Chemistry and Materials Science

Abstract: Novel iodinated cobalt bis(dicarbollide) conjugates with acridine were synthesized by the direct iodination reaction of cobalt bis(dicarbollide) conjugates and acridine with crystalline iodine. The cytotoxicity of new compounds against different human cell lines was evaluated. One of these compounds was found to be non-toxic for all cell types and was combined with polyvinylpyrrolidone to form a non-covalent complex to increase its water solubility. The BNCT experiment showed that pre-incubation with a new boron-containing complex followed by neutron irradiation reduces the survival of T98G glioblastoma cells to 25% and B16 melanoma cells to 17%. The biodistribution of the boron-containing compound ACR-PVP was investigated in a B16F10 melanoma murine model. Maximum uptake in tumor and healthy tissues was observed 15 minutes following single intravenous administration. ACR-PVP exhibited a considerably higher tumor-to-muscle ratio (5.4) relative to BPA (3.0), thereby indicating its potential as a promising candidate for boron neutron capture therapy. This study creates prerequisites for further research in the development of methods for synthesizing BNCT agents based on acridine.

Abstract: Soy isoflavones exhibit diverse health-promoting effects, including antioxidant and anti-inflammatory activities. However, these biological effects have largely been attributed to the modulation of cellular signaling pathways, whereas the influence of intestinal microbial metabolism on their direct radical-scavenging properties remains poorly understood. In this study, efficient synthetic routes were established for the major intestinal bacterial metabolites daidzein and genistein, equol (Eq), dehydroequol (DEq), 5-hydroxyequol (5-OH-Eq), and, for the first time, 5-hydroxydehydroequol (5-OH-DEq), and their direct radical-scavenging activities, reaction mechanisms, radical-scavenging capacities, and DNA protective effects were systematically evaluated. Introduction of a C-ring double bond markedly enhanced direct radical-scavenging activity, whereas the parent isoflavones and their reduced metabolites exhibited little or no activity. Among the compounds examined, 5-OH-DEq exhibited the highest antioxidant activity, scavenging radicals predominantly through a hydrogen atom transfer, with a second-order rate constant of 1.44 × 10³ M⁻¹ s⁻¹, exceeding that of Trolox and a radical-scavenging capacity of approximately three radical equivalents per molecule. Moreover, 5-OH-DEq protected plasmid DNA against radiation-induced oxidative damage. These findings demonstrate that intestinal microbial metabolism can function as a form of metabolic activation, converting dietary isoflavones into potent direct antioxidants. 5-OH-DEq was identified as a previously unexplored antioxidant metabolite and a promising lead scaffold for further development of next-generation phenolic antioxidants.

Abstract: Campylobacter jejuni tops the list of bacteria responsible for gastroenteritis in humans. Knowledge of capsular polysaccharide (CPS) fine structure allows for the design of chemical conjugation strategies and identification of gene clusters for bioconjugations. CPSs are the basis for a multivalent C. jejuni glycoconjugate vaccine that has as key serological markers variably linked O-methyl-phosphoramidate (MeOPN) moieties and heptoses of rare configurations. Previously, the activation strategy for C. jejuni CPSs whose backbones contained no vicinal diols (serotypes HS:4, HS:10, HS:15, HS:23/36 and HS:53) was based on oxidation of the non-reducing end sugar with periodate, followed by conjugation to protein via reductive amination. Here, we describe the approach taken to functionalize C. jejuni CPSs with inner regions susceptible to periodate centered on TEMPO/bleach-mediated oxidation of primary hydroxyls to carboxyls followed by carbodiimide-directed conjugation. This work describes the syntheses and immunogenicities of such C. jejuni CPS-conjugates, specifically those of serotypes HS:1, HS:2 and HS:3. The stoichiometric TEMPO/bleach-oxidation of CPSs showed preference for specific primary hydroxyl groups, such as C7 of 6-deoxy-heptoses, and furnished conjugates that induced strong IgG responses against the native C. jejuni CPSs. It is postulated that the enhanced immunogenicity of the described conjugates is due to the preservation of CPS structures and the zwitterionic character of CPSs, afforded by the native MeOPN units and unreacted carboxyls.

