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Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 38607

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Dr. Tomasz Plech

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Guest Editor

Department of Pharmacology, Medical University of Lublin, Lublin, Poland
Interests: drug design; bioactive molecules; organic synthesis; preclinical studies; antiepileptic agents; neuroprotective agents; enzyme inhibition

Dr. Marta Andres-Mach

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Guest Editor

Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland
Interests: experimental epilepsy; drug testing; neurogenesis/neuroprotection study; behavioral study

Special Issue Information

Dear Colleagues,

The progress we are currently witnessing in civilization has contributed significantly to prolonged life expectancy. However, humans’ increased longevity has its dark side, too. The incidence of neurological and especially neurodegenerative disorders increases dramatically with age. Since such diseases have a multifactorial pathophysiology, today, multifunctional ligands, simultaneously targeting different molecular pathways, seem to be the most favorable as new drug candidates. Thus, the main objective of this Special Issue is to gather the results of the most recent studies utilizing hybridization strategy to obtain hybrid/chimeric compounds as promising candidates for the treatment of neurological and neurodegenerative diseases.In particular, the following topics (but not limited to) will be included: Hybridization strategy in the development of new agents for the treatment of neurodegenerative disorders; Hybrid/chimeric compounds in the search for new effective anticonvulsants; Multifunctional ligands in the discovery of new substances effective in the treatment of neuropathic pain; Novel molecular targets for the treatment of cognitive impairment. Both original papers and review articles are welcome.

Dr. Tomasz Plech
Dr. Marta Andres-Mach
Guest Editors

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Keywords

Hybridization strategy
Multifunctional ligands
Neurodegeneration
Enzyme inhibitors
Receptor agonists/antagonists
In vitro/in vivo studies

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Published Papers (10 papers)

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18 pages, 1726 KiB

Open AccessArticle

C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model

by Mirosław Zagaja, Aleksandra Szewczyk, Joanna Szala-Rycaj, Grzegorz Raszewski, Magdalena Chrościńska-Krawczyk, Michał Abram, Krzysztof Kamiński and Marta Andres-Mach

Molecules 2021, 26(11), 3144; https://doi.org/10.3390/molecules26113144 - 24 May 2021

Cited by 6 | Viewed by 2935

Abstract

C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED₅₀ values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber’s rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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16 pages, 5064 KiB

Open AccessArticle

A Novel Galantamine-Curcumin Hybrid as a Potential Multi-Target Agent against Neurodegenerative Disorders

by Rumyana Simeonova, Dimitrina Zheleva, Iva Valkova, Georgi Stavrakov, Irena Philipova, Mariyana Atanasova and Irini Doytchinova

Molecules 2021, 26(7), 1865; https://doi.org/10.3390/molecules26071865 - 25 Mar 2021

Cited by 22 | Viewed by 3288

Abstract

The acetylcholinesterase (AChE) inhibitors are the main drugs for symptomatic treatment of neurodegenerative disorders like Alzheimer’s disease. A recently designed, synthesized and tested hybrid compound between the AChE inhibitor galantamine (GAL) and the antioxidant polyphenol curcumin (CU) showed high AChE inhibition in vitro. Here, we describe tests for acute and short-term toxicity in mice as well as antioxidant tests on brain homogenates measured the levels of malondialdehide (MDA) and glutathione (GSH) and in vitro DPPH, ABTS, FRAP and LPO inhibition assays. Hematological and serum biochemical analyses were also performed. In the acute toxicity tests, the novel AChE inhibitor given orally in mice showed LD₅₀ of 49 mg/kg. The short-term administration of 2.5 and 5 mg/kg did not show toxicity. In the ex vivo tests, the GAL-CU hybrid performed better than GAL and CU themselves; in a dose of 5 mg/kg, it demonstrates 25% reduction in AChE activity, as well as a 28% and 73% increase in the levels of MDA and GSH, respectively. No significant changes in blood biochemical data were observed. The antioxidant activity of 4b measured ex vivo was proven in the in vitro tests. In the ABTS assay, 4b showed radical scavenging activity 10 times higher than the positive control butylhydroxy toluol (BHT). The GAL-CU hybrid is a novel non-toxic AChE inhibitor with high antioxidant activity which makes it a prospective multitarget drug candidate for treatment of neurodegenerative disorders. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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15 pages, 13515 KiB

