Medicinal Chemistry Research最新文献

Type 2 diabetes mellitus (DM) is a heterogeneous metabolic disorder characterized by chronic hyperglycemia and glucose intolerance. The search for safer and more effective antihyperglycemic drugs of plant origin is a priority due to the limited number of drugs available to treat metabolic syndrome. This review aims to compile various classes of plant-derived diterpenes and elucidate the mechanisms underlying their potential roles in key pathways involved in regulating diabetes and metabolic disorders. It also provides a critical evaluation of their preclinical efficacy, bioavailability, and translational potential. Studies show that diterpenes have a prominent effect on various biochemical pathways that help maintain glucose homeostasis by either interfering with insulin secretion and signaling pathways or modulating carbohydrate metabolism. Notable diterpenes include labdanes like andrographolide (targeting insulin signaling, inflammation, and gluconeogenesis), pimarane and abietane types (inhibiting α-glucosidase and protein tyrosine phosphatase 1B), and kauranes (enhancing insulin secretion and sensitivity). The SwissTargetPrediction software was utilized to predict the targets of major diterpenes from each class, suggesting that these compounds interact with a broad spectrum of protein classes (e.g., kinases, nuclear receptors, proteases), thereby reflecting multitarget pharmacological profiles. A few members of this group, such as stevioside and rebaudioside A, have progressed to clinical trials, demonstrating safety and modest reductions in postprandial glucose levels. Although other diterpenes have shown promise in preclinical models of diabetes and metabolic disorders, robust clinical data on their efficacy and safety are still lacking. These findings highlight the therapeutic potential of plant-derived diterpenes, but further research is needed to overcome limitations related to bioavailability, mechanistic clarity, and translational validation, thereby advancing them toward clinical application.

West Nile Virus (WNV) is a mosquito-borne emerging virus, which can result in the development of meningitis or encephalitis. Our medicinal chemistry effort was initiated to identify potent small-molecule inhibitors of WNV with the potential for lead optimization. The initial hit compound 8-(4-(2,5-dimethylbenzyl)piperazin-1-yl)-7-(2-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione 1 was identified from a high-throughput screening (HTS) campaign of 197 K compounds using a cytopathic effect (CPE) cell-based assay against WNV, and showed antiviral inhibition against WNV (EC₉₀ = 0.93 µM), moderate cytotoxicity (CC₅₀ = 12 µM), low solubility (solubility = 9.7 µM) and metabolic stability [mouse and human microsomal stability (MLM and HLM) half-lives < 10 min]. To improve the antiviral activity and drug-like properties of this hit compound, a structure-activity relationship (SAR) campaign led to the discovery of a new potent inhibitor, 8-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-7-(2-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione 21, which retained its potency and efficacy and minimal cytotoxicity (EC₉₀ = 0.87 μM, CC₅₀ > 30 μM) as compared to hit compound 1. In addition to its desired anti-WNV activity profile, analog 21 showed improved microsomal stability (MLM t_1/2 = 21 min, HLM t_1/2 = 41 min) with acceptable pharmacokinetic properties for an initial in vivo proof-of-concept (POC) study, though the compound was inactive. Herein, we report the hit-to-lead optimization study that led to the discovery of this xanthine series.

The urate transporter 1 (URAT1) plays an important role in the reabsorption of uric acid, so URAT1 inhibitors are considered as the promising therapy for gout. To explore potent URAT1 inhibitors with new scaffold, we have designed a series of novel derivatives based on the scaffold hopping strategy by merging the structural feature of URAT1 inhibitor SHR4640 into probenecid. The subsequently structure-activity relationship study led to the discovery of a series of potent URAT1 inhibitors, including the typical acid derivative 8 (IC₅₀ = 2.5 μM) and non-carboxylic acid derivative 10 (IC₅₀ = 3.8 μM). Moreover, these compounds also exhibit excellent metabolic stability in human liver microsomes. In the docking study, compounds 8 and 10 fitted very well to the same binding pocket of Lesinurad. In hyperuricemic model mice, compounds 7, 8 and 10 exhibited significantly uric acid-lowering effect, and compound 8 revealed dose-dependent uric acid-lowering effect to the level of benzbromarone. Moreover, compound 8 has significant potential in alleviating chronic hyperuricemia, improving renal function, and reducing inflammation in chronic hyperuricemia mice. These results extend the chemical space in this field and might help to design more promising URAT1 inhibitors.

Alnus glutinosa (Betulaceae), commonly known as black alder, is a traditional medicinal tree with ecological, ethnobotanical, and pharmacological importance. This review presents the first comprehensive assessment of its medicinal potential, integrating botanical background, phytochemistry, and bioactivities. Scientific investigations have validated the traditional applications and revealed diverse pharmacological properties, including anticancer, antioxidant, antibacterial, antifungal, anti-inflammatory, hepatoprotective, and wound-healing effects. These effects can be attributed, in large part, to bioactive chemical compounds such as diarylheptanoids, flavonoids, phenolics, tannins, terpenoids, and steroids. These constituents modulate oxidative stress, inflammatory pathways, and other important cellular functions. This work highlights the therapeutic value of A. glutinosa and exposes crucial gaps in knowledge by combining chemical composition with pharmacological insights. Specifically, the work focuses on the relationship between the two. In particular, additional mechanistic investigations and clinical validation are required in order to advance its function in contemporary medical practice. Overall, the review provides a foundation for future studies on A. glutinosa, supporting its potential as a promising source of bioactive compounds for drug development.