Abstract: Rapid screening methods reflecting the metabolic profile of urine are promising for assessing the risk of decreased renal function in children with obstructive uropathies. The aim of this pilot study was to evaluate the applicability of a reaction-based fingerprinting strategy for this purpose, which has previously demonstrated its effectiveness in recognizing samples with similar composition. The study included 27 children with hydronephrosis (HN, 5 patients) and vesicoureteral reflux (VUR, 15 patients), as well as healthy children without urinary pathology who comprised the control group (7 patients). Supervised chemometric analysis demonstrated that standard clinical and laboratory indicators enabled discrimination of urine samples from children with HN and VUR from the control group; however, the recognition accuracy was only satisfactory, ranging from 79% to 86%. Using the kinetic variant of fingerprinting, six indicator reactions of different natures involving dyes were investigated, with absorbance and fluorescence of the reaction products monitored photographically throughout the reaction. The introduction of urine samples into the indicator reactions enabled discrimination of both diagnoses (VUR and HN) from the control group and from each other, with recognition accuracy reaching 100%. Furthermore, no correlation was observed between the results obtained using kinetic-based methods and standard clinical and laboratory indicators, which may reflect different levels of the pathological process, namely functional and molecular. Thus, the reaction-based optical fingerprinting strategy can be considered a promising approach for in-depth non-invasive diagnostics in pediatric urology.

Abstract: Five new cembrane-type diterpenes (1–5), one new casbane-type diterpene (7), along with ten known related ones (6, 8–16), were isolated from the South China Sea soft coral Sinularia nanolobata. The structures of new compounds were elucidated through comprehensive spectroscopic analysis, NMR calculation with DP4+ probability analysis, time dependent density functional theory-electronic circular dichroism (TDDFT-ECD) calculations, and comparison with the reported spectroscopic data of known analogues. Structurally, compounds 2–5 featured rare five- to seven-membered oxygen-containing heterocyclic rings with diverse joints, reflecting remarkable chemical diversity of secondary metabolites. In bioassays, all isolates have been evaluated for their cytotoxic and anti-inflammatory effects.

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Functionalizing textiles with nanoparticles is a promising strategy for developing sustainable materials with antimicrobial activity and reduced potential for resistance. This study aimed to develop antimicrobial cotton and polyester (PE) textiles functionalized with gold and silver nanoparticles (Au@UP and Ag@UP) biosynthesized using Undaria pinnatifida (UP) aqueous extracts. Nanoparticle-functionalized textiles were characterized by UV–vis spectroscopy, SEM, and FTIR, and nanoparticle attachment–detachment and stability were evaluated on both substrates. Antioxidant activity was assessed by the DPPH assay, while antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa and cytocompatibility using the L-929 cell line were determined. UV–vis spectroscopy revealed a slow-release profile, while SEM, UV–vis, and FTIR confirmed nanoparticle binding. Cotton exhibited higher nanoparticle affinity and stability (KS=0.5007 for Au@UP and 0.4817 for Ag@UP), attributed to its abundance of reactive hydroxyl groups. Although antioxidant activity decreased after nanoparticle binding (<5%), functionalized cotton gauzes retained antimicrobial activity. Au@UP and Ag@UP textiles were non-cytotoxic (>80% cell viability) and inhibited the growth of S. aureus (~15% and 90%, respectively) and P. aeruginosa (~90% for both). These findings support the potential of UP-mediated nanoparticle-functionalized textiles, particularly Ag@UP-containing materials, as sustainable antimicrobial surfaces.

