Medicinal Chemistry Research最新文献

In this study, we discovered compounds comprising a piperidine skeleton in Piper retrofractum; the compounds exhibit PC12 dendrite elongation activity. Furthermore, we examined the structure-activity relationship by comparing the activities of the isolated compounds 1, 3-7. Among the isolated compounds, two alkaloids (6 and 7) displayed significant neurite outgrowth (NOG) effects in the presence of 5 ng/mL nerve growth factor (NGF) in a dose-dependent manner. Comparison of the activity of 3 (Pipercide; 1.8% NOG positive at 100 µM), 6 (Dehydropipernonaline; 21.1% NOG positive at 100 µM), and 7 (Pipernonaline; 24.3% NOG positive at 100 µM) (Nobiletin; 25.4% at 50 µM as positive control) demonstrated that the piperidine skeleton is key to NOG activity. Furthermore, the carbon chain length and number of double bonds influence NOG activity. Moreover, the Barnes maze test showed that oral administration of compound 7 in mice improved memory disorders induced by scopolamine and corticosterone. These results provide extremely valuable foundational knowledge for elucidating the cognitive function-improving effects of P. retrofractum, a food spice.

Herein, we report a systematic ML-embedded virtual screening strategy for the repurposing of antifolates (hTS inhibitors) targeting Histone Lysine Methyltransferase (G9a/EHMT2), with experimental validation. Three pharmacophore models (3D QSAR, Common Feature, and Interaction), derived from known G9a inhibitors, were used in a database mining of the 1120 hTS inhibitors from the ChEMBL database. Candidates were filtered using a multi-tier screening strategy based on fit values, drug-likeness, ADMET, and TOPKAT criteria, followed by molecular docking to assess interactions with G9a's active site, including compounds such as UNC0642 and Raltitrexed as references. The top candidates were selected for strong docking scores, the ability to form at least three hydrogen bonds, and interaction with the lysine-binding tunnel. Among these, Pemetrexed exhibited a binding mode similar to Raltitrexed, forming critical hydrogen bonds and pi interactions with residues Leu1086, Ser1084, Tyr1154, Arg1157, and Phe1158, indicating its potential as a G9a inhibitor. Further analyses of RMSD, RMSF, ROG, and protein-ligand interactions confirmed the stability of Pemetrexed, and MM-GBSA binding energy calculations, along with residue-wise decomposition analysis, supported its strong affinity for G9a. An in vitro assay of Pemetrexed revealed G9a inhibitory activity with an IC₅₀ of 304.90 nM, demonstrating its potency. Additionally, Pemetrexed exhibits lower activity against the G9a-like methyltransferase GLP than the references, confirming the compound's preferential activity for G9a over GLP. Furthermore, Pemetrexed improves the locomotor deficits associated with Aβ expression in C. elegans CL2006 worms in a dose-dependent manner, showing its potential as an epigenetic therapeutic for Alzheimer's Disease.

Neurodegenerative diseases are one of the most pressing challenges of modern medicine, a problem from which no one is immune. Many medications used to treat dementia are ineffective in eliminating the root cause of pathogenesis, or exhibit a number of side effects. Great interest has been shown in positive allosteric modulators (PAMs) of AMPA receptors and PAM-43 is one of the most promising PAMs to date. Peptide allosteric modulators are another promising area of AMPA receptor PAMs. There are numerous cases where peptide-based drugs have a gentler effect and do not cause negative side effects or addiction with prolonged use. Here we designed and synthesized two peptide structures, potential PAMs of AMPA receptors. Our studies have shown that tetrapeptide WPPW and its derivative Boc-WPPW are stable enough to bind a target receptor and do bind to it. Molecular docking of the peptides and PAM-43 revealed several specific binding sites on AMPA receptor, some of which partially overlap. These peptides notably modulate the interaction of [³H]PAM-43 at various sites of its specific binding. WPPW partially blocks [³H]PAM-43 binding at both its specific sites (high- and low-affine) in a dose-dependent manner. At certain concentrations, Boc-WPPW enhances the exposure of additional binding sites of PAM-43 that may be located not only on AMPA receptors. The peptides WPPW and Boc-WPPW may be of interest as AMPA receptor potential allosteric modulators or cofactor molecules.

Lead optimization is a resource-intensive stage of drug discovery requiring the simultaneous optimization of potency, selectivity, pharmacokinetics, safety, and synthetic feasibility. Although artificial intelligence (AI) and machine learning (ML) have substantially advanced predictive modeling, virtual screening, de novo molecular design, and multiparameter optimization, their translation into routine medicinal chemistry remains challenging. This review critically examines current AI approaches for lead optimization, emphasizing the gap between computational benchmark performance and practical medicinal chemistry applications. Recent advances in graph neural networks (GNNs), transformer architectures, diffusion models, and chemical foundation models have expanded AI-assisted molecular design and property prediction. We further discuss emerging concepts including data-centric AI, uncertainty quantification, trustworthy AI, the AI optimization paradox, and the shift from molecular prediction toward scientific decision-making as key determinants of successful implementation. Despite increasing industrial adoption, AI remains dependent on high-quality experimental data, model generalizability, and rigorous experimental validation. We conclude that future progress will depend less on increasingly sophisticated algorithms than on trustworthy AI systems that improve scientific decision-making within iterative lead optimization workflows and ultimately enhance translational success in drug discovery.

