Search Results (126)

Quinoline is a bicyclic aromatic heterocycle composed of a fused benzene and pyridine ring, and it has held an important place in medicinal chemistry for nearly two centuries. F. Runge first isolated it from coal tar in 1834, and it was later found to form the structural core of well-known natural products such as quinine, camptothecin, and γ-fagarine. Its asymmetric electron distribution, amphoteric character, and ability to undergo both electrophilic and nucleophilic substitution confer considerable pharmacophoric versatility on the quinoline scaffold. This review covers the chemistry and therapeutic relevance of quinoline derivatives, with an emphasis on their pharmacological significance rather than on their synthesis alone. It begins with a brief account of the scaffold’s structural features and main synthetic routes, then examines the biological activities reported for quinoline-based compounds, including antibacterial, anticancer, anti-inflammatory, antimalarial, antiparasitic, antitubercular, antioxidant, and antiviral activities, together with structure–activity relationships discussed at the level of specific ligand–target interactions where data allow. The last section covers more recent directions in quinoline-based drug discovery, including PROTAC degraders, kinase inhibitors, and multitarget-directed ligands, an area not extensively addressed in earlier reviews of this scaffold. The literature surveyed here shows that quinoline derivatives continue to serve as a versatile scaffold for generating new leads, linking established synthetic chemistry with current mechanistic and computational approaches. The continued diversification of quinoline-based chemotypes and their biological mechanisms reinforces the importance of this scaffold as a versatile platform for medicinal chemistry and drug discovery. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, highlighting the need for safe and effective therapeutic strategies targeting multiple oncogenic pathways. Cinnamon (Cinnamomum spp.) contains several bioactive phytochemicals with reported antioxidant and anticancer properties; however, their potential interactions with key cancer-associated signaling proteins have not been comprehensively investigated. In this study, an integrated computational and preliminary experimental approach was employed to evaluate four major cinnamon phytochemicals, namely e-cinnamaldehyde, eugenol, p-cymene, and cinnamic acid. Consensus molecular docking was performed using AutoDock Vina (v1.2.7), Smina (v2020.12.10), and GNINA (v1.3.3) against phosphoinositide 3-kinase (PI3K), nuclear factor kappa B (NF-κB), and mammalian target of rapamycin (mTOR). Docking analyses were complemented by protein-ligand interaction profiling, pharmacokinetic and toxicity prediction (ADMET), and a 100 ns molecular dynamics simulation with MM/GBSA binding free-energy analysis of the selected mTOR-p-cymene complex. In addition, the antioxidant activity and cytotoxic effects of a crude methanolic cinnamon bark extract were evaluated using in vitro antioxidant assays and MTT assays against HCT-116 and HT-29 colorectal cancer cell lines. Consensus docking predicted that all four phytochemicals were capable of interacting with the selected protein targets, although the predicted binding profiles varied among the compounds. Eugenol showed comparatively more favorable predicted interactions with PI3K, p-cymene produced the lowest predicted docking score for NF-κB, and cinnamic acid displayed a comparatively consistent predicted multitarget binding profile across PI3K, NF-κB, and mTOR. ADMET analysis suggested that all compounds satisfied major drug-likeness criteria and exhibited predicted oral bioavailability, although potential cytochrome P450 interactions and hepatotoxicity were predicted for some compounds. Molecular dynamics simulation indicated that the selected mTOR-p-cymene complex maintained a stable binding pose throughout the simulation, while MM/GBSA analysis yielded a modest binding free-energy estimate (ΔG_bind = −4.70 ± 8.20 kcal/mol), which should be interpreted cautiously because of the observed energetic variability. The crude methanolic cinnamon bark extract exhibited antioxidant activity and reduced the viability of HCT-116 and HT-29 colorectal cancer cells in a concentration-dependent manner. Collectively, these findings provide computational predictions of potential interactions between selected cinnamon-derived phytochemicals and cancer-associated signaling proteins and are consistent with the preliminary observation that the crude cinnamon extract exhibits antioxidant activity and cytotoxic effects in colorectal cancer cell lines. However, the computational analyses do not establish direct inhibition of the PI3K/NF-κB/mTOR signaling pathway, and the biological assays were performed using a crude extract rather than isolated phytochemicals. Therefore, further studies using purified compounds, biochemical target validation, pathway-specific cellular analyses, and in vivo models are required to determine whether the predicted protein-ligand interactions contribute to the observed biological activity. Full article