Open AccessFeature PaperArticle

Novel Donepezil–Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer’s Disease

by Fausto Queda, Sonia Calò, Karolina Gwizdala, João D. Magalhães, Sandra M. Cardoso, Sílvia Chaves, Luca Piemontese and M. Amélia Santos

Molecules 2021, 26(6), 1658; https://doi.org/10.3390/molecules26061658 - 16 Mar 2021

Cited by 18 | Viewed by 4138

Abstract

Alzheimer’s disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC₅₀ 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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21 pages, 2935 KiB

Open AccessFeature PaperArticle

New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

by Galina F. Makhaeva, Nadezhda V. Kovaleva, Elena V. Rudakova, Natalia P. Boltneva, Sofya V. Lushchekina, Irina I. Faingold, Darya A. Poletaeva, Yuliya V. Soldatova, Raisa A. Kotelnikova, Igor V. Serkov, Anatoly K. Ustinov, Alexey N. Proshin, Eugene V. Radchenko, Vladimir A. Palyulin and Rudy J. Richardson

Molecules 2020, 25(24), 5891; https://doi.org/10.3390/molecules25245891 - 12 Dec 2020

Cited by 36 | Viewed by 3290

Abstract

New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC₅₀(AChE) = 1.90 ± 0.16 µM, IC₅₀(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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17 pages, 2820 KiB

Open AccessArticle

Pharmacological Characterization of 4-Methylthioamphetamine Derivatives

by Fabrizzio G. Guajardo, Victoria B. Velásquez, Daniela Raby, Gabriel Núñez-Vivanco, Patricio Iturriaga-Vásquez, Rodrigo A. España, Miguel Reyes-Parada and Ramón Sotomayor-Zárate

Molecules 2020, 25(22), 5310; https://doi.org/10.3390/molecules25225310 - 13 Nov 2020

Cited by 3 | Viewed by 4251

Abstract

Amphetamine derivatives have been used in a wide variety of pathologies because of their pharmacological properties as psychostimulants, entactogens, anorectics, and antidepressants. However, adverse cardiovascular effects (sympathomimetics) and substance abuse problems (psychotropic and hallucinogenic effects) have limited their use. 4-Methylthioamphetamine (MTA) is an amphetamine derivative that has shown to inhibit monoamine uptake and monoamine oxidase. However, the pharmacological characterization (neurochemical, behavioral, and safety) of its derivatives 4-ethylthioamphetamine (ETA) and 4-methylthio-phenil-2-butanamine (MT-But) have not been studied. In the current experiments, we show that ETA and MT-But do not increase locomotor activity and conditioned place preference with respect to MTA. At the neurochemical level, ETA and MT-But do not increase in vivo DA release in striatum, but ETA and MT-But affect the nucleus accumbens bioaccumulation of DA and DOPAC. Regarding cardiovascular effects, the administration of MTA and ETA increased the mean arterial pressure and only ETA significantly increases the heart rate. Our results show that the pharmacological and safety profiles of MTA are modulated by changing the methyl-thio group or the methyl group of the aminoethyl chain. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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30 pages, 5940 KiB

Open AccessArticle

Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands

by Christopher Cerda-Cavieres, Gabriel Quiroz, Patricio Iturriaga-Vásquez, Julio Rodríguez-Lavado, Jazmín Alarcón-Espósito, Claudio Saitz, Carlos D. Pessoa-Mahana, Hery Chung, Ramiro Araya-Maturana, Jaime Mella-Raipán, David Cabezas, Claudia Ojeda-Gómez, Miguel Reyes-Parada and Hernán Pessoa-Mahana

Molecules 2020, 25(20), 4614; https://doi.org/10.3390/molecules25204614 - 10 Oct 2020

Cited by 7 | Viewed by 3329

Abstract

A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a–o) and (2-{4-[3-(1H-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a–l) were synthesized and evaluated as novel multitarget ligands towards dopamine D₂ receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D₂ ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D₂ receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D₂ receptor (D₂/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure–activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q² = 0.625, 0.523 for CoMFA and CoMSIA and r²_ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively). Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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8 pages, 1220 KiB

