Medicinal Chemistry Research最新文献

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.

Bacterial biofilms are surface-attached communities comprised of slow- or non-replicating bacteria. Transcriptomic responses of bacterial biofilms to anti-biofilm small molecules have been largely unexplored, with existing studies typically involving long treatment periods (>18 h). In this study, we used a halogenated quinoline biofilm-killing agent (RA-HQ-12) to investigate the transcriptional responses of MRSA and S. epidermidis biofilms. Utilizing RT-qPCR, we observed RA-HQ-12 activated iron uptake pathways in both MRSA and S. epidermidis biofilms after 4 h treatment at 1 µM. A time-course analysis further revealed dynamic variation in up- and down-regulation patterns of various target genes (sbnC, isdB, opp1C, ribA, nasE, and crtM), shedding light on the time-dependent dynamics of biofilm responses to RA-HQ-12.

Neglected tropical diseases caused by protozoan parasites such as Leishmania (L.) and Trypanosoma (T.) species pose significant health, social, and economic challenges globally. Current treatments are often toxic, with complex administration routes. Additionally, these drugs are prone to parasite resistance, necessitating the search for novel therapeutic agents. To this end, we initiated a program to investigate the antiparasitic potential of arylidene compounds. In this preliminary study, a small series of 5-benzylidene-2-thiohydantoin esters was synthesised in a multi-step process and evaluated for antitrypanosomatid activity against Leishmania and Trypanosoma species. The in vitro biological evaluation revealed promising leishmanicidal activity against the antimony-resistant L. donovani strain 9515 and L. major strain NIH S, as well as trypanocidal activity against the T. congolense strain IL3000. Most compounds exhibited low cytotoxicity toward mammalian cells, resulting in high selectivity indices. Several early leads against visceral and cutaneous leishmaniasis, with similar potency to the reference drug amphotericin B, were identified (IC₅₀ < 1 µM, SI > 100). For example, A1-13 demonstrated cidal activity in the nanomolar range against intracellular amastigotes of L. donovani (IC₅₀ 0.41 µM, SI 244) and A2-4 against L. major (IC₅₀ 0.49 µM, SI 204). Additionally, A2-5 (IC₅₀ 0.35 µM, SI 452) was identified as an early lead against animal-infective T. congolense trypomastigotes, a causative agent of the cattle wasting disease nagana. Drug-likeness predictions confirmed favourable physicochemical properties with minimal predicted toxicity risks. These findings provide valuable insights into the development of thiohydantoin-based therapeutics for neglected tropical diseases; however, the mechanism of action and in vivo antitrypanosomatid efficacy of the promising early leads should be further determined.

Drug repurposing has evolved as an attractive approach in the search for new therapeutic applications that are shorter in development time and lower in cost. At the core of drug repurposing, the key challenge in this field is the accurate prediction of drug-target interactions (DTIs) and drug-target binding affinities (DTBAs). Various Artificial Intelligence (AI) techniques, including machine learning (ML) and deep learning (DL) methods, have proven to be significant in improving the prediction capability of the DTI and DTBA models. In this review, we provide critical insights into the current state-of-the-art AI methods used for the prediction of DTI and DTBA by highlighting major progress, bottlenecks, and potential future research directions. Classify these approaches according to their algorithmic framework, feature extraction methods, data source, and performance measures, and provide an extensive review of their strengths against limitations. Lastly, the limitations of current AI-assisted DTI and DTBA prediction methods in drug repurposing applications are summarized and highlight possible directions to address those challenges.

Portulaca oleracea L., commonly known as purslane or pigweed, is a fleshy, drought-resistant weed belonging to the family Portulacaceae. It grows worldwide, including regions such as Asia, Europe, China, the Mediterranean, Japan, the U.S., Africa, and Australia. P. oleracea leaves have long been used in traditional cuisine, eaten as a steamed green, added to pickles, tossed in salads, or used to thicken soups. Rich in essential nutrients, this plant is especially valued for its abundant omega-3 fatty acids, which play a vital role in growth, development, and protection against diseases. It also contains diverse bioactive compounds, including flavonoids, carotenoids, monoterpene glycosides, phenolic glycosides, triterpenoids, alkaloids, carbohydrates, proteins, vitamins, minerals, and electrolytes. These bioactive compounds give P. oleracea its diverse medicinal benefits, including antioxidant, heart protective, anti-atherosclerotic, anti-inflammatory, cholesterol-lowering, blood-thinning, glucose regulating and antimicrobial effects. Recent research has also explored using P. oleracea extracts to produce biogenic metallic nanoparticles, opening new possibilities in photocatalysis and advanced medical nanotechnology. This review comprehensively summarizes the updated phytochemical profile and pharmacological activities of purslane extracts, linking traditional knowledge with cutting-edge applications with emphasizing its role as a vital resource for human health.

Cancer is a wound that never heals and is the second leading cause of death worldwide. Ginsenoside Rh2 (G-Rh2) is the main active substance extracted from Panax ginseng c.a. Meyer, has anticancer activity. G-Rh2 can inhibit tumor cell proliferation, migration, invasion, and neovascularization, regulate immune function, and induce apoptosis and cycle blockade in vitro and in vivo. In addition, G-Rh2 can be used as an adjuvant to chemotherapeutic drugs to enhance their anticancer effects and reverse adverse effects. In this study, the anti-tumor mechanism of G-Rh2 was organized and reviewed by reviewing relevant reports in recent years to provide guidance for the application of G-Rh2 in clinical tumor therapy.

METTL3 and METTL14, key components of the m⁶A writer complex, are frequently overexpressed in various malignancies, including acute myeloid leukemia (AML), where aberrant methylation has been linked to the upregulation of oncogenic transcription. Therefore, targeting the METTL3/METTL14 complex represents a potential therapeutic approach for AML. Although several METTL3 inhibitors have been discovered, their SAM-competitive mode of action often results in reduced cellular potency, prompting interest in alternative strategies such as targeted protein degradation. In this article, we expand upon reported METTL3/METTL14 complex degraders through exploration of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) from multiple exit vectors of UZH2, a reported METTL3 inhibitor. The most potent PROTAC, 4j, demonstrated sub-micromolar degradation potency in MV4.11 cells with DC₅₀ values of 0.44 µM for METTL3 and 0.13 µM for METTL14. Notably, 4j showed enhanced cytotoxicity in MV4.11 cells compared to well-validated METTL3 inhibitors, underscoring the therapeutic potential of targeted degradation of the METTL3/METTL14 complex in AML.