ABSTRACT
This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a-l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities.
ABSTRACT
INTRODUCTION: Alzheimer's disease (AD) is a progressive, irreversible, and multifactorial brain disorder that gradually and insidiously destroys individual's memory, thinking, and other cognitive abilities. AREAS COVERED: In this perspective, the authors examine the complex and multifactorial nature of Alzheimer's disease and believe that the best approach to develop new drugs is the MTDL strategy, which obviously faces several challenges. These challenges include identifying the key combination of targets and their suitability for coordinated actions, as well as developing an acceptable pharmacokinetic and toxicological profile to deliver a drug candidate. EXPERT OPINION: Since calcium plays a crucial role in the pathology of AD, a polypharmacological approach with calcium channel blockers reinforced by activities targeting other factors involved in AD is a serious option in our opinion. This is exemplified by a phase III clinical trial using a drug combination approach with Losartan, Amlodipine (a calcium channel blocker), and Atorvastatin, as well as several MTDL-based calcium channel blockade approaches with a promising in vitro and in vivo profile.
Subject(s)
Alzheimer Disease , Calcium Channel Blockers , Humans , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Alzheimer Disease/drug therapy , Drug Discovery , Losartan/therapeutic use , PolypharmacologyABSTRACT
Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer's disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine-ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good ß-amyloid (Aß) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as Aß1-40, Aß1-42, and H2O2, and promising ADMET properties that support translational developments. A passive avoidance task in mice with experimentally induced amnesia was carried out, MBA121 being able to significantly decrease scopolamine-induced learning deficits. In addition, MBA121 reduced the Aß plaque burden in the cerebral cortex and hippocampus in APPswe/PS1ΔE9 transgenic male mice. Our in vivo results relate its bioavailability with the therapeutic response, demonstrating that MBA121 is a promising agent to treat the cognitive decline and neurodegeneration underlying AD.
Subject(s)
Alzheimer Disease , Male , Mice , Humans , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/psychology , Tacrine/pharmacology , Tacrine/therapeutic use , Butyrylcholinesterase , Hydrogen Peroxide/therapeutic use , Amyloid beta-Peptides , Mice, Transgenic , Disease Models, Animal , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic useABSTRACT
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.
Subject(s)
Alzheimer Disease , Dihydropyridines , Neurodegenerative Diseases , Humans , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Ligands , Neurodegenerative Diseases/drug therapy , Dihydropyridines/pharmacology , Dihydropyridines/therapeutic use , Calcium Channels , Cholinesterases/metabolism , Acetylcholinesterase/metabolismABSTRACT
Ten new differently substituted 3-benzyl-5-aryl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidin-4,6,11-triones 3 were synthesized by a simple and cost-efficient procedure in a one-pot, three-component reaction from readily available ethyl 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carboxylates, benzylamine and triethyl orthoformate under solvent- and catalyst-free conditions. All the new compounds were screened for their antiproliferative activity against two colorectal-cancer-cell lines. The results showed that the compounds 3-benzyl-5-phenyl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11-trione (3a) and 3-benzyl-5-(3-hydroxyphenyl)-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11-trione (3g) exhibited the most potent balanced inhibitory activity against human LoVo and HCT-116 cancer cells.
Subject(s)
Colorectal Neoplasms , Pyrimidines , Humans , Pyrimidines/chemistry , HCT116 Cells , Benzopyrans/chemistry , Colorectal Neoplasms/drug therapyABSTRACT
A novel coronavirus, SARS-CoV-2, emerged in China at the end of 2019 causing a large global outbreak. As treatments are of the utmost importance, drugs with broad anti-coronavirus activity embody a rich and rapid drug discovery landscape, where candidate drug compounds could be identified and optimized. To this end, we tested ten small-molecules with chemical structures close to ferulic acid derivatives (FADs) (n = 8), caffeic acid derivatives (CAFDs) (n = 1) and carboxamide derivatives (CAMDs) (n = 1) for their ability to reduce HCoV-229E replication, another member of the coronavirus family. Among these ten drugs tested, five of them namely MBA112, MBA33, MBA27-1, OS4-1 and MBA108-1 were highly cytotoxic and did not warrant further testing. In contrast, we observed a moderate cytotoxicity for two of them, MBA152 and 5c. Three drugs, namely MBA140, LIJ2P40, and MBA28 showed lower cytotoxicity. These candidates were then tested for their antiviral propreties against HCoV-229E and SARS-CoV2 replication. We first observed encouraging results in HCoV-229E. We then measured a reduction of the viral SARS-CoV2 replication by 46% with MBA28 (EC50 > 200 µM), by 58% with MBA140 (EC50 = 176 µM), and by 82% with LIJ2P40 (EC50 = 66.5 µM). Overall, the FAD LIJ2P40 showed a reduction of the viral titer on SARS-CoV-2 up to two logs with moderate cytotoxicity which opens the door to further evaluation to fight Covid-19.