Driven by the growing demand for quality assurance within the essential oil (EO) industry, this study builds upon prior seasonal chemical and anticholinergic characterizations of Azorean Cryptomeria japonica foliage (Az–CJF) EO by presently evaluating the seasonal variations in its antibacterial, antioxidant, and anti-inflammatory activities. Autumn (Aut–EO) and spring (Spr–EO) samples exhibited a uniform, targeted antibacterial profile exclusively against Gram-positive bacteria, with a MIC of 5.0 mg/mL for Micrococcus luteus and ≥10.0 mg/mL for Bacillus licheniformis, B. subtilis, and Staphylococcus aureus. Antioxidant capacities also remained seasonally consistent within each of the three individual assays, namely the DPPH, ABTS, and β-carotene bleaching assays (EC₅₀ ≤ 10.5, ≤ 6.0, and ≤0.3 mg/mL, respectively), suggesting a stable potential for lipid peroxidation inhibition. In addition, both EOs protected against bovine serum albumin denaturation (84–98%) with no statistically significant differences, generally outperforming diclofenac sodium (70–87%). Notably, anti-inflammatory activity via COX pathways proved to be seasonally dependent: Spr–EO inhibited COX-1 and COX-2 more significantly than Aut–EO, with both EOs showing COX-1 selectivity (IC₅₀ of 284 vs. 560 µg/mL). Although less potent than diclofenac sodium (COX IC₅₀ < 0.2 µg/mL), the superior activity of Spr–EO was supported by molecular docking, suggesting this enhanced effect is driven by higher contents of kaur-16-ene and oxygenated sesquiterpenes (such as α- and β-eudesmol). These bioactivities provide baseline parameters for batch standardization. By merging stable core properties with seasonal anti-inflammatory profiles, Az–CJF EO shows promise as a natural multi-target-directed ligand (MTDL) for therapeutic applications within a circular bioeconomy. Full article

Pyrazole derivatives have attracted considerable interest in medicinal chemistry as adaptable frameworks for developing cholinesterase inhibitors, owing to their advantageous physicochemical properties and structural flexibility. The heteroaromatic characteristics of the pyrazole core allow for various substitution patterns, promoting selective interactions with both the catalytically active site (CAS) and the peripheral anionic site (PAS) of cholinesterase enzymes. These attributes enable pyrazole-based drugs to be viable candidates for the therapy of cognitive disorders, especially Alzheimer’s disease. This study aims to systematically describe medicinal chemistry studies on pyrazole-based cholinesterase inhibitors conducted from 2020 to 2025. The focus is on structural alterations of the pyrazole core and their impact on the inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using structure–activity relationship (SAR) analysis. Recent advancements in in vitro enzymatic inhibition studies, molecular docking, kinetic analysis, ADME predictions, and multi-target-directed ligand (MTDL) techniques are rigorously evaluated to elucidate trends in potency, selectivity, and drug-like characteristics based on information retrieved from three search engines: Scopus, PubMed, and Google Scholar. This review addresses significant challenges in pharmacokinetics, blood–brain barrier permeability, and safety while delineating prospects for integrating rational design, computational modeling, and biological validation to expedite the development of clinically relevant pyrazole-based cholinesterase inhibitors for Alzheimer’s disease. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and is driven by complex metabolic and inflammatory disturbances. Extra virgin olive oil (EVOO), a hallmark of the Mediterranean diet, contains numerous bioactive compounds that may exert beneficial effects on liver and cardiometabolic health. This preliminary study investigated the interactions of selected EVOO-derived compounds, with molecular targets implicated in MASLD using an integrated in silico approach. Methods: Phenolic compounds, secoiridoids, fatty acids, sterols, squalene, and vitamin E were evaluated. Physicochemical properties, drug-likeness, and pharmacokinetic profiles were predicted using ADMETlab 3.0. Molecular docking analyses were performed against liver X receptors (LXRα and LXRβ), peroxisome proliferator-activated receptors (PPARα and PPARγ), hydroxymethylglutaryl-CoA reductase, cyclooxygenase-1, and cyclooxygenase-2. Binding modes were further examined by three-dimensional interaction analyses. Results: The investigated compounds displayed heterogeneous physicochemical and pharmacokinetic profiles. Oleuropein, oleacein, and oleocanthal demonstrated the most consistent binding patterns across targets involved in lipid metabolism, inflammation, and cardiometabolic regulation. In contrast, highly lipophilic compounds, including squalene, β-sitosterol, and vitamin E, frequently achieved high docking scores but formed fewer biologically relevant interactions. Conclusions: EVOO phenolics, particularly oleuropein, oleacein, and oleocanthal, emerged as promising multi-target modulators of MASLD-related pathways, supporting the potential role of EVOO in MASLD prevention and management. Full article

