química , Antioxidantes/farmacología , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacocinética , Disfunción Cognitiva/tratamiento farmacológico , Femenino , Humanos , Cinética , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores/farmacocinética , Oxadiazoles/farmacocinética , Piperazinas/farmacocinética , Agregado de Proteínas , Piridinas/farmacocinética , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Multitargeted hybrids of N-benzylpiperidine and substituted 5-phenyl-1,3,4-oxadiazoles were designed, synthesized, and evaluated against Alzheimer's disease (AD). Tested compounds exhibited moderate to excellent inhibition against human acetylcholinesterase (hAChE), butyrylcholinesterase (hBChE), and beta-secretase-1 (hBACE-1). The potential leads 6g and 10f exhibited balanced inhibitory profiles against all the targets, with a substantial displacement of propidium iodide from the peripheral anionic site of hAChE. Hybrids 6g and 10f also elicited favorable permeation across the blood-brain barrier and were devoid of neurotoxic liability toward SH-SY5Y neuroblastoma cells. Both leads remarkably disassembled Aß aggregation in thioflavin T-based self- and AChE-induced experiments. Compounds 6g and 10f ameliorated scopolamine-induced cognitive dysfunctions in the Y-maze test. The ex vivo studies of rat brain homogenates established the reduced AChE levels and antioxidant activity of both compounds. Compound 6g also elicited noteworthy improvement in Aß-induced cognitive dysfunctions in the Morris water maze test with downregulation in the expression of Aß and BACE-1 proteins corroborated by Western blot and immunohistochemical analysis. The pharmacokinetic study showed excellent oral absorption characteristics of compound 6g. The in silico molecular docking and dynamics simulation studies of lead compounds affirmed their consensual binding interactions with PAS-AChE and aspartate dyad of BACE-1.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Oxadiazoles/uso terapéutico , Piperidinas/uso terapéutico , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/metabolismo , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Oxadiazoles/farmacología , Piperidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC50â¯=â¯1.098⯵M; Kiâ¯=â¯0.960⯵M). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aß aggregation (38.2-65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Desarrollo de Medicamentos , Oxadiazoles/farmacología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/síntesis química , Disfunción Cognitiva/inducido químicamente , Relación Dosis-Respuesta a Droga , Electrophorus , Caballos , Humanos , Masculino , Memoria/efectos de los fármacos , Ratones , Estructura Molecular , Oxadiazoles/administración & dosificación , Oxadiazoles/síntesis química , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Agregado de Proteínas/efectos de los fármacos , Escopolamina/administración & dosificación , Relación Estructura-ActividadRESUMEN
The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N-benzylpiperidine analogs (17-31 and 32-46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and ß-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80⯵M. Meanwhile, both these compounds inhibited self- and AChE-induced Aß aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aß aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aß1-42-induced cognitive impairment was also observed by compound 41 in the Morris water maze experiment with significant oral absorption characteristics ascertained by the pharmacokinetic studies.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de la Colinesterasa/síntesis química , Diseño de Fármacos , Piperidinas/farmacología , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/psicología , Animales , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Inhibidores de la Colinesterasa/farmacología , Disfunción Cognitiva , Humanos , Ratones , Piperidinas/síntesis química , Agregación Patológica de Proteínas/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC50; 0.2⯱â¯0.01⯵M) compared to standard donepezil (AChE, IC50: 0.1⯱â¯0.002⯵M). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22⯱â¯1.11%) and showed good CNS permeability in PAMPA-BBB assay (Pe(exp), 6.93⯱â¯0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Nootrópicos/farmacología , Piperazinas/farmacología , Triazinas/farmacología , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Animales , Antioxidantes/síntesis química , Antioxidantes/metabolismo , Antioxidantes/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/metabolismo , Compuestos de Bifenilo/farmacología , Dominio Catalítico , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Diseño de Fármacos , Humanos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Nootrópicos/síntesis química , Nootrópicos/metabolismo , Piperazinas/síntesis química , Piperazinas/metabolismo , Unión Proteica , Torpedo , Triazinas/síntesis química , Triazinas/metabolismoRESUMEN
Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Nootrópicos/uso terapéutico , para-Aminobenzoatos/uso terapéutico , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Animales , Encéfalo/metabolismo , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Dominio Catalítico , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/toxicidad , Diseño de Fármacos , Femenino , Cinética , Masculino , Memoria/efectos de los fármacos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Nootrópicos/síntesis química , Nootrópicos/química , Nootrópicos/toxicidad , Relación Estructura-Actividad Cuantitativa , Ratas , Semicarbazonas/síntesis química , Semicarbazonas/química , Semicarbazonas/uso terapéutico , Semicarbazonas/toxicidad , para-Aminobenzoatos/síntesis química , para-Aminobenzoatos/química , para-Aminobenzoatos/toxicidadRESUMEN
BACKGROUND: Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial γ-aminobutyric acid (GABA) uptake in vitro. However, nipecotic acid does not readily cross the blood-brain barrier (BBB) following peripheral administration, owing to its hydrophilic nature. OBJECTIVE: A series of substituted acetonaphthones tethered nipecotic acid derivatives were designed and synthesized with an aim to improve the lipophilicity and the blood-brain barrier (BBB) permeation. METHODS: Synthesized compounds were tested in mice models of PTZ, pilocarpine, and DMCM induced epilepsy, in vivo. The rota-rod test was performed to determine the acute neurotoxicity of the potential leads (4a, 4b, and 4i). These potential hybrids were also evaluated for their ability to cross the BBB by an in vitro parallel artificial membrane permeability BBB assay (PAMPA-BBB). The leads were subjected to in silico molecular docking and dynamics studies on homology modelled protein of human GABA (γ-amino butyric acid) transporter 1 (GAT1) and prediction of their pharmacokinetic properties. RESULT: Amongst the synthesized derivatives, compounds 3a, 3b, 3i, 4a, 4b, and 4i exhibited increased latency of seizures against subcutaneous pentylenetetrazole (scPTZ) induced seizures in mice. Derivatives 4a, 4b, 4i were more effective compared to nipecotic acid ester counterparts 3a, 3b and 3i placing the importance of the presence of free carboxyl group in the centre. The findings revealed that 4i was comparatively more permeable (Pe= 8.89) across BBB than the standard tiagabine (Pe= 7.86). In silico studies proved the consensual interactions of compound 4i with the active binding pocket. CONCLUSION: Some nipecotic acid-acetonaphthone hybrids with considerable anti-epileptic activity, drug like properties and the ability to permeate the BBB have been successfully synthesized.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Naftalenos/uso terapéutico , Ácidos Nipecóticos/uso terapéutico , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Drosophila , Diseño de Fármacos , Femenino , Proteínas Transportadoras de GABA en la Membrana Plasmática/química , Inhibidores de Recaptación de GABA/síntesis química , Inhibidores de Recaptación de GABA/química , Inhibidores de Recaptación de GABA/uso terapéutico , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Naftalenos/síntesis química , Naftalenos/química , Ácidos Nipecóticos/síntesis química , Ácidos Nipecóticos/química , TiagabinaRESUMEN
Some novel indolizine derivatives were synthesized by bioisosteric modification of imidazo[1,2-a]pyridine for anti-inflammatory activity. The physicochemical characterization and structure of compounds were elucidated by state of the art spectroscopic technique. Induced fit docking was performed for initial screening to elucidate the interactions with corresponding amino acids of cyclooxygenase (COX-1, COX-2) and lipoxygenase (LOX) enzymes. The target compounds 53-60 were then evaluated against in vivo carrageenan and arachidonic acid induced rat paw edema models for anti-inflammatory activity. Amongst all the synthesized derivatives, compound 56 showed the significant anti-inflammatory activity in both rat paw edema models with very less ulcerogenic liability in comparison to standard diclofenac, celecoxib, and zileuton. The compounds 56 was further assessed to observe in vitro enzyme inhibition assay on both cyclooxygenase and lipoxygenase enzyme where it showed a preferential and selective non-competitive enzyme inhibition towards the COX-2 (IC50=14.91µM, Ki=0.72µM) over COX-1 (IC50>50µM) and a significant non-competitive inhibition of soybean lipoxygenase enzyme (IC50=13.09µM, Ki=0.92µM). Thus, in silico, in vivo, and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs.