Search Results (116)

Neurodegenerative disorders (NDs), such as Alzheimer’s and Parkinson’s diseases (AD and PD), despite having different main neuropathological hallmarks, share several interconnected aetiologic mechanisms and lack effective disease-modifying treatments. The multifactorial nature of these diseases has encouraged the development of new drugs such as multi-target-directed ligands (MTDLs). In this work, an anti-AD drug (rivastigmine, RIV) was fused and conjugated with a series of antioxidant scaffolds to obtain a small library of RIV–antiox hybrids. In addition to inhibitory activity towards both cholinesterases, these hybrids exhibited radical scavenging activity, inhibition of Aβ aggregation, and neuroprotection against cell death induced in AD models. The relevant anti-AD properties already found for these hybrids challenged us to also assess their capacity to modulate and interfere with ROS-associated harmful dysfunctions, namely in the dysregulation of biometal ions (Fe³⁺, Cu²⁺, and Zn²⁺) and upregulation of monoamine oxidases (MAOs). In particular, the capacity of the hybrids for metal chelation and inhibition of Cu-induced Aβ aggregation and MAO isoforms was evaluated, as well as their neuroprotection capacity in cell models of PD. Overall, some of these RIV hybrids appear as lead compounds for the development of novel multifunctional agents against NDs. Full article

Background: Hepatitis B virus (HBV) infection continues to be a major public health concern, especially in sub-Saharan Africa, where widespread epidemics and restricted availability of long-term antiviral therapies result in higher mortality and morbidity rates. Drug repurposing represents a strategic approach to accelerate the discovery of effective therapies by leveraging agents with demonstrated antiviral and immunomodulatory activity. Product Nkabinde (PN) is a patented African polyherbal formulation initially developed for the treatment of HIV. Recent experimental studies demonstrate PN’s potent anti-HIV activity and significant immunomodulatory effects in human immune cells, implicating host-directed mechanisms relevant to chronic viral infections. This study combines an integrative application of network pharmacology and molecular docking to evaluate the repurposing potential of PN as a multi-target agent in HBV. Method: Bioactive components of PN were screened, and compound-associated targets were intersected with HBV-associated genes (proteins) to construct a protein–protein interaction (PPI) network. Topological analysis identified 10 hub targets (STAT1, STAT3, SRC, HCK, EGFR, SYK, PIK3CA, PIK3CB, PIK3R1, and PTPN11). Gene Ontology and KEGG pathway enrichment were performed with an FDR cut-off < 0.05. Significantly enriched pathways included JAK–STAT signaling, chemokine signaling, EGFR-TKI resistance, PI3K complex signaling, and viral infection pathways, particularly those related to Kaposi sarcoma virus and HSV-1, indicating immunoregulatory and antiviral roles. Molecular docking was performed using AutoDock Vina 1.1.2 to evaluate binding affinity and interaction mode of key PN phytochemicals against the hub proteins, and results were compared to their respective co-crystallized ligands. Results: Molecular docking indicated that major phytochemicals from PN exhibited significant binding affinities across all 10 hub host targets, typically outperforming or closely matching their respective co-crystallized ligands. The strongest contacts were observed for β-sitosterol–PIK3CB (−14.2 kcal/mol) and oleanolic acid–SYK (−14.0 kcal/mol), which were significantly stronger than the co-crystallized ligands (−7.9 and −8.3 kcal/mol, respectively), indicating robust stabilization within catalytic and regulatory pockets. Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol) and PIK3CA (−9.5 vs. −7.3 kcal/mol), quercetin toward PIK3R1 (−10.6 vs. −8.2 kcal/mol) and PTPN11 (−9.2 vs. −7.5 kcal/mol), rutin toward SRC (−10.5 vs. 7.8 kcal/mol), and diosgenin toward EGFR (−9.4 vs. 8.4 kcal/mol). Procyanidin B2 maintained robust multi-hydrogen bonding networks, demonstrating significant binding, despite STAT1 and STAT3 docking showing identical affinities to co-crystals. Conserved hydrogen bonds, π–cation interactions, and significant hydrophobic packing at ATP-binding clefts and regulatory domains supported these interaction patterns, indicating competitive suppression of host signaling nodes taken over by HBV. Conclusions: Together, these results demonstrate that the components of PN possess strong multitarget binding capabilities across the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways, supporting their potential repurposing as host-directed HBV therapeutics with the ability to impede immune evasion, viral persistence, and HBV-associated oncogenic progression. Full article

