ASS234, as a new Multi-Target Directed propargylamine for Alzheimer’s disease therapy

MU and JMC thank MINECO (Spain) for support (Grant SAF2012-33304; SAF2015-65586-R). RRR, MU, GE and JMC thank EU (COST Action 1103) for support.The complex nature of Alzheimer’s disease (AD) has prompted the design of Multi-Target-Directed Ligands (MTDL) able to bind to diverse biochemical targets involved in the progress and development of the disease. In this context, we have designed a number of MTD propargylamines showing antioxidant, anti-betaamyloid, anti-inflammatory, as well as cholinesterase and monoamine oxidase inhibition capacities. Here, we describe these properties in the MTDL ASS234, our lead-compound ready to enter in pre-clinical studies for AD, as a new multipotent, permeable cholinesterase/monoamine oxidase inhibitor, able to inhibit Aβ- aggregation, possessing antioxidant and neuroprotective properties.Publisher PDFPeer reviewe

Synthesis and biological evaluation of benzochromenopyrimidinones as cholinesterase inhibitors and potent antioxidant, non-hepatotoxic agents for Alzheimer’s disease

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.JMC thanks Government of Spain for support (SAF2016-65586-R), JJ and OS thank MH CZ- DRO (UHHK 00179906).We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)

Pharmacophore Modelling and Synthesis of Quinoline-3-Carbohydrazide as Antioxidants

From well-known antioxidants agents, we developed a first pharmacophore model containing four common chemical features: one aromatic ring and three hydrogen bond acceptors. This model served as a template in virtual screening of Maybridge and NCI databases that resulted in selection of sixteen compounds. The selected compounds showed a good antioxidant activity measured by three chemical tests: DPPH radical,OH∘radical, and superoxide radical scavenging. New synthetic compounds with a good correlation with the model were prepared, and some of them presented a good antioxidant activity.</jats:p

Transition-metal complexes of N,N′-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide: synthesis, characterization, biological activities, ADMET and drug-likeness analysis

Coordination compounds of N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide (L1) were synthesized via the reaction of Cu (II), Co (II) and Zn (II) salts in molar ratio 1 : 1 in the presence of ammoniac as basic media. The Ligands and the complexes formed were characterized using FT-IR, UV–visible and fluorescence spectrophotometric analyses, mass spectrometry, elemental analyses and NMR spectroscopy. It was concluded that N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide (L1) coordinated as a mono ligand for all the complexes; it also coordinated via the –OH and –NH groups. The electrochemical behaviour of these compounds was determined by cyclic voltammetry. The synthesized compounds were screened for their antimicrobial and antioxidant activities. All the complexes except that of copper show good activities against the S. aureus and those of cobalt and zinc have very interesting diameters of inhibition but lower antioxidant activity than the ligand L1. Parameters drug-likeness and ADMET (Absorption, Distribution, Metabolism, and Excretion) properties have been calculated.publishe

Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca2+ 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 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.This work was supported by the Regional Council of Franche-Comté (2022Y-13659 and 13660 ACCURATE PROJECT).Peer reviewe

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. 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.This work was supported by the Regional Council of Franche-Comté (2022Y-13659 and 13660 Accurate Project).Peer reviewe

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 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/PS1¿E9 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.This work is part of the MINA-CM program (number S2022/BMD-7236), funded by the call for the implementation of programs of R&D activities between research groups of the Community of Madrid in Biomedicine 2022 (Order 1171/2022)

The Proof-of-Concept of MBA121, a Tacrine&ndash;Ferulic Acid Hybrid, for Alzheimer&rsquo;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&rsquo;s disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine&ndash;ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good &beta;-amyloid (A&beta;) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as A&beta;1&ndash;40, A&beta;1&ndash;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 A&beta; plaque burden in the cerebral cortex and hippocampus in APPswe/PS1&Delta;E9 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

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

In this communication, wereport 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 M), 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.R.A., M.S., P.B., and K.M. were supported by European Regional Development Fund/European Social Fund (ERDF/ESF, project PharmaBrain, no. CZ.02.1.01/0.0/0.0/16_025/0007444), University of Hradec Kralove (no. SV2113-2019, VT2019-2021), and EU COST action CA15135 MuTaLig. J.M.C. thanks Ministerio de Economía (MINECO, SAF2015-65586-R) and Universidad Camilo José Cela (UCJC, grants UCJC 2020-03, and UCJC 2020-33) for support