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Considering the failure of many enzyme inhibitors for Alzheimer's disease (AD), research is now focused on multi-target directed drug discovery. In this paper, inhibition of two essential enzymes implicated in AD pathologies, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), has been explored. Taking clues from our previous work, 41 novel indol-3-yl phenyl allylidene hydrazine carboximidamide derivatives were synthesized. The results indicated that compounds inhibited both enzymes in micromolar concentrations. Compound 1l is proposed as the most active. In silico, it was seen to occupy the binding pocket of AChE and BACE 1. The ADME predictions showed that these compounds have acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and BACE 1 dual inhibition as a promising strategy for AD treatment.
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Colchicine, one of the oldest anti-inflammatory natural products still used clinically, inhibits NF-κB signaling and NLRP3 inflammasome activation. Despite its cytotoxicity and narrow therapeutic range, colchicine continues to intrigue medicinal chemists exploring its anti-inflammatory potential. This study aimed to investigate the colchicine scaffold for its role in Alzheimer's disease by targeting neuroinflammation and cholinesterases. Molecular docking revealed that colchicine's hydrophobic trimethoxyphenyl framework can potentially bind to the peripheral anionic site of cholinesterases. Hybrid structures combining colchicine with aryl/alkyl amines were designed to bind both peripheral and catalytic sites of cholinesterases. We describe here the design, synthesis, and in vitro cytotoxicity evaluation of these colchicine-aryl/alkyl amine hybrids, along with their in silico interactions with the cholinesterase active site gorge. Nontoxic analogs demonstrating strong cholinesterase binding affinity were further evaluated for their anticholinesterase and antineuroinflammatory activities. The colchicine-donepezil hybrid, SBN-284 (3x), inhibited both acetylcholinesterase and butyrylcholinesterase as well as the NLRP3 inflammasome complex at low micromolar concentrations. It achieved this through noncompetitive inhibition, occupying the active site gorge and interacting with both peripheral and catalytic anionic sites of cholinesterases. Analog 3x was shown to cross the blood-brain barrier and exhibited no toxicity to neuronal cells, primary macrophages, or epithelial fR2 cells. These findings highlight the potential of this lead compound for further preclinical investigation as a promising anti-Alzheimer agent.
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Inhibidores de la Colinesterasa , Colchicina , Inflamasomas , Simulación del Acoplamiento Molecular , Proteína con Dominio Pirina 3 de la Familia NLR , Colchicina/farmacología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Inflamasomas/metabolismo , Humanos , Ratones , Aminas/farmacología , Aminas/química , Donepezilo/farmacología , Piperidinas/farmacología , Piperidinas/químicaRESUMEN
Natural products have always served as an important source of drugs for treating various diseases. Among various privileged natural product scaffolds, the benzopyrone class of compounds has a substantial presence among biologically active compounds. One of the pioneering anticoagulant drugs, warfarin approved in 1954 bears a benzo-α-pyrone (coumarin) nucleus. The widely investigated psoriasis drugs, methoxsalen, and trioxsalen, also contain a benzo-α-pyrone nucleus. Benzo-γ-pyrone (chromone) containing drugs, cromoglic acid, and pranlukast were approved as treatments for asthma in 1982 and 2007, respectively. Numerous other small molecules with a benzopyrone core are under clinical investigation. The present review discusses the discovery, absorption, distribution, metabolism, excretion properties, and synthetic approaches for the Food and Drug Administration-approved and clinical-stage benzopyrone class of compounds. The role of the pyrone core in biological activity has also been discussed. The present review unravels the potential of benzopyrone core in medicinal chemistry and drug development.
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Aprobación de Drogas , Descubrimiento de Drogas , United States Food and Drug Administration , Humanos , Estados Unidos , Animales , Pironas/química , Pironas/farmacologíaRESUMEN
Heterocyclic compounds play a crucial role in the discovery of therapeutics. Alzheimer's disease (AD) is an unfathomable sporadic neurodegenerative disorder that involves multiple pathological pathways. The failure of current single-target small molecules to address AD's underlying causes has prompted interest in discovering multi-target directed ligands (MTDLs) to slow down the disease's progression. Herein we report the synthesis and biological evaluation of indole-piperidine amides as MTDLs for AD. The 5,6-dimethoxy-indole N-(2-(1-benzylpiperidine) carboxamide (23a) inhibits hAChE and hBACE-1 with IC50 values of 0.32 and 0.39 µM, respectively. The MTDL 23a is a mixed-type inhibitor of both hAChE and hBACE-1 with Ki values of 0.26 µM and 0.46 µM, respectively. The MD simulation studies revealed that both AChE and BACE-1 experience minor conformational changes on binding with 23a. In the PAMPA-BBB assay, analog 23a demonstrated CNS permeability, indicating the possibility for future investigation in preclinical models of AD.