Subject(s)
COVID-19 Drug Treatment , Coronavirus 229E, Human , Humans , SARS-CoV-2 , RNA, ViralABSTRACT
Among neurodegenerative pathologies affecting the older population, Alzheimer's disease is the most common type of dementia and leads to neurocognitive and behavioral disorders. It is a complex and progressive age-related multifactorial disease characterized by a series of highly interconnected pathophysiological processes. Within the last decade, the multitarget-directed ligand strategy has emerged as a viable approach to developing complex molecules that exhibit several pharmacophores which can target the different enzymes and receptors involved in the pathogenesis of the disease. Herein, we focus on using multicomponent reactions such as Hantzsch, Biginelli and Ugi to develop these biologically active multitopic ligands.
Subject(s)
Alzheimer Disease , Humans , Ligands , Cholinesterase InhibitorsABSTRACT
Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.
Subject(s)
Alzheimer Disease , Antioxidants , Calcium Channel Blockers , Cholinesterase Inhibitors , Molecular Targeted Therapy , NF-E2-Related Factor 2 , Humans , Alzheimer Disease/drug therapy , Antioxidants/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Ligands , NF-E2-Related Factor 2/metabolism , Structure-Activity Relationship , Calcium Channel Blockers/chemical synthesisABSTRACT
Multidrug resistance constitutes a serious obstacle of the treatment success of cancer by chemotherapy. Mostly it is driven by expression of ABC transport proteins that actively efflux the anticancer agents out of the cell. This work describes the design and synthesis of 12 new pyrimidopyrimidines, as well as their inhibition of ABCG2 a transporter referred also to as breast cancer resistance protein, the selectivity versus ABCB1 (P-glycoprotein/P-gp) and ABCC1 as well as the investigation of their accumulation in single cells. From these results, N-(3,5-dimethoxyphenyl)-2-methyl-7-phenyl-5-(p-tolyl)pyrimido[4,5-d]pyrimidin-4-amine 7 h was identified as promising hit that deserves further investigation showing a selective and effective inhibition of ABCG2 with IC50 equal to 0.493 µM only 2-fold less active than Ko143.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Pyrimidines/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Humans , Molecular Structure , Neoplasm Proteins/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Background: Alzheimer's disease is a chronic neurodegenerative chronic disease with a heavy social and economic impact in our developed societies, which still lacks an efficient therapy. Method: This paper describes the Hantzsch multicomponent synthesis of twelve alkyl hexahydro-quinoline-3-carboxylates, 4a-l, along with the evaluation of their Ca2+ channel blockade capacity, cholinesterase inhibition and antioxidant power. Results: Compound 4l showed submicromolar inhibition of butyrylcholinesterase, Ca2+ channel antagonism and an antioxidant effect. Conclusion: Compound 4l is an interesting compound that deserves further investigation for Alzheimer's disease therapy.
Subject(s)
Antioxidants/pharmacology , Benzaldehydes/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Cholinesterase Inhibitors/pharmacology , Quinolines/pharmacology , Acetylcholinesterase/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Benzaldehydes/chemical synthesis , Benzaldehydes/chemistry , Butyrylcholinesterase/metabolism , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Electrophorus , Horses , Humans , Quinolines/chemical synthesis , Quinolines/chemistryABSTRACT
Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3ß and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and ß-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.
Subject(s)
Alzheimer Disease , Alzheimer Disease/drug therapy , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Calcium Channels , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Glycogen Synthase Kinase 3 beta , Humans , Ligands , Monoamine Oxidase/metabolismABSTRACT
Herein we have reviewed our recent developments for the identification of new tacrine analogues for Alzheimer's disease (AD) therapy. Tacrine, the first cholinesterase inhibitor approved for AD treatment, did not stop the progression of AD, producing only some cognitive improvements, but exhibited secondary effects mainly due to its hepatotoxicity. Thus, the drug was withdrawn from the clinics administration. Since then, many publications have described non-hepatotoxic tacrines, and in addition, important efforts have been made to design multitarget tacrines by combining their cholinesterase inhibition profile with the modulation of other biological targets involved in AD.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Tacrine/analogs & derivatives , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Cell Line, Tumor , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Humans , Molecular Docking Simulation , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/metabolism , Protein Binding , Tacrine/metabolismABSTRACT
We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca+2 channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 3a-p, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL 3h [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 µM) and BuChE (2 µM), Ca+2 channel antagonist (47.72% at 10 µM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H2O2, and O/R, respectively, at 0.3 µM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.