A series of 30 novel azole-sulfonamide urea and thiourea conjugates was rationally designed and synthesized as potential multitarget inhibitors of acetylcholinesterase (AChE) and the human carbonic anhydrase isoforms hCA I and hCA II. The molecular design combined azole-based heterocyclic scaffolds with the classical sulfonamide zinc-binding pharmacophore through urea or thiourea linkers. The synthesized compounds were characterized by FT-IR, ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry and subsequently evaluated in vitro against the three target enzymes. Several derivatives exhibited potent nanomolar inhibitory activity. Compounds 11, 6, 26, and 16 were the most active AChE inhibitors, with IC₅₀ values of 23.89, 30.13, 34.65, and 36.47 nM, respectively. Compounds 25, 26, 29, and 20 displayed the strongest inhibition of hCA I, with IC₅₀ values ranging from 40.76 to 46.82 nM, whereas compounds 11 and 17 were the most active against hCA II, both exhibiting an IC₅₀ value of 57.75 nM. Selectivity analysis based on the IC₅₀(hCA I)/IC₅₀(hCA II) ratio indicated limited isoform discrimination overall, with selectivity indices ranging from 0.42 to 1.26. Most derivatives showed a modest relative preference toward hCA I, whereas compounds 13, 17, 18, and 21 displayed modest preference toward hCA II, with compound 17 showing the highest hCA II selectivity index (SI = 1.26). Notably, compounds 11 and 26 showed a well-balanced multitarget profile across all three tested enzymes. Molecular docking and MM-GBSA calculations suggested plausible binding modes involving hydrogen bonding, aromatic interactions, hydrophobic contacts, and, for selected carbonic anhydrase complexes, sulfonamide-mediated coordination with the catalytic Zn²⁺ ion. Overall, the experimental and computational findings identify azole-sulfonamide urea/thiourea conjugates as promising scaffolds for the further development of multitarget enzyme inhibitors and provide preliminary structure-activity insights for subsequent optimization.

Calotropis procera (Aiton) W.T. Aiton, a perennial shrub of the Apocynaceae family, is widely valued in Ayurveda, Unani, Siddha, and homeopathy for its broad therapeutic potential, attributed to a diverse phytochemical repertoire that includes alkaloids, triterpenoids, flavonoids, saponins, steroids, fatty acids, glycosides, and proteases. Traditionally, it is used to treat bronchitis, asthma, leprosy, eczema, elephantiasis, joint disorders, various skin ailments, and is also employed as a laxative, anthelmintic, and antiulcer agent. Phytochemical investigations of its latex, leaves, flowers, and stem bark reveal abundant terpenoids, cardenolides, steroids, and proteolytic enzymes, which underpin its antimicrobial, anti-inflammatory, analgesic, hypoglycemic, hepatoprotective, and wound-healing activities; notably, the stem bark demonstrates strong anti-inflammatory and gastroprotective effects. This review compiles and evaluates literature from PubMed, Google Scholar, and Web of Science up to November 2025, providing an integrated account of the plant's traditional uses, botanical characteristics, phytochemistry, pharmacology, and safety, while also incorporating comparative insights on the closely related species Calotropis gigantea. Given its rich bioactive profile and multifaceted pharmacological value, C. procera emerges as a promising candidate for future drug development, warranting detailed mechanistic studies, extract standardization, and evidence-based integration into modern healthcare systems.

O-Methylation is a rational optimisation strategy for resveratrol in which phenolic hydroxyl groups are replaced with methoxy groups to increase lipophilicity, metabolic stability, membrane permeability, and systemic exposure. The resulting pharmacokinetic (PK) improvements may contribute to enhanced pharmacodynamic (PD) effects, as exemplified by methoxylated stilbenes such as pterostilbene, which generally retain the core biological activities of resveratrol while mostly exhibiting greater in vivo efficacy. However, extending this concept to other phenolic natural products shows that improved PK does not uniformly translate into improved PD. Examples from flavonoids, phenolic acids, lignans, ellagitannins, and classical pharmacological analogues illustrate that, although O-methylation frequently enhances metabolic stability and bioavailability, PD outcomes depend on intrinsic target interactions, therapeutic mechanisms, and, in some cases, microbiota-dependent bioactivation. In some examples, O-methylation may even improve PK while reducing intrinsic pharmacodynamic potency. Increased lipophilicity also presents formulation challenges, particularly in aqueous nutraceutical and functional beverage systems, highlighting the need for advanced delivery strategies such as nanoemulsions, nanoliposomes, micellar systems, and cyclodextrin inclusion complexes. Using resveratrol as a model, this review critically evaluates the available, predominantly preclinical, evidence on the relationship between O-methylation, PK, and PD, identifies important exceptions to this relationship, and discusses the implications for pharmaceutical, nutraceutical, and functional beverage development.