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Enfermedad de Alzheimer , Colinesterasas , Humanos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Barrera Hematoencefálica/metabolismo , Inhibidores de la Colinesterasa/química , Colinesterasas/metabolismo , Diseño de Fármacos , Indoles/farmacología , Indoles/metabolismo , Piperidinas , Relación Estructura-Actividad , Amidas/química , Amidas/farmacologíaRESUMEN
Caffeine is one of the privileged natural products that shows numerous effects on the central nervous system. Herein, thirty-one caffeine-based amide derivatives were synthesized and evaluated in vitro for their anticholinesterase activity. The introduction of the amide group to the caffeine core augmented its anticholinesterase activity from an IC50 value of 128 to 1.32 µM (derivative, 6i). The SAR study revealed that N7 substitution on caffeine core is favorable over N1, and the presence of amide 'carbonyl' as a part of the linker contributes to the biological activity. The caffeine core of 6i exhibits interactions with the peripheral anionic site, whereas the N-benzyl ring fits nicely inside the catalytic anionic site. Analog 6i inhibits AChE in a mixed-type mode (Ki 4.58 µM) and crosses the BBB in an in-vitro PAMPA assay. Compound 6i has a descent metabolic stability in MLM (>70% remaining after 30 min) and favorable oral pharmacokinetics in Swiss albino mice.
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Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Ratones , Animales , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/metabolismo , Cafeína/farmacología , Acetilcolinesterasa/metabolismo , Barrera Hematoencefálica , Amidas/farmacología , Amidas/metabolismo , Simulación del Acoplamiento Molecular , Enfermedad de Alzheimer/metabolismo , Relación Estructura-ActividadRESUMEN
The chromone alkaloid is one of the classical pharmacophores for cyclin-dependent kinases (CDKs) and represents the first CDK inhibitor to reach clinical trials. Rohitukine (1), a chromone alkaloid isolated from Dysoxylum binectariferum inspired the discovery of several clinical candidates. The N-oxide derivative of rohitukine occurs naturally, with no reports on its biological activity. Herein, we report isolation, biological evaluation, and synthetic modification of rohitukine N-oxide for CDK9/T1 inhibition and antiproliferative activity in cancer cells. Rohitukine N-oxide (2) inhibits CDK9/T1 (IC50 7.6 µM) and shows antiproliferative activity in the colon and pancreatic cancer cells. The chloro-substituted styryl derivatives, 2b, and 2l, inhibit CDK9/T1 with IC50 values of 0.17 and 0.15 µM, respectively. These derivatives display cellular antiproliferative activity in HCT 116 (colon) and MIA PaCa-2 (pancreatic) cancer cells with GI50 values of 2.5-9.7 µM with excellent selectivity over HEK293 (embryonic kidney) cells. Both analogs induce cell death in MIA PaCa-2 cells via inducing intracellular ROS production, reducing mitochondrial membrane potential, and inducing apoptosis. These analogs are metabolically stable in liver microsomes and have a decent oral pharmacokinetics in BALB/c mice. The molecular modeling studies indicated their strong binding at the ATP-binding site of CDK7/H and CDK9/T1.
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Alcaloides , Antineoplásicos , Neoplasias Pancreáticas , Ratones , Animales , Humanos , Células HEK293 , Cromonas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Quinasas Ciclina-Dependientes , Alcaloides/química , Neoplasias Pancreáticas/tratamiento farmacológico , Quinasa 9 Dependiente de la CiclinaRESUMEN
The multifaceted nature of Alzheimer's disease (AD) indicates the need for multitargeted agents as potential therapeutics. Both cholinesterases (ChEs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), play a vital role in disease progression. Thus, inhibiting both ChEs is more beneficial than only one for effectively managing AD. The present study provides a detailed lead optimization of the e-pharmacophore-generated pyridinium styryl scaffold to discover a dual ChE inhibitor. A structure-activity relationship analysis indicated the importance of three structural fragments, methoxy-naphthyl, vinyl-pyridinium, and substituted-benzyl, in a dual ChE inhibitor pharmacophore. The optimized 6-methoxy-naphthyl derivative, 7av (SB-1436), inhibits EeAChE and eqBChE with IC50 values of 176 and 370 nM, respectively. The kinetic study has shown that 7av inhibits AChE and BChE in a non-competitive manner with ki values of 46 and 115 nM, respectively. The docking and molecular dynamics simulation demonstrated that 7av binds with the catalytic and peripheral anionic sites of AChE and BChE. Compound 7av also significantly stops the self-aggregation of Aß. The data presented herein indicate the potential of 7av for further investigation in preclinical models of AD.