Multitarget-directed ligands offer a promising strategy for overcoming tumor complexity through simultaneous modulation of complementary oncogenic pathways. In this work, a novel (E)-6-(3-(4-methyl-2-thioxo-2,3-dihydrothiazol-5-yl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (compound 6) was synthesized and evaluated as a dual inhibitor of tubulin polymerization and tumor-associated carbonic anhydrases (CAs) IX and XII. Compound 6 displayed potent antiproliferative activity, particularly against MDA-MB-231 triple-negative breast cancer cells (IC₅₀ = 0.37 µM), with excellent selectivity toward non-tumorigenic cells. Mechanistic studies demonstrated strong tubulin polymerization inhibition (IC₅₀ = 3.40 ± 0.09 µM) and submicromolar inhibition of CA IX (IC₅₀ = 0.102 ± 0.005 µM) and CA XII (IC₅₀ = 0.213 ± 0.004 µM), accompanied by downregulation of CA-IX and CA-XII protein expression. Cellular investigations revealed pronounced G₂/M phase arrest and apoptosis induction via mitochondrial signaling and caspase activation. Anti-angiogenic activity was supported by inhibition of endothelial migration and concentration-dependent suppression of VEGFR-2 (Tyr1175) phosphorylation in HUVEC cells. Human liver microsomal assays indicated measurable metabolic stability, while molecular docking and in silico ADMET predictions supported target engagement and drug-like properties. Collectively, these findings identify compound 6 as a promising multitarget anticancer lead integrating antimitotic, metabolic, and anti-angiogenic mechanisms. Full article

A new series of tacrine–coumarin hybrids (compounds 15a–18b) linked by 1,2,3-triazole had been designed and synthesized as multifunctional ligands for the treatment of Alzheimer’s disease (AD). The inhibitory effects of the synthesized compounds on AChE and BuChE, their ability to inhibit Aβ aggregation, and their MAO inhibitory activities were evaluated. In vitro studies showed that some of the hybrids (compounds 17a–18b) exhibited significant abilities to inhibit both AChE and BuChE, self-induced Aβ aggregation, and MAO-B. In particular, compound 17d showed a well-balanced inhibitory profile against AChE and BuChE (IC₅₀ = 0.080 ± 0.007 μM for AChE, IC₅₀ = 0.044 ± 0.004 μM for BuChE), self-induced Aβ aggregation (58.4% ± 2.1% at 20 μM), and MAO-B (IC₅₀ = 0.18 ± 0.01 μM), suggesting that 17d might be an excellent multifunctional agent for AD treatment. In addition, compounds 15a and 15b were identified as selective inhibitors of BuChE at micromolar concentrations. Full article

Background: The development of Multi-Target-Directed Ligands (MTDLs) has emerged as a significant strategy for addressing complex, overlapping pathologies such as cancer and Alzheimer’s disease (AD). This study aims to provide a robust computational framework for the design of dual-target inhibitors. Methods: This study presents an integrated and rigorous computational pipeline combining Quantitative Structure–Activity Relationship (QSAR) modeling, Molecular Docking, and Molecular Dynamics (MD) simulations with Dynamic Cross-Correlation Matrix (DCCM) analysis. Using a dataset of 57 known tubulin inhibitors, two high-performing QSAR models were developed to guide the rational design of 16 novel trimethoxyphenyl-based analogues. Results: Following ADMET and drug-likeness filtering, Lead Candidates 15 and 16 were identified. Quantitative activity predictions confirmed their enhanced potency thresholds, which were subsequently validated through static docking against β-tubulin (PDB: 4O2B) and Acetylcholinesterase (PDB: 1EVE). In total, 100 ns MD simulations and MM-GBSA calculations demonstrated superior binding stability and energetically favorable profiles for both targets, while DCCM analysis confirmed the functional synchrony of the protein–ligand complexes. Conclusions: The results provide a validated structural hypothesis for dual-target inhibition. The identified leads, 15 and 16, demonstrate strong predictive potential and are prioritized for chemical synthesis and in vitro biological evaluation. Full article

New arylbenzofuran derivatives were designed, synthesized, and evaluated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Five hybrid compounds (31–35) feature a 2-phenylbenzofuran core linked via a heptyloxy spacer to an N-methylbenzylamine moiety, to enhance interactions within the active site of BChE. Biological evaluation revealed that brominated derivatives 34 and 35 showed the highest cholinesterases (ChE) inhibition compared to their chlorinated analogs, with compound 34 showing the highest activity for both AChE (IC₅₀ = 27.7 μM) and BChE (IC₅₀ = 0.7 μM). These compounds proved to be non-cytotoxic and demonstrated significant antioxidant activity in SH-SY5Y cells exposed to hydrogen peroxide (H₂O₂), highlighting their potential to mitigate oxidative stress: a key pathological factor in Alzheimer’s disease. Structural activity analysis suggests that bromine substitution at position 7 and the presence of a seven-carbon linker are critical for dual ChE inhibition and selectivity towards BChE. ADMET prediction indicates favorable pharmacokinetic properties, including drug-likeness and oral bioavailability. Overall, these findings highlight the potential of the 2-arylbenzofuran as a promising scaffold for multitarget-directed ligands in Alzheimer’s disease therapy. Full article

A series of novel granatane–triazole hybrid molecules was designed, synthesized, and evaluated as dual acetylcholinesterase (AChE) and β-secretase 1 (BACE1) inhibitors. The compounds were obtained through a convergent synthetic route involving azide formation, triazole construction via dipolar cycloaddition, and final coupling with a granatane scaffold to give a pseudopelletierine (3-granatanone) analogue. In vitro assays demonstrated that all target compounds inhibited both AChE and BACE1. Molecular docking and molecular dynamics simulations revealed stable interactions with key catalytic residues, suggesting distinct binding modes compared to reference ligands. QSAR-based pharmacokinetic predictions indicated favorable blood–brain barrier permeability and compliance with key drug-likeness filters. These findings identify granatane–triazole hybrids as promising multi-target directed ligand (MTDL) candidates with potential for further optimization in the search for new anti-Alzheimer therapeutics. Full article

Phosphatidylinositol-3-kinases (PI3Ks) constitute an important validated therapeutic class involved in crucial cellular processes, and their dysregulation is associated with cancer initiation and progression. Nonetheless, intrinsic and acquired resistance mechanisms associated with PI3K pathway modulation have underscored the need for alternative therapeutic strategies. In this context, recent studies have shown that simultaneous inhibition of PI3K and histone deacetylases (HDAC) promotes synergistic antitumor effects in different cancer cell lines. HDACs are validated epigenetic targets that are extensively explored in clinical practice and have a pharmacophore with versatility for structural modifications, which facilitates the design of multitarget inhibitors. This review examines the rational design and synthetic evolution of dual PI3K/HDAC inhibitors, an area catalyzed by the development of fimepinostat, the first clinically evaluated agent exhibiting potent and balanced inhibition of both targets. We provide a critical overview of PI3K/HDAC multitarget inhibitors reported in recent years that have progressed to preclinical or clinical investigation, discussing the structural frameworks employed, medicinal chemistry strategies adopted, and structure–activity relationships established. Particular attention is given to advantageous molecular features as well as challenges related to toxicity, pharmacokinetic behavior, and pharmacodynamic modulation. From this comprehensive analysis, we outline key considerations and emerging design principles that may inform the next generation of PI3K/HDAC multitarget drug candidates. Insights derived from the diversity of chemical scaffolds, activity profiles, and selectivity patterns described herein may support the development of innovative therapeutic agents capable of overcoming current limitations in anticancer treatment. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design. Full article