Natural coumarins are a structurally privileged group of bioactive benzopyranone lactones widely spread across the Apiaceae, Rutaceae, and Leguminosae families, and hold significant potential as inhibitors of pathological protein aggregation in Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes mellitus. The fully planar, rigid bicyclic structure of the coumarin nucleus (~3.4–3.5 Å thickness) is geometrically compatible with intercalative π–π stacking with aggregation-nucleating aromatic residues, including Phe19 of Aβ(1–42), providing a mechanistically coherent pharmacophoric basis for anti-aggregation activity according to computational and indirect biophysical evidence. This review critically evaluates the peer-reviewed literature on naturally occurring coumarins and their synthetic derivatives as candidate β-sheet intercalators, with analysis of SAR at C-3 to C-8 positions; multi-target-directed ligand designs with dual activities of inhibiting AChE, BACE-1, GSK-3β, and MAO-B, and as blood–brain barrier-penetrating neuroprotective agents validated in cellular and rodent models. The critical analysis identifies the translational gap between in vitro IC₅₀ values and attainable brain drug concentrations as the primary pharmacological obstacle. It identifies the absence of systematic investigation of coumarin against IAPP, a directly relevant amyloid target in metabolic neurodegeneration, as the most significant unmet research priority in the field. Full article

Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder and a major global health challenge. The traditional “one drug–one target” paradigm has shown limitations in addressing its multifactorial nature. Multitarget-directed ligands (MTDLs), designed to modulate multiple pathological pathways, have emerged as a promising therapeutic strategy. Objectives: To examine the structural, thematic, and temporal evolution of multitarget strategies for AD treatment between 2006 and 2025. Methods: A total of 1184 Web of Science-indexed articles were analyzed. Publication growth, h-index, author productivity, institutional and national contributions, and keyword co-occurrence networks were evaluated using VOSviewer. Bibliometric laws (Price, Bradford, Zipf, and Lotka) were applied to characterize productivity patterns and thematic organization. Results: Multitarget research shows exponential growth, suggesting a consolidation of the MTDL paradigm. China, India, the United States, Italy, and Spain were the most productive countries. Early studies focused on cholinesterase inhibition, particularly acetylcholinesterase-based hybrids. The field expanded to include β-amyloid aggregation, oxidative stress, metal chelation, and blood–brain barrier permeability. Recent trends emphasize integration of computational approaches, including molecular docking, molecular dynamics, virtual screening, and network pharmacology, alongside targets such as BACE1 and GSK-3β. Conclusions: Multitarget strategies have evolved toward a systems-oriented framework. Despite advances, challenges remain in reducing cholinesterase dependency and improving translational validation. This study provides a framework to interpret therapeutic evolution and guide future network-based drug design. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial–ROS–inflammatory signaling, aggregation–proteostasis failure, synaptic–neuroimmune dysfunction, and gut–brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP–AMP synthase (cGAS)—stimulator of interferon genes (STING) pathways—play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood–brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles. Full article