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Coumarin is a naturally occurring bioactive pharmacophore with wide occurrence among central nervous system (CNS)-active small molecules. 8-Acetylcoumarin, one of the natural coumarins, is a mild inhibitor of cholinesterases and ß-secretase, which are vital targets of Alzheimer's disease. Herein, we synthesized a series of coumarin-triazole hybrids as potential multitargeted drug ligands (MTDLs) with better activity profiles. The coumarin-triazole hybrids occupy the cholinesterase active site gorge from the peripheral to the catalytic anionic site. The most active analogue, 10b, belonging to the 8-acetylcoumarin core, inhibits acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-secretase-1 (BACE-1) with IC50 values of 2.57, 3.26, and 10.65 µM, respectively. The hybrid, 10b, crosses the blood-brain barrier via passive diffusion and inhibits the self-aggregation of amyloid-ß monomers. The molecular dynamic simulation study reveals the strong interaction of 10b with three enzymes and forming stable complexes. Overall, the results warrant a detailed preclinical investigation of the coumarin-triazole hybrids.
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The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Embelia ribes Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin-aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC50 values of 0.15, 1.6, and 0.6 µM, respectively. It inhibits both ChEs noncompetitively with ki values of 0.21 and 1.3 µM, respectively. It is orally bioavailable, crosses blood-brain barrier (BBB), inhibits Aß self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.
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Enfermedad de Alzheimer , Ratones , Animales , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/metabolismo , Barrera Hematoencefálica/metabolismo , Inhibidores de la Colinesterasa/química , Aminas , Relación Estructura-Actividad , Ratones Endogámicos C57BL , Escopolamina/farmacología , Escopolamina/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Diseño de Fármacos , Simulación del Acoplamiento MolecularRESUMEN
Natural products have been a great source of leads for cancer drug discovery. The cyclin-dependent kinases (CDKs) play a vital role in the initiation and progression of cancer. The CDK-activating kinase, CDK7/cyclin H/MAT1, has recently gained tremendous attention in targeted cancer drug discovery. Herein, we screened a small library of pure natural products in an ADP-Glo CDK7/H kinase assay that yielded a series of furano- and naphthoflavonoids among actives. Pongol (SBN-88), the hydroxy-substituted furanoflavonoid, inhibits CDK7/H as well as CDK9/T1 with IC50 values of 0.93 and 0.83 µM, respectively, and >20-fold selectivity over CDK2/E1 (IC50 > 20 µM). The molecular docking and molecular dynamics simulation revealed that the presence of phenolic -OH in pongol is vital for kinase inhibition, as its absence resulted in a significant loss in activity (e.g., lanceolatin B). The prime MM-GBSA calculations revealed the presence of strong lipophilic and H-bonding interactions of pongol with CDKs.
