Discovery of New Highly Potent Histamine H Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors.

At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named has emerged as a promising MTDL.

Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca Channels, Activating Nrf2 and Possessing Cathepsin S Inhibitory, and Antioxidant Properties.

This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds -, via a convenient one-pot three-component Hantzsch reaction.

Calcium channel blockers' contribution to overcoming Current drug discovery challenges in Alzheimer's disease.

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.

The Proof-of-Concept of MBA121, a Tacrine-Ferulic Acid Hybrid, for Alzheimer's Disease Therapy.

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 -amyloid (A) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as A, A, and HO, and promising ADMET properties that support translational developments.

Exploring the Potential of Sulfonamide-Dihydropyridine Hybrids as Multitargeted Ligands for Alzheimer's Disease Treatment.

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.

Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation.

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.

Ferulic acid derivatives block coronaviruses HCoV-229E and SARS-CoV-2 replication in vitro.

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.

Benzochromenopyrimidines: Synthesis, Antiproliferative Activity against Colorectal Cancer and Physicochemical Properties.

Ten new differently substituted 3-benzyl-5-aryl-3,5-dihydro-4-benzo[6,7]chromeno[2,3-]pyrimidin-4,6,11-triones 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-4-benzo[]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-4-benzo[6,7]chromeno[2,3-]pyrimidine-4,6,11-trione () and 3-benzyl-5-(3-hydroxyphenyl)-3,5-dihydro-4-benzo[6,7]chromeno[2,3-]pyrimidine-4,6,11-trione () exhibited the most potent balanced inhibitory activity against human LoVo and HCT-116 cancer cells.

Multicomponent reactions as a privileged tool for multitarget-directed ligand strategies in Alzheimer's disease therapy.

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.

Synthesis and biological assessment of new pyrimidopyrimidines as inhibitors of breast cancer resistance protein (ABCG2).

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.

Synthesis of new Hantzsch adducts showing Ca channel blockade capacity, cholinesterase inhibition and antioxidant power.

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. This paper describes the Hantzsch multicomponent synthesis of twelve alkyl hexahydro-quinoline-3-carboxylates, , along with the evaluation of their Ca channel blockade capacity, cholinesterase inhibition and antioxidant power. Compound  showed submicromolar inhibition of butyrylcholinesterase, Ca channel antagonism and an antioxidant effect.

(±)-: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease.

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 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±) was identified as a promising new hit compound showing balanced activities toward the aforementioned recognized AD targets.

Tacrines as Therapeutic Agents for Alzheimer's Disease. V. Recent Developments.

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.

Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives.

We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca 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 , have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL [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.

Triazolopyridopyrimidine: A New Scaffold for Dual-Target Small Molecules for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aβ) 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.

Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy.

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (-) and 13 dihydroquinolinones (-) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant MAO inhibition, but compounds , , and displayed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition. In particular, molecule was found to be a potent and quite selective non-competitive inhibitor of AChE (IC = 0.

Design, Synthesis and Biological Evaluation of New Antioxidant and Neuroprotective Multitarget Directed Ligands Able to Block Calcium Channels.

We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs -, resulting from the juxtaposition of nimodipine, a Ca 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 (), as an attractive antioxidant (1.

Chromenones as Multineurotargeting Inhibitors of Human Enzymes.

The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core.

Propargylamine-derived multi-target directed ligands for Alzheimer's disease therapy.

Current options for the treatment of Alzheimeŕs 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 Aβ 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.

Synthesis of new ferulic/lipoic/comenic acid-melatonin hybrids as antioxidants and Nrf2 activators via Ugi reaction.

Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases, and particularly in Alzheimer's disease. This work describes the Ugi multicomponent synthesis, antioxidant power and Nrf2 pathway induction in antioxidant response element cells of ()--(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-3-(4-hydroxy-3-methoxyphenyl)acryl amides , -(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-5-(1,2-dithiolan-3-yl)pentanamides and -(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-5-hydroxy-4-oxo-4-pyran-2-carboxamides . We have identified compounds and , showing a potent antioxidant capacity, a remarkable neuroprotective effect against the cell death induced by HO 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.

New Dual Small Molecules for Alzheimer's Disease Therapy Combining Histamine H Receptor (H3R) Antagonism and Calcium Channels Blockade with Additional Cholinesterase Inhibition.

New tritarget small molecules combining Ca channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound has been identified as a very promising lead, showing good Ca channels blockade activity (IC = 21 ± 1 μM), potent affinity against hH3R ( = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC = 7.83 ± 0.

Synthesis and Biological Evaluation of Novel Chromone+Donepezil Hybrids for Alzheimer's Disease Therapy.

Background: Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets.

Objective: We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals.

Multi-target 1,4-dihydropyridines showing calcium channel blockade and antioxidant capacity for Alzheimer's disease therapy.

In this work we describe the synthesis, Ca channel blockade capacity and antioxidant power of N,N-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxamides 1-9, a number of multi-target small 1,4-dihydropyridines (DHP), designed by juxtaposition of melatonin and nimodipine. As a result, we have identified antioxidant DHP 7 (Ca channel blockade: 55%, and 8.78 Trolox/Equivalents), the most balanced DHP analyzed here, for potential Alzheimer's disease therapy.