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, affecting millions of people and challenging the public health framework globally. While the definitive cause of AD remains unclear, researchers are concentrating their efforts on several prominent theories. Currently, there are very few FDA-approved medications for AD, and these primarily alleviate symptoms rather than alter the disease’s progression. In response, research efforts focus on developing new medicines that address the complex nature of AD through multi-targeted approaches. Multitarget-directed ligands (MTDLs) are a promising treatment strategy for AD, despite the significant challenges they pose. This review examines recent advancements in designing prospective targeted MTDLs to combat AD, with a focus on categorizing the lead generation process and investigating the integration methods of key pharmacophores within the 2024–2025 timeframe. The review highlights numerous examples of novel MTDLs that address various AD hallmarks, demonstrating their broad therapeutic potential. These targets and activities include cholinesterase (AChE and/or BuChE) inhibition, monoamine oxidase (MAO-A and/or MAO-B) inhibition, antioxidant activity, amyloid-beta (Aβ) aggregation inhibition, tau protein aggregation inhibition, glycogen synthase kinase 3β (GSK-3β) inhibition, calcium channel blockade, anti-inflammatory activity, and other hallmarks. Full article

Objective: This study aimed to systematically investigate the potential antibacterial mechanisms of ethacridine in the treatment of diabetic foot ulcers (DFUs) by integrating network pharmacology, molecular docking, and molecular dynamics simulation approaches. Methods: The potential targets of ethacridine were predicted using the SwissTargetPrediction and PharmMapper databases and subsequently converted to gene symbols via the UniProt database. DFU-related and antibacterial-related targets were retrieved from the GeneCards and OMIM databases. The overlapping targets among ethacridine, DFU, and antibacterial-related genes were identified as candidate therapeutic targets. A “drug–disease–target” network was constructed using Cytoscape, while protein–protein interaction (PPI) networks were built through the STRING database. GO and KEGG enrichment analyses were performed using R software. Molecular docking was conducted to evaluate the binding affinities between core compounds and hub targets. Furthermore, molecular dynamics (MD) simulation was applied to assess the binding stability of the top-ranked compound–target complex. Finally, RT-qPCR was conducted on wound edge tissue samples from DFU patients treated with ethacridine to experimentally validate the mRNA expression of predicted hub genes. Results: A total of 302 potential ethacridine-related targets, 4264 DFU-related targets, and 1942 antibacterial-related targets were identified. Intersection analysis revealed 105 common targets potentially involved in the antibacterial effects of ethacridine against DFU. PPI network analysis highlighted 10 hub targets, including AKT1, EGFR, SRC, HSP90AA1, and MMP9. GO enrichment indicated significant involvement in responses to reactive oxygen species, regulation of inflammatory responses, responses to lipopolysaccharide, and bacterial molecular patterns. KEGG pathway analysis identified 157 relevant pathways, including the lipid and atherosclerosis, TNF signaling, IL-17 signaling, and the AGE–RAGE signaling pathways in diabetic complications. Molecular docking demonstrated favorable binding affinities (all < −5.0 kcal/mol) between ethacridine and the hub targets, with the strongest binding observed between MMP9 and ethacridine (−9.8 kcal/mol). These docking results suggest possible interaction tendencies that may contribute indirectly to Ethacridine’s network-level regulatory effects, rather than direct binding to all targets in vivo. Molecular dynamics simulation further confirmed the stable interaction between MMP9 and ethacridine. RT-qPCR validation in clinical DFU tissue samples demonstrated expression trends of key genes consistent with in silico predictions. These results reflect transcriptional regulation consistent with pathway modulation predicted by the network analysis, rather than direct protein–ligand binding across all targets. Conclusion: Ethacridine may exert antibacterial effects against bacterial biofilms in DFU through multi-target and multi-pathway mechanisms. These findings highlight ethacridine’s translational potential as a safe, readily available, and mechanistically validated topical agent for the clinical management of biofilm-associated diabetic foot infections. Full article

Background: Multitarget-directed ligands (MTDLs), particularly those combining cholinesterase inhibition with additional mechanisms, are promising candidates for Alzheimer’s disease (AD) therapy. Based on our previous identification of a dual-active coumarin derivative, we designed a new series of 7-alkoxyamino-3-(1,2,3-triazole)-coumarins. Methods: These compounds were synthesized by a new Sonogashira protocol and evaluated for AChE and BChE inhibition, enzymatic kinetics, molecular docking, neurotoxicity in SH-SY5Y cells, neuroprotection against H₂O₂-induced oxidative stress, and additional interactions with H₃R and MAOs. Results: All derivatives inhibited AChE with IC₅₀ values of 4–104 nM, displaying high selectivity over BChE (up to 686-fold). Kinetic and docking studies indicated mixed-type inhibition involving both CAS and PAS. The most potent compounds (1h, 1j, 1k, 1q) were non-neurotoxic up to 50 µM, while 1h and 1k also showed neuroprotective effects at 12.5 µM. Selected derivatives (1b, 1h, 1q) demonstrated multitarget potential, including H₃R affinity (K_i as low as 32 nM for 1b) and MAO inhibition (IC₅₀ of 1688 nM for 1q). Conclusions: This series of coumarin–triazole derivatives combines potent and selective AChE inhibition with neuroprotective and multitarget activities, highlighting their promise as candidates for AD therapy. Full article