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OBJECTIVE: The current study evaluated various new colchicine analogs for their anticancer activity and to study the primary mechanism of apoptosis and in vivo antitumor activity of the analogs with selective anticancer properties and minimal toxicity to normal cells. METHODS: Sulforhodamine B (SRB) assay was used to screen various colchicine analogs for their in vitro cytotoxicity. The effect of N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(pyrrolidine-1-yl)5,6,7,9-tetrahydrobenzo[a] heptalene-7-yl] acetamide (IIIM-067) on clonogenicity, apoptotic induction, and invasiveness of A549 cells was determined using a clonogenic assay, scratch assay, and staining with 4',6-diamidino-2-phenylindole (DAPI) and annexin V/propidium iodide. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were observed using fluorescence microscopy. Western blot analysis was used to quantify expression of proteins involved in apoptosis, cell cycle, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Pharmacokinetic and in vivo efficacy studies against Ehrlich ascites carcinoma (EAC) and Ehrlich solid tumor models were conducted using Swiss albino mice. RESULTS: IIIM-067 showed potent cytotoxicity and better selectivity than all other colchicine analogs screened in this study. The selective activity of IIIM-067 toward A549 cells was higher among other cancer cell lines, with a selectivity index (SI) value of 2.28. IIIM-067 demonstrated concentration- and time-dependent cytotoxicity against A549 cells with half-maximal inhibitory concentration values of 0.207, 0.150 and 0.106 µmol/L at 24, 48 and 72 h, respectively. It also had reduced toxicity to normal cells (SI > 1) than the parent compound colchicine (SI = 1). IIIM-067 reduced the clonogenic ability of A549 cells in a dose-dependent manner. IIIM-067 enhanced ROS production from 24.6% at 0.05 µmol/L to 82.1% at 0.4 µmol/L and substantially decreased the MMP (100% in control to 5.6% at 0.4 µmol/L). The annexin V-FITC assay demonstrated 78% apoptosis at 0.4 µmol/L. IIIM-067 significantly (P < 0.5) induced the expression of various intrinsic apoptotic pathway proteins, and it differentially regulated the PI3K/AKT/mTOR signaling pathway. Furthermore, IIIM-067 exhibited remarkable in vivo anticancer activity against the murine EAC model, with tumor growth inhibition (TGI) of 67.0% at a dose of 6 mg/kg (i.p.) and a reduced mortality compared to colchicine. IIIM-067 also effectively inhibited the tumor growth in the murine solid tumor model with TGI rates of 48.10%, 55.68% and 44.00% at doses of 5 mg/kg (i.p.), 6 mg/kg (i.p.) and 7 mg/kg (p.o.), respectively. CONCLUSION: IIIM-067 exhibited significant anticancer activity with reduced toxicity both in vitro and in vivo and is a promising anticancer candidate. However, further studies are required in clinical settings to fully understand its potential.
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Antineoplásicos Fitogénicos , Proteínas Proto-Oncogénicas c-akt , Animales , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Antineoplásicos Fitogénicos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Colchicina/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Mamíferos/metabolismoRESUMEN
Berberrubine is a naturally occurring isoquinoline alkaloid and a bioactive metabolite of berberine. Berberine exhibits a wide range of pharmacological activities, including cholinesterase inhibition. The cholinesterase inhibitors provide symptomatic treatment for Alzheimer's disease; however, multitarget-directed ligands have the potential as disease-modifying therapeutics. Herein, we prepared a series of C9-substituted berberrubine derivatives intending to discover dual cholinesterase and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Most synthesized derivatives possessed balanced dual inhibition (AChE and BChE) activity in the submicromolar range and a moderate inhibition against BACE-1. Two most active ester derivatives, 12a and 11d, display inhibition of AChE, BChE, and BACE-1. The 3-methoxybenzoyl ester derivative, 12a, inhibits electric eel acetylcholinesterase (EeAChE), equine serum butyrylcholinesterase (eqBChE), and human hBACE-1 with IC50 values of 0.5, 4.3, and 11.9 µM, respectively and excellent BBB permeability (Pe = 8 × 10-6 cm/s). The ester derivative 12a is metabolically unstable; however, its ether analog 13 is stable in HLM and exhibits inhibition of AChE, BChE, and BACE-1 with IC50 values of 0.44, 3.8, and 17.9 µM, respectively. The ether analog also inhibits self-aggregation of Aß and crosses BBB (Pe = 7.3 × 10-6 cm/s). Administration of 13 at 5 mg/kg (iv) in Wistar rats showed excellent plasma exposure with AUC0-∞ of 28,834 ng min/ml. In conclusion, the multitargeted berberrubine ether derivative 13 is CNS permeable and has good ADME properties.
