RSC medicinal chemistry最新文献

Carabrol, isolated from Carpesium macrocephalum Franch. & Sav., showed anti-inflammatory potential in LPS-induced RAW264.7 murine macrophages. We transformed the structure of carabrol and modified the carbon atoms at positions 11 and 13 to obtain a series of carabrol derivatives. The anti-inflammatory activity of 26 carabrol derivatives was synthesized and screened. Their structures were established using ¹H NMR, ¹³C NMR, and HRMS spectroscopic data. All compounds were tested against RAW264.7 cells using the Griess assay; the bioassay test suggested that most of the compounds were found to have in vitro anti-inflammatory activities with low cytotoxicity. We identified several novel carabrol derivatives, which have potent anti-inflammatory activities for tested RAW264.7 cells with IC₅₀ values that ranged from 0.82 to 1.31 μM. Among these, compound a9 was identified as the most potent anti-inflammatory agent, effectively suppressing key pro-inflammatory mediators such as nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In a xylene-induced ear swelling model in mice, compound a9 demonstrated a significant inhibitory effect on ear swelling, highlighting its potent in vivo anti-inflammatory activity.

The updated guidelines from the World Health Organization highlight that treatment options for multidrug-resistant tuberculosis (MDR-TB) remain limited due to the scarcity of effective drugs. As a result, there is an urgent necessity to develop novel or repurposed drugs that demonstrate efficacy against multidrug-resistant (MDR) strains. In this study, a new series of thiazole-pyridine hybrids were thoughtfully designed and synthesized to assess their potential as antitubercular agents. These compounds were specifically created to target enoyl acyl carrier protein reductase (InhA), a crucial enzyme in the pathogenesis of Mycobacterium tuberculosis. The majority of the compounds evaluated demonstrated substantial antitubercular activity, with minimum inhibitory concentrations (MIC) ranging from 0.5 to 3.9 μg mL^-1 against Mycobacterium tuberculosis H37Rv. Among them, compound 5a was the most effective, with an MIC of 0.5 μg mL^-1. Further evaluations of compound 5a demonstrated its ability to disrupt bacterial biofilms and its strong inhibition of InhA, with an IC₅₀ of 0.19 ± 0.008 μg ml^-1, demonstrating superior efficacy compared to triclosan, which was employed as the reference drug. Molecular docking and dynamics analyses demonstrated that the pyridine ring and thiazole group are essential for binding affinity, and the pyridine-thiazole framework in compound 5a formed stable interactions within the active site of InhA.

Chitinase-3-like protein 1 (CHI3L1, also known as YKL-40) has emerged as a central effector of astrocyte-mediated neuroinflammation and a promising biomarker for Alzheimer's disease (AD). However, small molecule CHI3L1 inhibitors that modulate neuroinflammation are limited. Here, we report the discovery of a CHI3L1-targeted small molecule, DEL-C1, identified through DNA-encoded library (DEL) screening and validated using orthogonal biophysical, computational, and cellular approaches. DEL-C1 demonstrated direct CHI3L1 binding in microscale thermophoresis (MST) and surface plasmon resonance (SPR) assays, with reversible and concentration-dependent association. Molecular docking and 100 ns molecular dynamics simulations revealed a stable binding mode within the CHI3L1 substrate groove, anchored by Tyr206 and flanked by Trp99 and Trp352, supporting a thermodynamically favorable interaction. In vitro ADME profiling indicated a balanced physicochemical profile, permeability, and metabolic stability, consistent with CNS drug-like properties. Functionally, DEL-C1 reversed CHI3L1-induced astrocyte dysfunction by restoring Aβ uptake, lysosomal acidification, and proteolytic activity, while reducing CHI3L1 and IL-6 secretion. DEL-C1 also suppressed CHI3L1-driven NF-κB transcriptional activation, highlighting its anti-inflammatory potential. Collectively, this study establishes DEL-C1 as a promising small molecule modulator of CHI3L1 and a chemical tool to interrogate astrocyte-driven neuroinflammation in AD.

