Medicinal Chemistry Research最新文献

A group of sixteen symmetric (1,4-diazepane-1,4-diyl)bis(phenylmethanone) derivatives (3a–p) containing a 1,4-diazepane scaffold were designed, synthesized, and evaluated as potential inhibitors of Aβ42 and Aβ40 aggregation. In the in vitro fluorescence aggregation kinetics compounds 3k (R = naphthalen-1-yl) and 3o (R = benzo[d][1,3]dioxole) exhibited concentration-dependent inhibition of Aβ42 aggregation, with compound 3k demonstrating 50% inhibition of aggregation whereas compound 3o exhibited 33% inhibition at 25 µM. In the Aβ40 aggregation assay, compounds 3c and 3o demonstrated superior inhibitory activity, with inhibition ranging from 60–63%. These findings were corroborated by transmission electron microscopy, which confirmed reductions in both Aβ42 and Aβ40 fibril load in the presence of 1,4-diazepane derivatives 3c, 3k and 3o. The dual Aβ42 and Aβ40 aggregation inhibitor 3o identified from this study was not toxic to mouse hippocampal HT22 cells (cell viability ⁓96% at 25 µM) and demonstrated significant reductions in Aβ42-induced cytotoxicity at 25 µM (⁓48% cell viability) compared to Aβ42-alone treated group (37% cell viability). Furthermore, 3o demonstrated neuroprotective effects in hydrogen peroxide-induced cytotoxicity and ability to get into the brain in the in vitro blood-brain barrier permeation assay. Computational studies showed that compound 3o binds within the narrow channel formed by the N- and C-terminal residues of Aβ42 pentamer and Aβ40 dimer models, potentially stabilizing the peptide assemblies and inhibiting further aggregation. These results highlight the application of conformationally flexible sp3 hybridized 1,4-diazepane scaffold as a promising and novel template to design novel dual inhibitors of both Aβ42 and Aβ40 aggregation.

URAT1 represents a critical therapeutic target for the treatment of hyperuricemia. However, current URAT1 inhibitors are limited by high toxicity and adverse effects, underscoring the urgent need to develop safe and effective therapeutic agents. In this study, nine novel nuciferine derivatives were synthesized by modifying the N7-position substituent to enhance URAT1 inhibitory activity. CCK-8 assays revealed that most compounds exhibited no significant cytotoxicity in HK-2 cells at concentrations up to 60 μM, supporting their suitability for further investigation. Western blot analysis demonstrated that the majority of derivatives downregulated URAT1 protein expression in HK-2 cells, with compound 3-4 exhibiting the most potent inhibition, approaching the efficacy of benzbromarone. Structure-activity relationship (SAR) studies indicated that sulfonyl substituents improved URAT1 inhibition, while aromatic amides reduced activity. Molecular docking showed that 3-4 formed stronger interactions with URAT1 and had higher binding affinity (-6.794 kcal/mol). Molecular dynamics simulations showed that 3-4 formed a stable complex with URAT1. ADME analysis confirmed 3-4 complied with Lipinski’s Rule of Five, featuring balanced lipophilicity and favorable pharmacokinetic properties. These results underscore the N7-position as a key modifiable site for developing nuciferine-based anti-hyperuricemic agents with improved efficacy.

The schematic diagram was created with FigDraw (https://www.figdraw.com) (ID: OIISI69bef).

Macrocyclization has emerged as a versatile design strategy in medicinal chemistry, offering unique opportunities to address limitations of conventional small molecules. By conformationally constraining ligands, macrocycles can enhance potency, selectivity, and metabolic stability, while in some cases also achieving favorable permeability and oral bioavailability. Over the past decade, applications of macrocyclization have expanded across diverse therapeutic areas, with particularly strong advances in oncology, alongside progress in immunology, inflammation, neurodegeneration, and antiviral research. Several macrocyclic agents have advanced to clinical development, and recent approvals, including daraxonrasib, highlight the translational potential of this approach. This review provides an updated synthesis of macrocyclization strategies, emphasizing their impact on potency optimization, selectivity for challenging targets, mutant-specific activity, cellular efficacy, and pharmacokinetic improvements. While macrocyclization is not universally applicable and often requires structural insights from crystallography or molecular modeling, it has become a mainstream and provide an important option in candidate optimization. By consolidating recent advances, we aim to clarify emerging design principles and highlight the future role of macrocyclization in shaping next-generation therapeutics.

In this study, we successfully designed and synthesized a new series of coumarin-based hydroxamate derivatives as potent histone deacetylase (HDAC) inhibitors. Among them, several compounds showed strong inhibitory effects on whole-cell HDAC and exhibited moderate to significant antiproliferative activity against three human cancer cell lines, including MCF-7, A549 and SK-Lu-1. Notably, compounds 4c and 4 d emerged as the most promising candidates. They inhibited HDAC with an IC₅₀ of 0.16 and 0.33 µM respectively, outperforming suberoylanilide hydroxamic acid (SAHA) (IC₅₀ = 0.63 µM) and demonstrated potent cytotoxicity against MCF-7 cancer cell line – from 1.2 to 6.8 times stronger than SAHA. Docking simulations further clarified their interactions with HDAC isoforms and explained its binding profile. Taken together, these findings highlight compound 4c and 4 d as highly promising HDAC inhibitors with significant therapeutic potential in cancer treatment.

Inflammation is an immediate physiological response for defense and tissue repair against external stress, however it contributes to the pathogenesis of several chronic diseases when dysregulated. Plant-derived natural products, including flavonoids, terpenoids, alkaloids, phenolic acids, tannins, and essential oils, possess potential anti-inflammatory activity through modulation of key signaling pathways including NF-κB, MAPKs, PI3K/Akt, and inflammasomes. These compounds influence immune responses by promoting the polarization of anti-inflammatory macrophages, regulating T-cell responses and inhibiting neutrophil activation. Additionally, these compounds possess significant antioxidant properties that alleviate oxidative stress and downstream inflammatory signaling. Despite robust preclinical and evolving clinical evidence, their therapeutic potential is limited by several pharmacokinetic challenges, including poor solubility, rapid metabolism, and slight bioavailability. Here, the use of advanced drug delivery approaches, including nanoparticles, liposomes, and phytosomes, together with bioenhancers and prodrugs can be crucial in improving systemic exposure and efficacy of these compounds. Integrating omics technologies and artificial intelligence can accelerate the identification and optimization of novel anti-inflammatory phytochemicals. Nevertheless, several challenges persist, including standardization, quality control, regulatory approval, and safety assessments. This review summarizes the pharmacological mechanisms, pharmacokinetic limitations, clinical evidence, and provide future directions for plant-derived anti-inflammatory agents. It highlights their potential use as safe, effective, and affordable therapeutic options against inflammation-related diseases.

Hyperuricemia arises from disrupted uric acid metabolism, where xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) serve as key therapeutic targets for uric acid production and reabsorption, respectively. While current single-target drugs inhibit either XOR or URAT1, dual-target strategies combining both inhibitors are clinically promising. In this research, fragment-based drug design coupled with virtual screening was employed to obtain hit compounds A1-4. Among them, A4 exhibited strong inhibitory effects on URAT1 (IC₅₀ = 33.10 ± 7.82 μM), comparable to benzbromarone (IC₅₀ = 21.67 ± 7.31 μM). Additionally, A4 showed a certain degree of inhibition on XOR, with an IC₅₀ value of 20.73 ± 2.19 μM, significantly weaker than allopurinol (IC₅₀ = 1.43 ± 0.02 μM). Thus, the first round of optimization from A4 focused on enhancing the inhibitory activity against XOR. By molecular docking studies of A4 with XOR, compounds B1-13 were designed and synthsized. Among those compounds, B8 showed the best inhibitory activity against XOR (IC₅₀ = 10.14 ± 1.43 μM), approximately twice enhancement as compared to that of A4. Unfortunately, the inhibitory activity of B series compounds on URAT1 (IC₅₀ = 10.14 ± 1.43 μM) were significantly reduced compared to A4. By the structure-activity relationships analysis, it was considered that further optimization studies can be conducted based on B8 and A4.

In present work a series of sulfonamide-containing 3-hydroxy-2-oxindoles was designed and synthesized via condensation of isatins with malonic or cyanoacetic acids and their biological activity was evaluated. All synthesized compounds are effective nanomolar carbonic anhydrase II inhibitors, the best inhibitors 4a and 4 h showed IC₅₀ 20 and 28 nM, respectively. Two animal models (rats, rabbits) were used to study the influence of compounds on intraocular pressure (IOP) in vivo. Instillation of 0.1% aq. solution of compounds 4a, 4 h and 5i showed 17, 21 and 25% decrease in IOP in rabbits, respectively. At the same time instillation of 0.4% aq. solution of almost all compounds caused a moderate IOP decrease in rats, with compounds 4i and 5i have shown the best effect (30 and 34% ΔIOP, respectively). All synthesized compounds showed moderate Fe²⁺-induced lipid peroxidation inhibition in rat brain homogenate and do not exhibit mitochondrial toxicity.

BRPF1, a key component of the MOZ/MORF histone acetyltransferase complex, regulates chromatin remodeling and gene expression via its bromodomain, PHD fingers, and PWWP domain. Dysregulated BRPF1 is linked to neurodevelopmental disorders (e.g., syndromic mental retardation) and cancers (e.g., hepatocellular carcinoma, prostate cancer), making it a promising therapeutic target. This review summarizes BRPF1’s domain architecture, biological functions, and disease associations. It highlights progress in developing BRPF1 bromodomain inhibitors, including 1,3-dimethyl benzimidazolone derivatives (e.g., GSK6853), N-methylquinolin-2-one-based compounds (e.g., NI-42), and 3-acetylindole derivatives, along with dual-target inhibitors. Current limitations (suboptimal pharmacokinetics, poor selectivity, insufficient in vivo validation) are addressed. Finally, future directions (mechanistic exploration via advanced technologies, AI-aided drug design, and clinical translation) are proposed to advance BRPF1-targeted therapies.