In this study, a series of 2-aminothiazole derivatives were designed, synthesized, and evaluated as potential cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer’s disease (AD). Subsequently, the antioxidant activities of these synthesized compounds were assessed using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay. The results of the cholinesterase (ChE) inhibition assays revealed that most of the compounds exhibited certain inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 14s demonstrated the most potent inhibitory activity against AChE, with IC₅₀ value of 3.54 μM. Meanwhile, compound 14s also exhibited moderate inhibitory activity against BuChE, with IC₅₀ value of 7.95 μM. The inhibitory activities of compound 14s against both AChE and BuChE were superior to those of galantamine (AChE: IC₅₀ = 3.47 μM; BuChE: IC₅₀ = 17.31 μM). The type of inhibition for compound 14s was determined through enzyme kinetic studies, and the results showed that the compound was a mixed type inhibitor. In addition, molecular docking results showed that compound 14s could interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, which was consistent with the enzyme kinetic experimental results. Molecular dynamics (MD) simulation studies demonstrated the stability of the 14s-AChE/BuChE complexes. Moreover, results from the DPPH free radical scavenging assay indicated that the compounds also exhibited antioxidant activity. Collectively, these experimental results indicated that the designed and synthesized ChEI 14s exhibits potential for further research.

A novel series of triazole alcohols containing an indole-3-methyl(phenyl)a- mino side chain have been synthesized as derivatives of fluconazole. The title compounds were synthesized via the ring-open reaction of epoxide with various N-aryl indole-3-methylamine. Compound C04 exhibited significant inhibitory activity against fluconazole-resistant Candida albicans (ATCC-14053) with an MIC₅₀ of 2.31 μM. Notably, compound C08 displayed potent inhibition against seven fungal pathogens including two clinically isolated fluconazole-resistant strains. The time-kill assays demonstrated that compounds C04 and C08 exhibited significant growth inhibitory effects against Candida albicans ATCC 14053. Further studies confirmed their potent inhibitory activity against C. albicans biofilm development. Cytotoxicity evaluation demonstrated that both compounds exhibited favorable safety profiles. These results indicate that C04 and C08 are promising antifungal drug candidates, providing novel therapeutic strategies to combat clinically resistant fungal infections.

Drug resistance in cancer therapy, often due to the evasion of apoptosis, highlights the need for alternative treatments. Pyroptosis is a type of inflammatory programmed cell death mediated by gasdermin proteins. It offers a promising approach as it can trigger anti-tumour immunity through cytokine release. Plant-derived compounds, rich in bioactive metabolites, can induce pyroptosis via inflammasome activation, gasdermin cleavage and reactive oxygen species (ROS) generation. Phytochemicals like curcumin, quercetin, cucurbitacin B and kaempferol selectively target cancer cells while modulating inflammation in healthy tissues. Combining these compounds with chemotherapy, immunotherapy or nanoparticle-based delivery systems enhance their therapeutic efficacy and overcome drug resistance. Despite promising preclinical findings, clinical translation remains challenging, necessitating further research to optimise safety, specificity, and delivery mechanisms. This review consolidates current knowledge on plant-derived pyroptosis inducers, highlighting their mechanisms, therapeutic potential, and future directions in combating drug-resistant cancers.

Silibinin, the principal bioactive flavonolignan of Silybum marianum (milk thistle), has emerged as a promising natural agent with multifaceted anticancer potential. Extensive preclinical studies demonstrate its diverse pharmacological properties, including antioxidant, anti-inflammatory, and chemopreventive activities, which collectively contribute to its antitumor effects. At the molecular level, silibinin exerts cytotoxicity through the induction of apoptosis, involving both extrinsic (death receptor-mediated) and intrinsic (mitochondria-dependent) pathways. It modulates key signaling cascades such as EGFR, STAT3, and PI3K/AKT/mTOR, leading to suppression of proliferation, angiogenesis, invasion, and modulation of autophagy, stemness and Senescence. Importantly, silibinin acts as a modulator of apoptosis by restoring the balance between pro- and anti-apoptotic proteins, thereby sensitizing cancer cells to programmed cell death. Evidence across multiple malignancies, including hepatocellular carcinoma, breast, lung, and colorectal cancers etc, highlights its broad-spectrum therapeutic relevance. Clinical studies, though limited, suggest that silibinin may enhance the efficacy of standard chemotherapeutic, radiotherapeutic, and targeted regimens while reducing associated toxicities, underscoring its role as a synergistic adjuvant. However, challenges such as poor bioavailability, variable pharmacokinetics, and limited large-scale clinical validation constrain its translational application. To address these limitations, novel strategies such as nanocarrier-based delivery, structural modifications, and combination therapies are being actively investigated. Overall, silibinin represents a compelling natural flavonoid with dual preventive and therapeutic roles in oncology, though future research must overcome pharmacological barriers to fully harness its clinical potential.