Abstract: Poor aqueous solubility limits roughly 40% of marketed oral drugs and up to ~90% of development candidates. One established remedy is the prodrug strategy: the covalent attachment of a bioreversible promoiety that regenerates the parent drug in vivo. The same conjugation can move a molecule in either of two opposite directions along the hydrophilic–lipophilic axis: hydrophilization raises aqueous solubility, whereas lipophilization instead raises membrane and oil solubility for permeation-limited or topical uses. This review addresses the hydrophilizing route and asks a single question: can enzymatic (biocatalytic) synthesis replace conventional chemistry in building water-soluble prodrugs? We examine, class by class of hydrophilic promoiety (polyol and sugar esters, glycosides, amino-acid esters, poly(ethylene glycol) and ionizable phosphates), the biocatalytic toolbox (lipases, acyltransferases, glycosidases and glycosyltransferases), the molecular determinants of its selectivity, the pharmacokinetic consequences of hydrophilization, and the translation of these reactions to process, benchmarking each against the corresponding chemical route. A consistent three-part test emerges: enzymes suffice, and frequently surpass chemistry, wherever an accessible hydroxyl or carboxyl must be functionalized regioselectively on a promoiety bearing no competing group and a moderate solubility gain is required. This is the regime of polyols, sugars and glycosides, with reported aqueous-solubility increases spanning roughly 4-fold to 5500-fold; chemistry remains necessary for ionizable phosphates, amino-acid esters and PEG carriers. Enzymatic routes are sufficient and advantageous for polyol and sugar prodrugs, yet the field’s central ‘green’ claim is asserted far more often than it is measured (E-factor, PMI, life-cycle assessment), and in-vivo pharmacokinetic data for enzymatically synthesized hydrophilizing prodrugs remain almost absent, the two gaps that most limit translation and set the agenda for the field.

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Medicinal plants are important sources of bioactive phytochemicals and essential mineral elements with therapeutic potential. This study investigated the effects of extraction solvent polarity on the total phenolic content (TPC), total flavonoid content (TFC), and elemental composition of Nerium oleander, Bulbine frutescens, and Cotyledon orbiculata. Phenolic and flavonoid contents were determined spectrophotometrically, while elemental nutrients in N. oleander extracts were analyzed using inductively coupled plasma-optical emission spectroscopy. N. oleander exhibited the highest phenolic and flavonoid contents among the three species. Dichloromethane extracts yielded the highest TPC (6.936 ± 0.613 mg GAE/100 mg), whereas hexane extracts produced the highest TFC (8.793 ± 0.020 mg QE/100 mg). Extraction solvent significantly affected phenolic recovery (p < 0.05), with a significant interaction between solvent and plant species. Essential macroelements (Ca, Mg, Na and K) and micronutrients (Al, Mn, Zn and Fe) were detected, while Cr, Cu, Ni and Pb were absent or below detectable limits. These findings demonstrate the importance of solvent selection and highlight N. oleander as a promising source of phytochemicals and mineral nutrients for phytomedicinal and nutraceutical applications.

Abstract: Background/Objectives: Piperazine constitutes a versatile heterocyclic core commonly used in drug development because of its ability to engage with different biological targets. The current research focuses on the computation-based drug-likeness analysis, gastrointestinal absorption prediction, and toxicity estimation of derivatives (1–27) of piperazine, where four compounds (1–4) belong to the list of commercially available drugs. Methods: Parameters related to drug-likeness, solubility and bioavailability were calculated by using the SwissADME and ADMETlab 3.0 web tools as well as MoloVol software (v1.2.0) and MarvinSketch software (v4.1.13). Aftewards, GI absorption, blood-brain barrier permeability, P-glycoprotein recognition and CYP450 inhibition were modeled. The toxicological characteristics were assessed by DataWarrior software (v06.05.04), which classified compounds as mutagenic, carcinogenic, reproductive, and irritant. Results: According to the BOILED‑Egg approach, compounds 2, 4–6, 10–21, 23–25, and 27 were estimated to exhibit good blood–brain barrier permeation. Majority of compounds (1–4, 7–9, 14, 16, 17, and 19–25) were recognized as P-glycoprotein substrates. The metabolic profile suggested inhibition of different CYP450 enzymes: 1A2, 2C19, 2C9, 2D6, and 3A4. None of the compounds (1–27) were indicated to pose mutagenic hazard. Compounds 5 and 13 were predicted to be carcinogenic. Compounds 6, 12, and 14 were anticipated to exhibit reproductive toxicity. Compounds 11–15 were expected to act as irritants. Conclusions: Computational data generate several hypotheses requiring further experimental validation of studied compounds as promising antiparasitic drugs (7, 8, 10), an antimicrobial drug (11), a neuroactive drug (16), anti-inflammatory drugs (18, 20–24), antitubercular drugs (25, 26), and an antitumor drug (27).