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Enfermedad de Alzheimer , Berberina , Ratas , Animales , Caballos , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/metabolismo , Berberina/farmacología , Relación Estructura-Actividad , Éter/uso terapéutico , Simulación del Acoplamiento Molecular , Ratas Wistar , Inhibidores de la Colinesterasa , Éteres de Etila/uso terapéutico , Éteres/uso terapéutico , Estructura MolecularRESUMEN
Rumex abyssinicus Jacq. is a perennial medicinal herb widely used in traditional medicine to treat many diseases. Phytochemicals of the plant were isolated using column chromatography and thin layer chromatography techniques. Extract, fractions and pure compounds were screened for antimicrobial activity against sensitive and multi-drug resistant microbes and their cytotoxicity was performed on different cancer cell lines. The mechanism of action of purified helminthosporin as well as the potent fraction containing a mixture of two compounds was assessed. Fraction R7C3 was the most potent antibacterial with the lowest MIC value of 0.12 µg/mL. Helminthosporin was the most potent compound with the lowest MIC value of 1.95 µg/mL. The compound was more potent than the antibiotic chloramphenicol against multi-drug resistant (MDR) bacteria with MIC equal to 16 µg/mL. The fraction and helminthosporin were shown to destroy the cell wall of the yeast and bacteria, and DNA fragmentation effect on the genome of Candida albicans and Bacillus cereus. Helminthosporin was the most cytotoxic compound with IC50 Ë 10 µM. Fraction R7C3 showed the most potent cytotoxic effects on all cancer cell lines, with IC50 ranging from Ë1 to 4.35 ng/mL. Our study is the first report on the mechanism of action of helminthosporin, a potent candidate in the development of new drugs against multi-resistant bacteria and cancer cells. In addition, this study uncovered Rumex abyssinicus as a new source of syringic acid and bis(2-ethyloctyl) phthalate.
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Antiinfecciosos , Antineoplásicos , Rumex , Antiinfecciosos/farmacología , AntibacterianosRESUMEN
Natural products have significantly contributed to drug discovery for neurodegenerative diseases. Caffeine is one of the well-known central nervous system(CNS)-active natural products. Besides its CNS stimulant properties, it is a mild inhibitor of acetylcholinesterase (AChE) and possesses memory-enhancing properties. The present work aimed to improve the AChE inhibition activity of the caffeine. The rationally designed caffeine-based triazoles were synthesized and evaluated in vitro for cholinesterase and ß-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitory activities. The attachment of triazole to the caffeine enhances its AChE inhibition activity from half-maximal inhibitory concentration (IC50 ) of 129 µM to 0.49 µM (derivative, 6l). The caffeine core interacts with the peripheral anionic site, whereas the benzyl triazole occupies the catalytic anionic site located at the bottom of the active site gorge. The structure-activity relationship revealed that the four-atom ester linker is superior to shorter linkers for connecting the caffeine core to the triazole. The 2,6-difluorobenzyl triazole-linked caffeine derivative, 6d, exhibits dual inhibition of AChE and BACE-1 with IC50 values of 1.43 and 10.9 µM, respectively. The derivative 6d inhibits AChE via a mixed-type mode with an inhibition rate constant (Ki ) value of 2.35 µM, which was corroborated by docking studies. The triazole 6d has an acceptable stability profile in human liver microsomes (t1/2 = 54 min) and was found to possess CNS permeability when evaluated using the parallel artificial membrane permeability blood-brain barrier assay. The results presented herein warrant investigating caffeine-based triazoles in preclinical models of Alzheimer's disease.
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Enfermedad de Alzheimer , Productos Biológicos , Humanos , Acetilcolinesterasa/metabolismo , Cafeína/farmacología , Inhibidores de la Colinesterasa/química , Triazoles/farmacología , Estructura Molecular , Relación Estructura-Actividad , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Simulación del Acoplamiento MolecularRESUMEN
[This corrects the article DOI: 10.1039/C3RA42884B.].
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Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder involving various pathological events. The existing options for managing the disease utterly rely on cholinesterase (ChE) inhibitors. In recent years, the dual inhibition of ChEs as a potential AD therapeutics has substantially attracted the attention of medicinal chemists. Recently, we reported benzyl piperidinyl-linked methoxy-naphthamides as dual ChE inhibitors. Herein, we investigated the peripheral anionic binding site-binding methoxy-naphthamide fragment that yielded benzyl piperidinyl-linked benzyl aminobenzamide as another class of dual ChE inhibitors. The 3,5-dimethoxy benzyl aminobenzamide, 8c1, exhibits inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with half-maximal inhibitory concentration values of 0.61 and 2.04 µM, respectively. The enzyme kinetics and molecular modeling study indicated the noncompetitive and mixed-type mode of inhibition for AChE and BChE with ki values of 0.14 and 0.46 µM, respectively. The derivative 8c1 crosses the blood-brain barrier as indicated by the Pe value of 14.34 × 10-6 cm/s in the parallel artificial membrane permeability assay. Besides this, it also inhibits the self-aggregation of amyloid-ß. The results presented herein indicate the potential of benzamide 8c1 for further investigation in preclinical models of AD.