Open AccessFeature PaperArticle

Neoglycosylated Collagen: Effect on Neuroblastoma F-11 Cell Lines

by Antonella Sgambato, Valentina Pastori, Laura Russo, Simone Vesentini, Marzia Lecchi and Laura Cipolla

Molecules 2020, 25(19), 4361; https://doi.org/10.3390/molecules25194361 - 23 Sep 2020

Cited by 2 | Viewed by 2589

Abstract

The regeneration of the nervous system is a challenging task. Currently, regenerative medicine approaches that exploit nature-inspired cues are being studied and hold great promise. The possibility to use protein-based matrices functionalized with small oligo- and monosaccharides is of interest since these can be finely tuned to better mimic the native environment. Collagen has been selected as a promising material that has the potential to be further tailored to incorporate carbohydrates in order to drive cell behavior towards neuroregeneration. Indeed, the grafting of carbohydrates to collagen 2D matrices is proved to enhance its biological significance. In the present study, collagen 2D matrices were grafted with different carbohydrate epitopes, and their potential to drive F-11 neuroblastoma cells towards neuronal differentiation was evaluated. Collagen functionalized with α-glucosides was able to differentiate neuroblastoma cells into functional neurons, while sialyl α-(2→6)-galactosides stimulated cell proliferation. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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16 pages, 10620 KiB

Open AccessArticle

Novel Class of Chalcone Oxime Ethers as Potent Monoamine Oxidase-B and Acetylcholinesterase Inhibitors

by Jong Min Oh, T. M. Rangarajan, Reeta Chaudhary, Rishi Pal Singh, Manjula Singh, Raj Pal Singh, Anna Rita Tondo, Nicola Gambacorta, Orazio Nicolotti, Bijo Mathew and Hoon Kim

Molecules 2020, 25(10), 2356; https://doi.org/10.3390/molecules25102356 - 18 May 2020

Cited by 41 | Viewed by 4459

Abstract

Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except COE-17 and COE-24, had potent and/or significant selective inhibitory effects on MAO-B. COE-6 potently inhibited MAO-B with an IC₅₀ value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. COE-7, and COE-22 were also active against MAO-B, both had an IC₅₀ value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. COE-13 most potently inhibited MAO-A (IC₅₀ = 0.88 µM) and also significantly inhibited MAO-B (IC₅₀ = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. COE-19 and COE-22 inhibited AChE with IC₅₀ values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of COE-22 for MAO-B was higher than that of COE-6 (SI = 778.6 vs. 222.2), but the IC₅₀ value (0.028 µM) was slightly lower than that of COE-6 (0.018 µM). In reversibility experiments, inhibitions of MAO-B by COE-6 and COE-22 were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with K_i values of 0.0075 and 0.010 µM, respectively. Our results show that COE-6 and COE-22 are potent, selective MAO-B inhibitors, and COE-22 is a candidate of dual-targeting molecule for MAO-B and AChE. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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26 pages, 2281 KiB

Open AccessArticle

Antagonism of Histamine H3 receptors Alleviates Pentylenetetrazole-Induced Kindling and Associated Memory Deficits by Mitigating Oxidative Stress, Central Neurotransmitters, and c-Fos Protein Expression in Rats

by Alaa Alachkar, Sheikh Azimullah, Mohamed Lotfy, Ernest Adeghate, Shreesh K. Ojha, Rami Beiram, Dorota Łażewska, Katarzyna Kieć-Kononowicz and Bassem Sadek

Molecules 2020, 25(7), 1575; https://doi.org/10.3390/molecules25071575 - 30 Mar 2020

Cited by 25 | Viewed by 4234

Abstract

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), γ-aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all P < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all P < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all P < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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25 pages, 1854 KiB

Open AccessReview

Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

by Joanna Starnowska-Sokół and Barbara Przewłocka

Molecules 2020, 25(23), 5520; https://doi.org/10.3390/molecules25235520 - 25 Nov 2020

Cited by 18 | Viewed by 5000

Abstract

When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce efficient analgesia—which is estimated to relate to more than half of the patients—opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach. Full article

(This article belongs to the Special Issue Multifunctional Hybrid and Chimeric Compounds as Candidates for the Treatment of Neurological and Neurodegenerative Disorders)

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