Abstract: Gonadotropin Releasing Hormone receptors (GnRHRs) are overexpressed in several hormone-dependent malignancies, making them attractive molecular targets for selective anticancer drug delivery. Peptide drug conjugates (PDCs) are a promising therapy for cancer and autoimmune diseases with high specificity and reduced toxicity. In this study, the three-dimensional structures of two previously synthesized mitoxantrone-GnRH conjugates, con3 and con7, were elucidated using high-resolution NMR spectroscopy in combination with molecular dynamics (MD) simulations. Complete ¹H and ¹³C resonance assignments were achieved in DMSO-d₆ through two-dimensional NMR experiments. NOESY-derived distance restraints were subsequently used to refine the conformational ensembles obtained from MD simulations performed in water and DMSO. Both conjugates exhibited compact bent conformations with a U-shaped peptide backbone. The mitoxantrone moiety is positioned close to the peptide backbone in water simulations and NMR-refined structures, while it is positioned farther away in DMSO, without affecting the orientation of key residues involved in GnRH receptor binding. Importantly, His², Trp³, and Arg⁸ remain solvent-exposed, whereas the disulfide bond is easily accessible to the solvent, consistent with the proposed drug release mechanism by the thioredoxin system. NMR-restrained molecular modeling confirmed the dominant conformational features predicted by the unconstrained theoretical simulations. Overall, these findings provide better structural understanding of the molecular organization of mitoxantrone–GnRH conjugates, highlighting key receptor-recognition residues and supporting both the proposed thioredoxin-mediated drug release mechanism and their previously reported biological properties. These insights may facilitate the rational design and optimization of improved GnRH peptide–drug conjugates for targeted therapy.

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Nerium oleander L is a medicinal plant of significant ethnopharmacological importance, yet its well-documented toxicity necessitates rigorous phytochemical characterization and standardization. This study comprehensively evaluated the influence of eight extraction solvents of varying polarity (water, methanol, ethanol, acetone, dichloromethane, chloroform, ethyl acetate, and hexane) and three analytical methods (foam-forming, optical activity, and spectrophotometric vanillin-acetic acid) on saponin quantification in N. oleander leaf extracts. Plant material was collected, dried, pulverized, and extracted via maceration, with saponin content determined using the three analytical approaches. Data were analyzed using two-way ANOVA with replication and Tukey’s HSD post-hoc testing. Results demonstrated statistically significant variation in saponin yield attributable to both extraction solvent (F = 143.44, p < 0.001) and analytical method (F = 90.53, p < 0.001), with a significant interaction effect (F = 6.35, p < 0.001). Polar solvents, particularly methanol (18.22 ± 0.57%) and ethanol (16.32 ± 3.94%), exhibited superior extraction efficiency, consistent with the glycosidic nature of saponins. Hexane yielded anomalously elevated content (18.00 ± 2.57%), potentially due to unique hydrogen-bonding interactions. The spectrophotometric method consistently produced the highest saponin values due to enhanced sensitivity, while the foam-forming method proved suitable only for preliminary screening, and optical activity lacked specificity due to interference from other chiral constituents. This study conclusively demonstrates that methodological selection critically influences saponin quantification, with significant implications for ethnopharmacological standardization and quality control. Based on these findings, methanol extraction followed by spectrophotometric vanillin-acetic acid analysis is recommended as the optimal protocol for routine quantitative analysis, providing the highest sensitivity, reproducibility, and practical feasibility. These findings provide an evidence-based framework for method selection and underscore the necessity of harmonized analytical protocols to ensure accuracy, reproducibility, and comparability in natural product research, thereby supporting the safe and effective development of N. oleander-based therapeutics and cosmetic formulations.

