Multitarget-directed Ligands Research Articles

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer's Disease by In Silico, InVitro, and InVivo Studies.

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out. CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands. The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay. Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs.

Discovery of novel thiosemicarbazone-acridine targeting butyrylcholinesterase with antioxidant, metal complexing and neuroprotector abilities as potential treatment of Alzheimer's disease: In vitro, in vivo, and in silico studies

Inhibition of cholinesterases, combined with antioxidant activity, metal-chelating capacity, and neuroprotection, is recognized as an effective multitarget therapy for the treatment of Alzheimer's disease (AD). Based on our in-house thiosemicarbazone-acridine compounds, this study recognized these derivatives as possible multi-target-directed ligand (MTDL). Initial screening against cholinesterases identified CL-01, which exhibited a promising IC50 value of 0.71 μM against butyrylcholinesterase (BChE). Twelve new derivatives were designed based on CL-01 aiming to retain the BChE inhibitory activity while incorporating a MTDL profile, including antioxidant properties and metal-complexing abilities. Among the new derivatives, CL-13 maintained a good BChE inhibition (IC50 = 1.15 μM) with improved selective index against acetylcholinesterase (SI = 9.2). The acridine nucleus was important for the activity, as its saturated tetrahydroacridine analogue (TA-01) showed a decrease in cholinesterases inhibition potencies and altered the mode of inhibition, revealing for the first time distinct functional roles for the two nuclei. Moreover, CL-13 emerged as a promising lead compound, demonstrating interesting antioxidant activity (DPPH EC50 = 47.01 μM), chelating capacity of biometals involved in Aβ aggregation and/or oxidative stress, and a lack of neurotoxicity at 50 μM in SH-SY5Y cells. It also exhibited neuroprotective effects in an in vitro oxidative stress model induced by H2O2. Finally, in vivo experiments confirmed that CL-13 effectively reversed scopolamine-induced cognitive impairment, without affecting locomotor activity in the mice.

Virtual Screening Approaches to Identify Promising Multitarget-Directed Ligands for the Treatment of Autism Spectrum Disorder

Autism spectrum disorder is a complex neurodevelopmental disorder. The available medical treatment options for autism spectrum disorder are very limited. While the etiology and pathophysiology of autism spectrum disorder are still not fully understood, recent studies have suggested that wide alterations in the GABAergic, glutamatergic, cholinergic, and serotonergic systems play a key role in its development and progression. Histamine neurotransmission is known to have complex interactions with other neurotransmitters that fit perfectly into the complex etiology of this disease. Multitarget-directed compounds with an affinity for the histamine H3 receptor indicate an interesting profile of activity against autism spectrum disorder in animal models. Here, we present the results of our research on the properties of (4-piperazin-1-ylbutyl)guanidine derivatives acting on histamine H3 receptors as potential multitarget ligands. Through the virtual screening approach, we identified promising ligands among 32 non-imidazole histamine H3 receptor antagonists/inverse agonists with potential additional activity against the dopamine D2 receptor and/or cholinesterases. The virtual screening protocol integrated predictions from SwissTargetPrediction, SEA, and PPB2 tools, along with molecular docking simulations conducted using GOLD 5.3 and Glide 7.5 software. Among the selected ligands, compounds 25 and 30 blocked radioligand binding to the D2 receptor at over 50% at a screening concentration of 1 µM. Further experiments allowed us to determine the pKi value at the D2 receptor of 6.22 and 6.12 for compounds 25 and 30, respectively. Our findings suggest that some of the tested compounds could be promising multitarget-directed ligands for the further research and development of more effective treatments for autism spectrum disorder.

Recent Advancements in the Treatment of Alzheimer's Disease: A Multitarget-directed Ligand Approach.

Alzheimer's disease (AD) is a neurodegenerative disease and one of the leading causes of progressive dementia, affecting 50 million people worldwide. Many pathogenic processes, including amyloid β aggregation, tau hyperphosphorylation, oxidative stress, neuronal death, and deterioration of the function of cholinergic neurons, are associated with its progression. The one-compound-one-target treatment paradigm was unsuccessful in treating AD due to the multifaceted nature of Alzheimer's disease. The recent development of multitarget-directed ligand research has been explored to target the complementary pathways associated with the disease. We aimed to find the key role and progress of MTDLs in treating AD; thus, we searched for the past ten years of literature on "Pub- Med", "ScienceDirect", "ACS" and "Bentham Science" using the keywords neurodegenerative diseases, Alzheimer's disease, and multitarget-directed ligands. The literature was further filtered based on the quality of work and relevance to AD. Thus, this review highlights the current advancement and advantages of multitarget-directed ligands over traditional single-targeted drugs and recent progress in their development to treat AD.

Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer's Pathogenesis.

Alzheimer's disease (AD) is the most common form of dementia around the world (~ 65%). Here, we portray the neuropathology of AD, biomarkers, and classification of amyloid plaques (diffuse, non-cored, dense core, compact). Tau pathology and its involvement with Aβ plaques and cell death are discussed. Amyloid cascade hypotheses, aggregation mechanisms, and molecular species formed in vitro and in vivo (on- and off-pathways) are described. Aβ42/Aβ40 monomers, dimers, trimers, Aβ-derived diffusible ligands, globulomers, dodecamers, amylospheroids, amorphous aggregates, protofibrils, fibrils, and plaques are characterized (structure, size, morphology, solubility, toxicity, mechanistic steps). An update on AD-approved drugs by regulatory agencies, along with new Aβ-based therapies, is presented. Beyond prescribing Aβ plaque disruptors, cholinergic agonists, or NMDA receptor antagonists, other therapeutic strategies (RNAi, glutaminyl cyclase inhibitors, monoclonal antibodies, secretase modulators, Aβ aggregation inhibitors, and anti-amyloid vaccines) are already under clinical trials. New drug discovery approaches based on "designed multiple ligands", "hybrid molecules", or "multitarget-directed ligands" are also being put forward and may contribute to tackling this highly debilitating and fatal form of human dementia.

Novel Emerging Targets Identification in Reducing Risk of Alzheimer's Disease.

The accumulation of tau-containing neurofibrillary tangles and beta-amyloid deposits has been identified as the hallmark of Alzheimer's disease. Alzheimer's disease (AD) is a hereditary and neurological condition that can result in non-amnestic cognitive decline in less common forms and amnestic memory loss in its classic form. While Alzheimer's disease is the most prevalent cause of memory loss in middle-aged and older adults, other neurodegenerative and cerebrovascular disorders can have an impact on the disease's clinical course. Designing multi-target-directed ligands (MTDLs) is a very promising modern approach. This methodology was designed specifically for treating disorders with complex pathological mechanisms. Among these disorders is Alzheimer's disease (AD), which is currently the most prevalent multifactorial neurodegenerative illness. Increased amounts of the amyloid βpeptide (Aβ) and hyperphosphorylated tau protein, together with the loss of neurons and synapses, are linked to Alzheimer's disease (AD). Additionally, there is evidence that the pathophysiology of this condition is influenced by oxidative stress, metal ion dysregulation, inflammation, and failure of the cell cycle regulatory system. Since Alzheimer's disease (AD) is a multi-factor illness, there are many attractive targets for the development of anti-AD medications. These molecules can be useful in treating AD since they are multi-target-directed. This review focuses on the discovery of dual and multi-acting anti-AD drug candidates, especially hybrids made by combining chemically active moieties that function against distinct targets. The first group of substances consists of cholinesterase inhibitors with extra properties or those that function as multiple binding site inhibitors. Natural products also provide numerous options for slowing the progression and symptoms of many diseases, including Alzheimer's Meanwhile, Natural chemical structures with the following characteristics: alkaloids, sterols, triterpenes, tannins, flavonoids, polyphenols, and antioxidants as well as anti-inflammatory and anti-amyloidogenic properties. We provide an overview of Alzheimer's disease pathophysiology and therapy targets in this study. We also show several isolated chemicals and medicinal plants that are used to treat and prevent the symptoms of Alzheimer's disease.

Targeting esophageal carcinoma: molecular mechanisms and clinical studies.