Cancers are intricate and multifactorial diseases. Despite progress in medicine, there are still some obstacles in their treatment due to drug resistance, the toxicity of combination therapy and lack of drug selectivity toward cancer cells. The solution to this may be multi-target directed ligands (MTDLs), which have gained more and more popularity over the years. This review presents a comprehensive overview of novel potential multi-targeted derivatives of nitrogen-containing heterocycles, as imidazole, pyrazole, 1,2,3-triazole and 1,2,4-triazole. The review gathers the selected literature from 2006 to 2026. The analysis focuses on the potency of the inhibitory activity of selected molecules against a variety of molecular targets, as well as on their interactions with protein binding sites. Additionally, the structure-activity relationship (SAR) studies within the collected series are included. The discussion may contribute to the development of new multi-target anticancer agents. Full article

Background: The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, remains a significant threat to global health. This continued threat is due to the emergence of new variants, the immune system’s limited ability to respond, and the limited effectiveness of available treatments for all individuals. Therefore, leveraging drug repurposing, a fast and inexpensive way to find other drugs that have already been shown to be safe and efficacious, becomes useful. This study leverages ADMET profiling, network pharmacology, and molecular docking to evaluate the repurposing of Product Nkabinde for COVID-19 treatment. Methods: ADMET analysis involving the bioactive phytochemicals of PN was evaluated for pharmacokinetic appropriateness and drug-likeness. Using topological analysis, a network of protein–protein interactions was built to identify hub genes, and predicted compound targets were intersected with COVID-19-associated genes to find shared targets. Their biological importance was characterized using functional enrichment analysis. The binding affinities of PN phytochemicals against hub proteins and SARS-CoV-2 viral proteases (Mpro and PLpro) were assessed by molecular docking using AutoDock Vina. To confirm docking accuracy, co-crystallized ligands were redocked using Schrodinger 2022-1. The multi-target therapeutic potential of PN in COVID-19 was assessed using this integrative network pharmacology and molecular docking technique. Results: Molecular docking demonstrated that PN phytochemicals displayed robust and persistent binding affinities for both viral and host targets. Oleanolic acid showed the best affinity toward Mpro (−12.9 kcal/mol vs. −8.3 kcal/mol), while quercetin-3-O-β-D-(6′-galloyl)-glucopyranoside showed better binding to PLpro (−8.4 kcal/mol vs. −6.4 kcal/mol). Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol), diosgenin toward EGFR (−9.4 vs. −8.4 kcal/mol), rutin toward SRC (−10.5 vs. −7.8 kcal/mol), and pimelea factor P2 toward PIK3R1 (−11.0 vs. −8.2 kcal/mol) all showed significantly higher affinities than their corresponding co-crystallized ligands. Furthermore, procyanidin B2 demonstrated consistent binding to STAT1 and STAT3, confirming its role in modulating immune signals. Most of the PN phytochemicals show advantageous pharmacokinetic properties, including elevated anticipated gastrointestinal absorption and adherence to Lipinski’s rule of five, signifying favorable oral bioavailability and drug-like properties. Moreover, PN exhibits a remarkable multi-target binding capacity against both SARS-CoV-2 proteases and key host signaling proteins involved in immune regulation and inflammatory responses, as determined by this integrative network pharmacology and molecular docking investigation. Conclusions: PN’s prospects as a host-directed, antiviral treatment for COVID-19 are demonstrated by its coordinated modulation of the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways. These results necessitate further experimental and clinical validation, providing a solid computational basis for repurposing PN in the treatment of COVID-19. Full article

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