Abstract: Background: Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide and ranks third in Colombia. Despite therapeutic advances, limitations such as reduced efficacy, adverse effects, and drug resistance persist. In the search for novel ther-apeutic strategies, molecular hybridization of melatonin and furanochalcone—compounds with antioxidant and antitumor properties—led to the synthesis of a novel hybrid mole-cule Mel-Fur (6f), a promising candidate for CRC treatment. Objectives: The aim of this study was to develop and validate an HPLC-DAD analytical method for quantification of Mel-Fur in serum and murine organ matrices. Methods: Chromatographic analysis used an Agilent Series 1200 system with a diode array detector and a C30 column under opti-mized conditions: acetonitrile: water (85:15, v/v) as mobile phase, flow rate 0.8 mL/min, detection at 342 nm, retention time 4.3 min. Results: The method fulfilled ICH Q2 (R1) and FDA validation guidelines, showing high selectivity, excellent linearity (R² > 0.999), sensitivity, precision, accuracy (RE% and CV% < 15%), recovery above 93%, and analyte stability for up to 8 days. The validated method was applied in a pilot in vivo biodistribu-tion study. Following oral administration of a single dose of Mel-Fur (1000 mg/kg) in BALB/c mice, rapid absorption and elimination were observed, with measurable systemic exposure and effective distribution into peripheral tissues. Pharmacokinetic analysis re-vealed preferential accumulation in lungs and liver, with sustained presence in colon. Conclusions: These findings provide a robust analytical tool and preliminary pharmaco-kinetic insights supporting further preclinical development of Mel-Fur as a potential therapeutic candidate for CRC.

Abstract: As machine learning (ML) becomes increasingly integrated into drug discovery, reliance on legacy datasets and superficial performance metrics threatens to stall genuine progress. This perspective examines common pitfalls in solubility modeling, specifically overreliance on flawed public datasets and insufficient similarity analysis between training and test sets. By comparing performance on "real-world" datasets with consistent experimental conditions, specifically the Biogen and ASAP Discovery sets, we demonstrate that inflated correlations can mask poor generalizability. We propose new guidelines for authors, reviewers, and journals to elevate the standard of ML validation.

Abstract: Background/Objectives: Cancer resistance, pathway redundancy, and compensatory signaling challenge traditional therapies. Dual-target strategies address this by engaging two disease-relevant proteins within a single molecule. This review compares classical dual inhibitors with dual proteolysis-targeting chimeras (dual PROTACs) to evaluate the therapeutic advantages of degradation over occupancy. Methods: We examine oncology target pairs featuring documented examples of both dual inhibitors and dual PROTACs. The biological rationale for co-targeting is analyzed alongside a comparative assessment of their chemical frameworks, focusing heavily on the synthetic strategies, length, and structure of linkers required for dual-PROTAC ternary complex formation. Results: While dual inhibitors rely on active-site occupancy, dual PROTACs leverage the ubiquitin–proteasome system for catalytic target elimination. Transitioning from dual inhibition to dual degradation frequently enhances antitumor efficacy, extends duration of action, and overcomes resistance mutations. Optimizing linker design remains the critical factor in balancing the simultaneous degradation kinetics of two distinct proteins. Conclusions: Dual PROTACs provide distinct advantages over traditional inhibitors by completely destroying target proteins rather than merely blocking them. This comparison offers a practical entry point and actionable synthetic strategies for medicinal chemists designing multi-target protein degraders.