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Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Humanos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/metabolismo , Barrera Hematoencefálica/metabolismo , Simulación del Acoplamiento Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Relación Estructura-ActividadRESUMEN
Plants have immensely contributed to the drug discovery for neurodegenerative diseases. Herein, we undertook the phytochemical investigation of Nardostachys jatamansi (D.Don) DC. rhizomes followed by semisynthetic modifications to discover cholinesterase (ChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors. The 8-acetyl-7-hydroxycoumarin isolated from the bioactive extract moderately inhibits acetylcholinesterase (AChE) and BACE-1 with IC50 values of 22.1 and 17.7â µM, respectively. The semisynthetic trifluoromethyl substituted coumarin chalcone display a 5-fold improvement in BACE-1 inhibition (IC50 3.3â µM). Another semisynthetic derivative, a coumarin-donepezil hybrid, exhibits dual inhibition of both ChEs with IC50 values of 1.22 and 3.09â µM, respectively. Molecular modeling and enzyme kinetics revealed that the coumarin-donepezil hybrid is a non-competitive inhibitor of AChE. It crosses the blood-brain barrier and also inhibits Aß self-aggregation. The results presented herein warrant a detailed investigation of the coumarin-donepezil hybrid in preclinical models of Alzheimer's disease.
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Enfermedad de Alzheimer , Chalconas , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Barrera Hematoencefálica/metabolismo , Chalconas/metabolismo , Inhibidores de la Colinesterasa/química , Colinesterasas/metabolismo , Cumarinas/química , Donepezilo/química , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
The aryl hydrocarbon receptor (AHR) is an environmental sensor that integrates microbial and dietary cues to influence physiological processes within the intestinal microenvironment, protecting against colitis and colitis-associated colorectal cancer development. Rapid tissue regeneration upon injury is important for the reinstatement of barrier integrity and its dysregulation promotes malignant transformation. Here we show that AHR is important for the termination of the regenerative response and the reacquisition of mature epithelial cell identity post injury in vivo and in organoid cultures in vitro. Using an integrative multi-omics approach in colon organoids, we show that AHR is required for timely termination of the regenerative response through direct regulation of transcription factors involved in epithelial cell differentiation as well as restriction of chromatin accessibility to regeneration-associated Yap/Tead transcriptional targets. Safeguarding a regulated regenerative response places AHR at a pivotal position in the delicate balance between controlled regeneration and malignant transformation.
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Mucosa Intestinal , Receptores de Hidrocarburo de Aril , Colon/patología , Mucosa Intestinal/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Células Madre/metabolismoRESUMEN
Rice (Oryza sativa L.) is one of the most important staple foods consumed in many countries of the world. It is mostly consumed in developing countries where different chemical fertilizers are used to improve the productivity of the crop plant. In the present study, endophytic actinomycetes isolated from Rumex dentatus were identified morphologically and by scanning electron microscopy. Butyl isobutyl phthalate (BIBP) was isolated from the root endophyte Streptomyces sp. JR9 using column chromatography and HPLC methods. The compound was tested for its effect on rice seed germination. BIBP, extracts, and isolates were evaluated for their plant growth effect on rice in a growth chamber. Isolates were also screened in vitro for phosphate solubilization activity and enzyme production. Indole-3-acetic acid (IAA) and BIBP produced in extracts were quantified and detected using high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) methods, respectively. BIBP was found to increase the germination of rice seeds by 6 to 12% in treated samples and displayed potent effect at lowest concentration (0.437 µM). Both the compound and the extract depicted significant increases in almost all growth parameters at lowest concentration of 0.125 µg/mL and 62.5 µg/mL, respectively. BIBP also increased significantly shoot length, fresh root, fresh shoot, and dried shoot weight at high concentrations and was more potent than the standard phytohormone IAA. HPLC quantification showed 7.952 µg/mg and 0.371 µg/mg of IAA in extracts of Streptomyces sp. JR9 and the stem endophyte Streptomyces sp. KS3, respectively. IAA containing extract of JR9 increased significantly most growth parameters at lowest concentration (125 µg/mL). The extract of KS3 depicted significant increases in almost all growth parameters at high concentration (500 µg/mL). Our investigation showed that streptomycetes isolated from R. dentatus and BIBP are potent growth promoting agents and can be used in agriculture as bio-fertilizer to improve the growth and productivity of rice. KEY POINTS: ⢠Butyl isobutyl phthalate (BIBP) isolated from endophytic Streptomyces sp. JR9 is a potent rice seed germination activator and promotes significantly the growth of rice ⢠Isolated endophytes showed the ability to produce enzymes and phytohormone IAA ⢠Isolates enhanced significantly the growth of rice.