Esophageal cancer (EC)is identified as a predominant health threat worldwide, with its highest incidence and mortality rates reported in China. The complex molecular mechanisms underlying EC, coupled with the differential incidence of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) across various regions, highlight the necessity for in-depth research targeting molecular pathogenesis and innovative treatment strategies. Despite recent progress in targeted therapy and immunotherapy, challenges such as drug resistance and the lack of effective biomarkers for patient selection persist, impeding the optimization of therapeutic outcomes. Our review delves into the molecular pathology of EC, emphasizing genetic and epigenetic alterations, aberrant signaling pathways, tumor microenvironment factors, and the mechanisms of metastasis and immune evasion. We further scrutinize the current landscape of targeted therapies, including the roles of EGFR, HER2, and VEGFR, alongside the transformative impact of ICIs. The discussion extends to evaluating combination therapies, spotlighting the synergy between targeted and immune-mediated treatments, and introduces the burgeoning domain of antibody-drug conjugates, bispecific antibodies, and multitarget-directed ligands. This review lies in its holistic synthesis of EC's molecular underpinnings and therapeutic interventions, fused with an outlook on future directions including overcoming resistance mechanisms, biomarker discovery, and the potential of novel drug formulations.

Multitarget-Directed Ligands Hitting Serotonin Receptors: A Medicinal Chemistry Survey.

Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate 5-HT activity. In agreement with the crucial roles played by 5-HT, many drugs target 5-HT receptors (5-HTRs). Therefore, it is unsurprising that many efforts have been devoted to discovering multitarget-directed ligands (MTDLs) capable of engaging one or more 5-HTRs plus another target phenotypically linked to a particular disease. In this review, we will describe medicinal chemistry efforts in designing MTDLs encompassing activity for one or more 5-HTRs, starting with atypical antipsychotics and moving to dual 5-HT1AR/serotonin transporter ligands, 5-HT6R antagonists/acetyl cholinesterases inhibitors, and 5-HT4R agonists/acetyl cholinesterases inhibitors. We will also provide an outlook on the most recent efforts made in the field.

From the "One-Molecule, One-Target, One-Disease" Concept towards Looking for Multi-Target Therapeutics for Treating Non-Polio Enterovirus (NPEV) Infections.

Non-polio enteroviruses (NPEVs), namely coxsackieviruses (CV), echoviruses (E), enteroviruses (EV), and rhinoviruses (RV), are responsible for a wide variety of illnesses. Some infections can progress to life-threatening conditions in children or immunocompromised patients. To date, no treatments have been approved. Several molecules have been evaluated through clinical trials without success. To overcome these failures, the multi-target directed ligand (MTDL) strategy could be applied to tackle enterovirus infections. This work analyzes registered clinical trials involving antiviral drugs to highlight the best candidates and develops filters to apply to a selection for MTDL synthesis. We explicitly stated the methods used to answer the question: which solution can fight NPEVs effectively? We note the originality and relevance of this proposal in relation to the state of the art in the enterovirus-inhibitors field. Several combinations are possible to broaden the antiviral spectrum and potency. We discuss data related to the virus and data related to each LEAD compound identified so far. Overall, this study proposes a perspective on different strategies to overcome issues identified in clinical trials and evaluate the "MTDL" potential to improve the efficacy of drugs, broaden the antiviral targets, possibly reduce the adverse effects, drug design costs and limit the selection of drug-resistant virus variants.

Exploiting the potential of rivastigmine-melatonin derivatives as multitarget metal-modulating drugs for neurodegenerative diseases

The multifaceted nature of the neurodegenerative diseases, as Alzheimer's disease (AD) and Parkinson's disease (PD) with several interconnected etiologies, and the absence of effective drugs, led herein to the development and study of a series of multi-target directed ligands (MTDLs). The developed RIV-IND hybrids, derived from the conjugation of an approved anti-AD drug, rivastigmine (RIV), with melatonin analogues, namely indole (IND) derivatives, revealed multifunctional properties, by associating the cholinesterase inhibition of the RIV drug with antioxidant activity, biometal (Cu(II), Zn(II), Fe(III)) chelation properties, inhibition of amyloid-β (Aβ) aggregation (self- and Cu-induced) and of monoamine oxidases (MAOs), as well as neuroprotection capacity in cell models of AD and PD. In particular, two hybrids with hydroxyl-substituted indoles (5a2 and 5a3) could be promising multifunctional compounds that inspire further development of novel anti-neurodegenerative drugs.

Discovery of New Highly Potent Histamine H3 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 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.

Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents

Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized. The newly obtained structures 3a-c, bearing riluzole key elements, were initially tested in an in vitro ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound 3b as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative 3b completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound 3b was then selected to assess its effects on voltage-dependent Na+ and K+ currents. The results indicated that derivative 3b induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for 3b, as it represents an elegant example of a MTDL and opens the way to further ex-vivo and/or in-vivo characterization.

Scutellarein derivatives with histamine H3 receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer’s disease therapy

A series of scutellarein 7-l-amino acid carbamate-4′-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer’s disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, l-Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC50 values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent H3R antagonistic activities than clobenpropit, with an IC50 value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu2+-induced Aβ1–42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu2+-induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aβ25-35. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood–brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation.

Developing a Semi-Supervised Approach Using a PU-Learning-Based Data Augmentation Strategy for Multitarget Drug Discovery.

Multifactorial diseases demand therapeutics that can modulate multiple targets for enhanced safety and efficacy, yet the clinical approval of multitarget drugs remains rare. The integration of machine learning (ML) and deep learning (DL) in drug discovery has revolutionized virtual screening. This study investigates the synergy between ML/DL methodologies, molecular representations, and data augmentation strategies. Notably, we found that SVM can match or even surpass the performance of state-of-the-art DL methods. However, conventional data augmentation often involves a trade-off between the true positive rate and false positive rate. To address this, we introduce Negative-Augmented PU-bagging (NAPU-bagging) SVM, a novel semi-supervised learning framework. By leveraging ensemble SVM classifiers trained on resampled bags containing positive, negative, and unlabeled data, our approach is capable of managing false positive rates while maintaining high recall rates. We applied this method to the identification of multitarget-directed ligands (MTDLs), where high recall rates are critical for compiling a list of interaction candidate compounds. Case studies demonstrate that NAPU-bagging SVM can identify structurally novel MTDL hits for ALK-EGFR with favorable docking scores and binding modes, as well as pan-agonists for dopamine receptors. The NAPU-bagging SVM methodology should serve as a promising avenue to virtual screening, especially for the discovery of MTDLs.

Molecular Transformers: Adaptive Multitarget Ligands for Esterase-Induced Transition from Analgesics to Anesthetics.

Multitarget strategies are essential in addressing complex diseases, yet developing multitarget-directed ligands (MTDLs) is particularly challenging when aiming to engage multiple therapeutic targets across different tissues. Here, we present a molecular transformer strategy, enhancing traditional MTDLs. By utilizing esterase-driven hydrolysis, this approach mimics the adaptive nature of transformers for enabling molecules to modify their pharmacological effects in response to the biological milieu. By virtual screening and biological evaluation, we identified KGP-25, a novel compound initially targeting the voltage-gated sodium channel 1.8 (Nav1.8) in the peripheral nervous system (PNS) for analgesia, and later the γ-aminobutyric acid subtype A receptor (GABAA) in the central nervous system (CNS) for general anesthesia. Our findings confirm KGP-25's dual efficacy in cellular and animal models, effectively reducing opioid-related side effects. This study validates the molecular transformer approach in drug design and highlights its potential to overcome the limitations of conventional MTDLs, paving new avenues in innovative therapeutic strategies.

Unveiling piperazine-quinoline hybrids as potential multi-target directed anti-Alzheimer's agents: design, synthesis and biological evaluation.

Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound (95) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC50 3.013 µM) and BuChE (IC50 = 3.144 µM). Compound (83) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC50 1.888 µM). Notably, compound (79) demonstrated 93-times higher selectivity for BuChE over AChE. Molecular docking and molecular dynamics simulations were also performed to explore the binding modes and stability of these compounds with the AChE amd BuChE proteins. Further, kinetics study was performed against AChE for comounds (83 and 95) which indicated mixed inhibition of the enzyme by these compounds, Amongs the synthesized compounds, nine compounds were assessed for their antioxidant activity, displaying significant antioxidant properties with IC50 values ranging from 156 µM to 310 µM. Moreover, all the compounds demonstrated metal chelating tendency with Cu+2, Zn+2, Fe+2, Fe+3 and Al+3. This study provides insights into the design of novel MTDLs, highlighting compound (95) as a potential candidate for combating Alzheimer's disease.

Harnessing the Therapeutic Potential of Peptides for Synergistic Treatment of Alzheimer's Disease by Targeting Aβ Aggregation, Metal-Mediated Aβ Aggregation, Cholinesterase, Tau Degradation, and Oxidative Stress.