Acetylcholinesterase (AChE) has emerged not only as a cholinergic enzyme but also as a modulator of β-amyloid (Aβ) aggregation via its peripheral anionic site (PAS), making it a dual-purpose target in Alzheimer’s disease. While classical AChE inhibitors provide symptomatic relief, they lack efficacy against the amyloidogenic cascade. This review highlights recent advances in multifunctional AChE pharmacophores that inhibit enzymatic activity while simultaneously interfering with Aβ aggregation, oxidative stress, metal dyshomeostasis, and neuroinflammation. Particular emphasis is placed on dual-site inhibitors targeting both catalytic and peripheral domains, multi-target-directed ligands (MTDLs) acting on multiple neurodegenerative pathways, and metal-chelating hybrids that address redox-active metal ions promoting Aβ fibrillization. We also discuss enabling technologies such as AI-assisted drug design, high-resolution structural tools, and human induced pluripotent stem cell (iPSC)-derived neuronal models that support physiologically relevant validation. These insights reflect a paradigm shift towards disease-modifying therapies that bridge molecular pharmacology and pathophysiological relevance. Full article

SARS-CoV-2 entry into host cells involves multiple steps and is a highly orchestrated process. Both the host protease TMPRSS2 and the HR1/HR2 segment within the spike (S) protein play a crucial role in promoting viral invasion. Herein, we report a series of bifunctional SARS-CoV-2 entry inhibitors formed by covalently linking a TMPRSS2 inhibitor, Camostat (Cm), and an HR1-targeting peptide fusion inhibitor IPB19 via a poly (ethylene glycol) (PEG) linker. Among them, IP4X and IP4Z display potent inhibitory activities against SARS-CoV-2 with similar IC₅₀ values of 0.16 μM and 0.17 μM, respectively. The efficacy surpassed that of their parent inhibitors by approximately 28-fold relative to Camostat and 15-fold relative to IPB19. We confirm that IP4X and IP4Z exhibit a dual-targeting mechanism by binding to both TMPRSS2 and HR1 region of S protein. These findings highlight the potential of the bifunctional inhibitors for further development as a novel multitarget therapy against SARS-CoV-2 infection and enrich the understanding of S-mediated entry of SARS-CoV-2 into host cells. Full article

A novel series of multifunctional tacrine–quinoline hybrids were designed, synthesized, and evaluated as potential anti-Alzheimer’s agents. These compounds incorporate tacrine for cholinesterase’s inhibition and 8-hydroxyquinoline for metal chelation. Piperazine was selected as a linker to provide conformational flexibility and to create favorable cation–π interactions with residues in the mid-gorge region of AChE, enhancing dual-site binding with AChE to inhibit Aβ aggregation. In vitro studies demonstrated submicromolar inhibitory activity toward both AChE and BuChE, particularly for compounds 16e (IC₅₀ = 0.10 μM for AChE, 0.043 μM for BuChE) and 16h (IC₅₀ = 0.21 μM for AChE, 0.10 μM for BuChE). These compounds also exhibited potent inhibition of self-induced Aβ_1–42 aggregation (16e: 80.5% ± 4.4%, 16h: 93.2% ± 3.9% at 20 μM). Kinetic analyses revealed mixed-type inhibition, suggesting dual binding to both CAS and PAS of AChE. UV–vis spectrometry confirmed the chelation of Cu²⁺ and Zn²⁺ ions by the 8-hydroxyquinoline moiety. These findings highlight the tacrine–quinoline scaffold as a promising platform for the discovery of a multitarget-directed anti-AD drug. Full article