Abstract: Colloidal instability remains a dominant cause of product failure, manufacturing attrition, and safety risk across biopharmaceutical modalities including monoclonal antibodies (mAbs), bispecific antibodies, antibody-drug conjugates (ADCs), and mRNA-lipid nanoparticle systems. Protein aggregation is a critical quality attribute (CQA) under ICH Q6B, linked to immunogenicity, reduced potency, and adverse patient outcomes. Despite the transformative impact of machine learning (ML) on protein structure prediction and molecular design, its application to formulation-dependent colloidal stability prediction remains fragmented, poorly benchmarked, and largely disconnected from regulatory frameworks. This review systematically examines ML approaches for predicting aggregation propensity, viscosity, solubility, liquid-liquid phase separation, and shelf-life across biopharmaceutical modalities. We critically assess experimental data sources, feature engineering strategies, and ML architectures spanning classical models, deep learning, graph neural networks, and protein language models, alongside the emerging role of explainable AI (XAI). No standardised, cross-modality ML benchmarking framework for colloidal stability currently exists -- a gap that constrains generalisation, reproducibility, and regulatory acceptance. Principal unresolved challenges include dataset scarcity, label noise, external validation deficits, and proprietary data silos. A decade roadmap for integrating physics-informed ML, autonomous formulation laboratories, and foundation models into next-generation biologics development is proposed.

Abstract: Molecular hydrogen (H₂) has emerged as a potential redox-active molecule with distinctive physicochemical and biological properties. Due to its small molecular size and rapid diffusion, H₂ readily penetrates biological membranes and selectively interacts with highly reactive oxygen and nitrogen species particularly hydroxyl radicals (•OH) and peroxynitrite (ONOO⁻) while largely preserving physiological redox signaling. Experimental and clinical studies further suggest that H₂ may influence intracellular signaling pathways associated with oxidative stress and inflammation, including activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway and suppression of nuclear factor κB (NF-κB) signaling. Human studies employing hydrogen-rich water (HRW), inhaled hydrogen gas, or hydrogen-enriched dialysate have reported improvements in biomarkers related to oxidative stress, inflammation, cardiometabolic risk, and immune function, although effect sizes and reproducibility vary across studies. To date, however, no peer-reviewed investigations have evaluated sublingual delivery of molecular hydrogen. This review synthesizes current mechanistic and clinical evidence supporting the biological activity of H₂ and examines the physicochemical rationale for exploring sublingual administration as a potential alternative delivery route. Considerations related to dissolved hydrogen concentration, oxidation–reduction potential, stability, and safety are discussed, alongside key translational gaps that must be addressed. Rigorous pharmacokinetic studies and randomized controlled trials will be essential to determine the feasibility, bioavailability, and clinical relevance of sublingual hydrogen delivery.

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This review consolidates current knowledge on the phytochemical composition, traditional uses, pharmacological properties, and industrial application of Ricinus communis L. This plant belongs to the Euphorbiaceae family and is a globally distributed plant of considerable medicinal and industrial importance. It is rich in bioactive compounds, notably ricinoleic acid as the dominant fatty acid in seed oil, as well as ricin, ricinine, phenolic acids and flavonoids distributed across different plant parts. Variations in phytochemical profiles among cultivars and tissues are influenced by genetic and environmental influences. Traditional medicinal uses of the leaves, roots, seeds, and oil particularly for inflammatory conditions, pain, infections, wound healing, and gastrointestinal disorders are critically examined in relation to experimental pharmacological evidence. Castor oil extracted from the R. communis plant remains central to the plant’s industrial value, serving as a renewable feedstock for pharmaceuticals, cosmetics, polymers, lubricants, and biofuels due to the unique hydroxyl functionality of ricinoleic acid. However, the presence of the highly toxic protein ricin in unprocessed seeds necessitates strict processing and safety controls. Overall, R. communis emerges as a chemically versatile species with significant therapeutic and industrial potential, warranting further research into cultivar-specific chemistry, standardisation of extraction and testing methods, and safe value-adding applications.