Subject(s)
Antioxidants/chemical synthesis , Calcium Channel Blockers/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Neuroprotective Agents/chemical synthesis , Antioxidants/pharmacology , Binding Sites , Calcium/metabolism , Calcium Channel Blockers/pharmacology , Cell Line, Tumor , Cholinesterase Inhibitors/pharmacology , Cholinesterases/chemistry , Cholinesterases/metabolism , Humans , Molecular Docking Simulation , Neurons/drug effects , Neuroprotective Agents/pharmacology , Protein BindingABSTRACT
Alzheimer's disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aß) peptide, and intracellular neurofibrillary tangles (NFTs), along with dramatic neuronal death and decreased levels of choline acetyltransferase. Given the limited therapeutic success of available drugs, it is urgent to explore all the opportunities available to combat this illness. Among them, the discovery of new heterocyclic scaffolds binding different receptors involved in AD should offer structural diversity and new therapeutic solutions. In this context, this work describes new triazolopyridopyrimidine easily prepared in good yields showing anticholinesterase inhibition and strong antioxidant power, particularly the most balanced: 6-amino-5-(4-methoxyphenyl)-2-phenyl-[1,2,4]triazolo[1',5':1,6] pyrido[2,3-d]pyrimidine-4-carbonitrile(3c) with IC50 equal to 1.32 µM against AChE and oxygen radical absorbance capacity (ORAC) value equal to 4.01 Trolox equivalents (TE); thus representing a new and very promising hit-triazolopyridopyrimidine for AD therapy.
Subject(s)
Antioxidants/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Quinoxalines/chemical synthesis , Alzheimer Disease/drug therapy , Drug Discovery , HumansABSTRACT
In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 µM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Quinolones/pharmacology , Acetylcholinesterase/metabolism , Drug Design , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Kinetics , Ligands , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Monoamine Oxidase/metabolism , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca2+ channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs 3a-t, resulting from the juxtaposition of nimodipine, a Ca2+ channel antagonist, and rasagiline, a known MAO inhibitor, have been obtained from appropriate and commercially available precursors using a Hantzsch reaction. Pertinent biological analysis has prompted us to identify the MTDL 3,5-dimethyl-2,6-dimethyl-4-[4-(prop-2-yn-1-yloxy)phenyl]-1,4-dihydro- pyridine- 3,5-dicarboxylate (3a), as an attractive antioxidant (1.75 TE), Ca2+ channel antagonist (46.95% at 10 µM), showing significant neuroprotection (38%) against H2O2 at 10 µM, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.
Subject(s)
Antioxidants/chemistry , Antioxidants/physiology , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Calcium/metabolism , Cell Line, Tumor , Dihydropyridines/chemistry , Dihydropyridines/pharmacology , Humans , Ligands , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Neuroprotection/drug effects , Nimodipine/chemistry , Nimodipine/pharmacologyABSTRACT
Current options for the treatment of Alzheimers disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aß expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported.
Subject(s)
Neuroprotective Agents/chemistry , Pargyline/analogs & derivatives , Propylamines/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Cholinesterases/chemistry , Cholinesterases/metabolism , Humans , Ligands , Monoamine Oxidase/chemistry , Monoamine Oxidase/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Oxidative Stress/drug effects , Pargyline/chemistry , Pargyline/pharmacology , Pargyline/therapeutic use , Propylamines/pharmacology , Propylamines/therapeutic useABSTRACT
Aim: Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases, and particularly in Alzheimer's disease. Results: This work describes the Ugi multicomponent synthesis, antioxidant power and Nrf2 pathway induction in antioxidant response element cells of (E)-N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-3-(4-hydroxy-3-methoxyphenyl)acryl amides 8a-d, N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-5-(1,2-dithiolan-3-yl)pentanamides 8e-h and N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-5-hydroxy-4-oxo-4H-pyran-2-carboxamides 8i,j. Conclusion: We have identified compounds 8e and 8g, showing a potent antioxidant capacity, a remarkable neuroprotective effect against the cell death induced by H2O2 in SH-SY5Y cells, and a performing activation of the Nrf2 signaling pathway, as very interesting new antioxidant agents for pathologies that curse with oxidative stress.