Medicinal Chemistry Research最新文献

Coumarin is a versatile scaffold occurring extensively in abundant natural compounds and synthetic pharmaceuticals. Coumarin derivatives have been proven to inhibit multiple stages of HIV-1 replication, and their unique structures enable them to interact with diverse targets involved in the HIV-1 replication cycle, thereby exerting potent antiviral activity. Currently, HIV-1 inhibitors with novel structures and mechanisms are in urgent need to overcome the existing challenges of drug resistance, safety, and efficacy. Based on the characteristics of the retroviral life cycle, this paper reviews the research progress of coumarin derivatives over the past two decades, aiming to provide valuable insights into the structure-activity relationships (SARs) and design strategies for novel coumarin-based HIV-1 inhibitors in the future.

Piperazine has become essential for designing anticancer drugs because of its basicity, conformational flexibility, and capacity to serve as a solubilizing agent and molecular linker between hybrid pharmacophores. Researchers have found piperazine to function as a medicinal chemistry component that helps develop bioactive scaffolds through its capacity to control solubility, linker design, and target binding properties. The review presents a comprehensive assessment of piperazine-based anticancer drug research published between 2015 and 2025 through its evaluation of clinically relevant medicinal chemistry findings. The literature is organized based on piperazine’s three main functional roles, which include its use as a linker and solubilizing/basic motif and direct target-recognition element. The study examines major cancer types through scaffold-based structure–activity relationship (SAR) analysis, which includes breast cancer, liver cancer, colon cancer, cervical cancer, prostate cancer, brain cancer, and leukemia models. The research demonstrated that various derivatives achieved IC₅₀ values in the low-nanomolar to low-micromolar range in MCF-7, HepG2, and HCT-116, HeLa, PC-3, and K562 cell lines. Researchers have demonstrated how protonatable piperazine nitrogens improve aqueous solubility and formulation development, and interactions of enzyme and kinase active sites with acidic residues, which results in better binding strength and selectivity. The review presents major translational obstacles, which include excessive dependence on 2D in vitro studies, insufficient in vivo and ADME/PK information, and limited progress in clinical applications. The research studies the development of clinically usable piperazine-based anticancer drugs through novel methods, which include green chemistry, click chemistry, molecular docking, and QSAR-focused design.

Graphical Abstract

Synthetic Approaches and Structure-activity relationship of Piperazine and its Derivatives as Anticancer Agents

Inhibiting tyrosinase is critical for managing pigmentation disorders and preventing enzymatic browning in food and crops. In this research, a series of novel hybrid coumarin- piperazine-N-phenylacetamide derivatives 11a-q were designed and synthesized to inhibit tyrosinase. The structural identification of compounds 11a-q was carried out using spectroscopic methods, including FTIR, ¹H-NMR, and ¹³C-NMR. The inhibitory activity of these compounds against mushroom tyrosinase and their antioxidant properties were evaluated in vitro. All derivatives showed inhibitory effects on tyrosinase at a concentration of 200 µM, and among them, compound 11 L with an IC₅₀ value of 176.65 µM exhibited the highest activity. Also, at this concentration, all compounds showed weak antioxidant activity. In addition, molecular docking and molecular dynamics studies were performed to investigate the type and energy of interactions of compound 11 L with the active site of the active site of the tyrosinase.

Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disorder and an important contributor to hepatocellular carcinoma. It is characterized by excessive hepatic lipid accumulation, which can progress to a more severe inflammatory condition known as non-alcoholic steatohepatitis (NASH). Recently, NAFLD has been globally redefined as metabolic dysfunction-associated steatotic liver disease (MASLD). It is closely associated with metabolic disorders such as type 2 diabetes mellitus, obesity, insulin resistance and dyslipidaemia. NAFLD is now a major cause of liver-related morbidity and mortality because proper pharmacological treatments are limited. Naturally occurring polyphenolic compounds such as flavonoids exert a potential role on NAFLD due to their antioxidant, anti-inflammatory, and lipid-regulating properties. The pathogenesis of NAFLD is complex and involves multiple interrelated mechanisms, including hepatic lipid accumulation, insulin resistance, oxidative stress, mitochondrial dysfunction, and chronic inflammation, which collectively contribute to disease progression toward NASH, fibrosis, and cirrhosis. Several flavonoids, including quercetin, naringenin, kaempferol, luteolin, dihydromyricetin, and tetrahydrocurcumin, have demonstrated beneficial effects in experimental and clinical studies by reducing hepatic lipid accumulation, oxidative stress, and inflammation. These compounds exert their effects by modulating key molecular pathways, including nuclear factor erythroid 2–related factor 2 (Nrf2), AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptors (PPARs). Activation of these pathways enhances mitochondrial function, promotes fatty acid oxidation, and improves insulin sensitivity. However, poor bioavailability and limited clinical evidence remain major challenges. Future studies should focus on optimized formulations, standardized dosing, and well-designed clinical trials.