Abstract: The continuous emergence of SARS-CoV-2 variants necessitates the identification of effective multi-target antiviral agents with enhanced stability and binding efficiency. This study employed an integrated computational approach, including molecular docking, molecular dynamics (MD) simulations, free energy landscape (FEL) analysis, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, to evaluate the inhibitory potential of twenty natural compounds against SARS-CoV-2 proteins 7XJW, 8DRW, and 9PFH. Molecular docking identified Amentoflavone as the most promising candidate, exhibiting strong binding affinities toward all targets through favorable hydrogen-bond and hydrophobic interactions within the active sites. Interaction analysis revealed that its biflavonoid scaffold promoted extensive ligand–protein complementarity through hydroxyl and aromatic functional groups. MD simulations demonstrated stable protein-ligand complexes, characterized by low fluctuations in RMSD, RMSF, SASA, and radius of gyration values throughout the 100 ns trajectories. Persistent hydrogen-bond interactions further supported complex stability. FEL analysis revealed compact low-energy conformational basins, indicating thermodynamically favorable binding states. MM-PBSA calculations confirmed favorable binding free energies primarily driven by van der Waals and electrostatic contributions, with the 7XJW-Amentoflavone complex exhibiting the most favorable energetic profile. Overall, these findings highlight Amentoflavone as a promising multi-target inhibitor and potential lead compound for future antiviral drug development and experimental validation against SARS-CoV-2.

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Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder with a complex pathomechanism. Acetylcholinesterase (AChE) and monoamine oxidase-B (MAO-B) are key targets regulating neurotransmitter levels, and dual inhibitors (compounds 1–46) were designed as experimental candidates for AD therapy. Methods: Drug-likeness parameters were estimated using pkCSM, SwissADME web tools, and MoloVol software (v1.2.0). SwissADME predicted gastrointestinal absorption and blood–brain barrier penetration, whereas pkCSM evaluated P-glycoprotein recognition and CYP450 inhibition. Toxicological profiles of compounds (1–46) were assessed with DataWarrior software (v06.05.04), which classified them as mutagenic, carcinogenic, reproductive, or irritant. Results: Most compounds complied with Lipinski’s rule (excluding 12 and 35) indicating favorable absorption and permeability. All compounds showed TPSA < 140 Å2, indicating good intestinal absorption, while compounds 1, 3–6, 8, 11-16, 18, 19, 27, 30, 31, 34, 36-38, and 44–46 displayed TPSA < 60 Å2, suggesting blood–brain barrier penetration. The majority of compounds were predicted P-glycoprotein substrates, potentially limiting oral absorption and blood-brain barrier penetration. Metabolic profiling revealed inhibition of CYP1A2, 2C19, 2C9, 2D6, and 3A4, highlighting drug–drug interaction risks. Toxicological analysis identified mutagenicity (compounds 4, 5, 19, 20 and 27), carcinogenicity (compounds 4, 5, 8, 18 and 19), reproductive toxicity (compounds 15, 16 and 19–23), and irritant effects (compounds 7, 11, 17 and 20). Conclusions: Computational findings support further in vitro and in vivo evaluation of compounds 1, 3, 6, 13, 14, 30, 31, 34, 36–38, and 44–46 as dual AChE/MAO-B inhibitors and potentially new drugs for AD treatment.

Abstract: The regeneration of the dentin-pulp complex remains a major challenge in regenerative endodontics. While conventional therapeutic approaches are effective in eliminating infection and preserving dental structure, they fail to restore the biological functionality of the pulp tissue. In recent years, three-dimensional (3D) printing and biopolymer-based bioprinting have opened unprecedented opportunities in dental tissue engineering, enabling the fabrication of biomimetic scaffolds with precisely controlled structural and bioactive properties. This review synthesizes current advances in bioprinting technolo-gies, the diversity of biomaterials and bioinks employed, and the various stem cell sources utilized in pulp regeneration. It further examines how the three-dimensional microenvironment modulates cell viability, odontogenic differentiation, and the pro-motion of angiogenesis and neurogenesis, emphasizing the role of scaffold composition, mechanical properties, and internal architecture in influencing regenerative outcomes. Additionally, persistent challenges are discussed, including the optimization of bioink formulations, the achievement of functional vascular integration, and long-term valida-tion of regenerated tissues, underscoring the need for multidisciplinary strategies to fa-cilitate clinical translation. By integrating recent evidence, this review establishes a conceptual framework for the development of personalized and predictable approaches to dentin-pulp complex reconstruction.