Alzheimer's disease (AD) is a progressive multifaceted neurodegenerative disease and remains a formidable global health challenge. The current medication for AD gives symptomatic relief and, thus, urges us to look for alternative disease-modifying therapies based on a multitarget directed approach. Looking at the remarkable progress made in peptide drug development in the last decade and the benefits associated with peptides, they offer valuable chemotypes [multitarget directed ligands (MTDLs)] as AD therapeutics. This review recapitulates the current developments made in harnessing peptides as MTDLs in combating AD by targeting multiple key pathways involved in the disease's progression. The peptides hold immense potential and represent a convincing avenue in the pursuit of novel AD therapeutics. While hurdles remain, ongoing research offers hope that peptides may eventually provide a multifaceted approach to combat AD.

Systematic Investigation of Dual-Target-Directed Ligands.

Multitarget-directed ligands (MTDLs) are compounds rationally designed to affect multiple targets, aiming for a better therapeutic profile. For over 20 years, MTDLs have garnered increasing attention, the idea being that their full potential would have been achieved, thanks to unprecedented target combinations and advanced medicinal chemistry strategies. This study presents a literature mining effort resulting in a data set of dual-target-directed ligands (DTDLs), the fundamental example of MTDLs. We used this data set to evaluate the rationale behind target selection and the chemical novelty of DTDLs targeting specific protein combinations. Our analysis focused on DTDL targets in terms of biological function, disease association, structure, and chemogenomic traits. We also compared DTDLs with single-target compounds. We found that well-known target pathology associations often guide DTDL design, leveraging existing chemical scaffolds and binding pocket similarities. These findings highlight the current state of the field and suggest substantial untapped potential for rational polypharmacology.

Pills of Multi-Target H2S Donating Molecules for Complex Diseases.

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs) able to modulate multiple targets of interest, including the pathways where hydrogen sulfide (H2S) is involved. By incorporating an H2S donor moiety into a native drug, researchers have been able to simultaneously target multiple therapeutic pathways, resulting in improved treatment outcomes. This review gives the reader some pills of successful multi-target H2S-donating molecules as worthwhile tools to combat the multifactorial nature of complex disorders, such as inflammatory-based diseases and cancer, as well as cardiovascular, metabolic, and neurodegenerative disorders.

DESIGN, SYNTHESIS, AND BIOLOGICAL ASSESSMENT OF NOVEL N'-(BENZYLIDENE)PROPANEHYDRAZIDES AS MTDL FOR ALZHEIMER’S DISEASE

Objective: In this study, following the multi-target directed ligands (MTDLs) strategy and drawing inspiration from the neuroprotective structure of ferulic acid, eight novel N'-(benzylidene)propanehydrazide derivatives were designed, synthesized, and tested to evaluate their cholinesterase inhibitory and antioxidant capacities. Material and Method: To obtain the final compounds, first, corresponding key intermediates, 3-(substitutedamino)propanehydrazides, were prepared by the hydrolysis with hydrazine hydrate of methyl 3-(substitutedamino)propanoate intermediates. These intermediates had been prepared from the Michael addition of methyl acrylate and commercially available tertiary amine derivatives. Subsequently, the final compounds were synthesized from the reaction of the starting compounds 4-hydroxybenzaldehyde or 4-methoxybenzaldehyde and the corresponding key intermediates. Structural analysis of the synthesized and purified compounds was carried out using 1H-NMR, 13C-NMR, and HRMS. Then, all the final compounds were examined for their cholinesterase inhibitory effect using the modified Ellman method, their antioxidant effect using the DPPH and ORAC methods, and their metal chelator effect using UV-spectroscopy analysis. Moreover, physicochemical parameters were calculated using QikProp Schrödinger Suite 2023 to predict the druggability of all compounds. Result and Discussion: Seven of the eight final compounds exhibited moderate cholinesterase inhibition at varying rates. Compounds 2a (IC50 = 12.83 µM) and 2d (IC50 = 16.02 µM) were identified as the most potent inhibitors for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. Moreover, all the final compounds exhibited antioxidant activity in the ORAC assay. Chelator effects of all compounds were also observed for Cu(II), Fe(II), and Zn(II) ions at varying rates. Additionally, the final compounds demonstrated acceptable lead-like properties according to in-silico predictions.