A novel series of 1,2,4-triazole–benzoxazepine hybrid derivatives was designed, synthesized, and biologically evaluated as α-glucosidase inhibitors using an in vitro enzyme inhibition assay with acarbose as a reference standard. Several compounds demonstrated significant inhibitory activity, with compound 14 emerging as the most potent inhibitor (IC₅₀ = 49.26 µM), surpassing acarbose by approximately 3.6-fold, while compound 28 also showed notable activity (IC₅₀ = 72.14 µM). Structure–activity relationship analysis revealed that halogen substitution, particularly at the ortho position, plays a critical role in enhancing inhibitory potency. Molecular docking studies (PDB ID: 7KB6) provided mechanistic insights into ligand–enzyme interactions, showing that the most active compounds establish key π–π stacking interactions with residues TRP423, TRP525, and PHE307, along with π-anion interactions involving ASP640 and ASP564, and extensive hydrophobic contacts with PHE571, PHE673, MET565, and ARG624. Additionally, water-mediated hydrogen bonding (e.g., HOH1356, HOH1625) helps stabilize the ligand within the active site. These interactions enable simultaneous engagement of the catalytic active site and peripheral regions, supporting strong binding affinity. Overall, these results define clear structure–activity relationships and identify 1,2,4-triazole–benzoxazepine hybrids as promising lead scaffolds for further optimization toward novel antidiabetic agents.

Cyclooxygenase-2 (COX-2), an inducible enzyme pivotal to prostaglandin biosynthesis from arachidonic acid, is aberrantly upregulated in inflammatory pathologies, neurodegenerative disorders, and malignancies. Non-invasive real-time quantification of COX-2 expression in vivo via nuclear imaging method (positron emission tomography (PET) and single-photon emission computed tomography (SPECT)) has an important significance. It not only enables disease stratification and prognostic assessment but also clarifies COX-2’s pathophysiological roles, thereby guiding therapeutic decision-making. As COX-2 inhibitors are widely used to manage acute/chronic inflammation and pain, their radiolabeling has facilitated the development of targeted molecular probes for COX-2 imaging. This review systematically categorizes radiotracers derived from structurally modified COX-2 inhibitors, with a focus on ¹¹C-, ¹⁸F-, and ^123/124/125I-labeled compounds, and analyses their synthesis as well as in vitro and in vivo properties in detail. Despite these advances, clinical translation still faces considerable difficulties. Ongoing efforts in structural optimization, combined with the development of advanced COX-2-expressing transgenic models, are expected to address these limitations. Future radiotracers may ultimately enable reliable COX-2 quantification via nuclear imaging, thus bridging a critical gap in precision medicine.

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Oligonucleotide therapeutics are becoming representatives of the “Third Wave” of pharmaceutical innovation, expending from initial rare diseases to oncology and chronic indications, following small molecules and proteins. Globally, hundreds of clinical trials are currently underway, in addition to the 26 oligonucleotide drugs that have already been approved. Although nearly thirty years have elapsed since the initial approval of Fomivirsen, oligonucleotide therapeutics continue to pose unique CMC (Chemistry, Manufacturing, and Controls) challenges that are distinct from small molecules. Furthermore, the lack of harmonized ICH guidelines specifically for oligonucleotides forces developers to navigate a “regulatory grey area” between new molecular entities (NMEs) and biologics. This perspective focuses on the technical and regulatory hurdles of API (Active Pharmaceutical Ingredient) CMC development, covering synthesis (including conjugation strategies with delivery systems), analysis and regulatory aspects, with a specific emphasis on stage-appropriate requirements from the Investigational New Drug (IND) application to the New Drug Application (NDA).

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Heparanase (HPSE) plays a critical role in tumor progression by degrading heparan sulfate chains in the extracellular matrix and modulating the tumor microenvironment. As a result, it has emerged as a promising therapeutic target. Aminoglycoside-derived sulfated glycan mimetics have shown potential as HPSE inhibitors, but rational optimization is challenged by complex steric and electrostatic interactions. Here, we used three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling to identify key structural features governing HPSE inhibition, providing new predictive structure–activity insights for sulfated aminoglycoside-based HPSE inhibitors. Guided by these insights, we evaluated the lead compound L17 in HPSE-dependent cancer cell lines and observed concentration-dependent inhibition of proliferation, suppression of invasion, and reduction of extracellular HPSE levels. In silico ADMET predictions flagged CYP3A4 as a potential liability, but experimental assays confirmed minimal inhibition, indicating a favorable metabolic profile. This integrated approach provides mechanistic insight into aminoglycoside-based HPSE inhibitors and supports their rational optimization as anticancer therapeutics.

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Ischemic injury triggers extracellular ATP release, activating P2X4 receptors (P2 × 4R) on immune and cardiac cells, which exacerbates inflammation and tissue damage. We evaluated MRS4719, a selective P2 × 4R antagonist, in aged mice subjected to transient middle cerebral artery occlusion (tMCAo) and cardiac ischemia/reperfusion (CI/R) injury. MRS4719 exhibited a nonlinear dose response, with an intermediate dose (2.25 mg/kg/day) and short-term treatment (2 days) optimally improving sensorimotor and cognitive recovery while reducing brain tissue atrophy. Treatment initiated up to 12 h post-stroke significantly decreased infarct volume. Additionally, MRS4719 preserved cardiac contractile function following ischemia/reperfusion injury. These findings suggest that targeted P2X4R inhibition mitigates inflammatory injury across multiple organs and supports functional recovery, highlighting MRS4719’s therapeutic potential for cerebral and cardiac ischemic disorders.