VEGFR-2 signaling is the primary driver of angiogenesis, a process essential for tumor development and metastasis. Although trans-ferulic acid (TFA), a naturally occurring polyphenol, has demonstrated anticancer and antiangiogenic potential, its low solubility and rapid metabolism limit its therapeutic application. To overcome these drawbacks, seven novel TFA derivatives with chemically masked hydroxyl (-OH) groups were designed and synthesized, aiming to improve their metabolic stability and pharmacokinetic properties. This study evaluates their safety in normal WI-38 fibroblasts and anticancer efficacy in HepG2, Hep3B, and Huh7 hepatocellular carcinoma (HCC) cells. Compound 4e emerged as the lead candidate, demonstrating exceptional cytotoxicity against HCC cells (HepG2: IC₅₀ = 1.8 μg mL^-1; Huh7: IC₅₀ = 6.7 μg mL^-1, and Hep3B: IC₅₀ = 7.1 μg mL^-1) with 23-fold greater potency than TFA and 2-fold superiority to doxorubicin while maintaining minimal toxicity in WI-38 fibroblasts. Further mechanistic studies revealed that 4e significantly modulates key cancer-associated biomarkers in HepG2 lysates, including the downregulation of AFP (α-fetoprotein), BCL-2, MCL-1, and γ-carboxyprothrombin, accompanied by the upregulation of pro-apoptotic caspase-3 and the tumor suppressor P53. The compound also exhibited good inhibitory activity against VEGFR-2, with its binding interaction further supported by molecular docking studies. These findings suggest that compound 4e is a promising anticancer candidate worthy of further therapeutic development research.

[This corrects the article DOI: 10.1039/D5MD00425J.].

Vector-borne diseases are causes of global health concern and mosquitoes are the primary transmitters of health-threatening pathogens. Botanicals are sources of compounds structurally modifiable into versatile hits for novel plant-based insecticides. Carlina oxide (1) is a natural compound isolated from Carlina acaulis L. (Asteraceae) with promising insecticidal potential, whose industrial production is limited by the absence of a plant supply chain. Herein, a one-step synthesis producing 1 in 81% yield was developed and a structure-activity relationship (SAR) study for the larvicidal activity on Aedes albopictus (Skuse, 1894) and Anopheles stephensi (Liston, 1901) was performed. The most promising analogue (5) displayed an encouraging larvicidal action (LC₅₀ < 6.0 μg mL^-1), safety profile on human keratinocytes (IC₅₀ > 100 μg mL^-1) and non-target organisms if compared to 1. Untargeted metabolomic analysis on mosquito larvae revealed that 1 and 5 target the carbohydrates and amino acid metabolism.

Small substituents such as chloro (Cl), fluoro, methyl, and methoxy (OCH₃) are often used in drug discovery to optimize ligand-protein interactions. Even though Cl is an electron-withdrawing group and OCH₃ is an electron-donating group exerting opposite effects on an aromatic ring, Cl and OCH₃ also display similarities in that they both exhibit dual electrostatic behavior. In a C-Cl bond, Cl is electronegative and adopts negative electrostatic potential, but at the same time, it has a σ-hole that is depleted of electron density and has an area of positive electrostatic potential. Similarly, the oxygen atom of OCH₃ displays negative electrostatic potential, but inductive electron-withdrawing effects bestow positive electrostatic potential at the terminal methyl group. This dual nature allows a versatile interaction with partially positive (δ ⁺) and partially negative (δ ^-) regions of a protein pocket. In this study, four main types of intermolecular interactions are discussed from the vantage point of Cl and OCH₃ substituents: 1) hydrogen bonding, 2) orthogonal multipolar interactions, 3) halogen bonding and CH-O hydrogen bonding, and 4) Cl-π bonding and CH-π bonding. A comprehensive search of the PDB and analysis of X-ray co-crystal structures for each type of interaction unveiled parallels between Cl and OCH₃ in the manner in which these substituents engage with amino acid residues. The opposing electronic effects of Cl and OCH₃ substituents on an aromatic ring, along with the dual electrostatic versatility of these two groups, render them useful scouts to probe protein pockets for potency optimization.

2,5-Diazabicyclo[2.2.1]heptane (2,5-DBH) has emerged as a valuable scaffold in medicinal chemistry owing to its conformational rigidity and favorable three-dimensional architecture. In recent years, 2,5-DBH has been increasingly incorporated into biologically active molecules, functioning as a core unit or structural modulator to improve target engagement and pharmacological profiles. Despite growing interest and scattered reports describing its synthesis and biological evaluation, a unified and systematic assessment of this framework has been lacking. This review critically summarizes recent advances in the synthesis of 2,5-DBH and its derivatives, with particular emphasis on efficient construction strategies, functionalization patterns, and derivatization approaches developed over the past decade. In parallel, the biological applications of 2,5-DBH-based compounds are comprehensively discussed across major therapeutic areas, including oncology, neurological disorders, and antimicrobial research. By integrating synthetic progress with biological insights, this review delineates current trends, identifies key structure-activity relationships, and highlights existing challenges and opportunities. Collectively, this work aims to guide future scaffold design and stimulate further exploration of 2,5-DBH as a versatile platform in drug discovery.

Radiotherapy is a standard treatment for breast cancer, but its therapeutic efficacy is often limited by tumor radioresistance and systemic toxicity. Hence, the development of effective radiosensitizers with favorable biocompatibility is urgently needed. We designed and synthesized a biomimetic nanoparticle system, Pt@BSA-RM, by encapsulating platinum nanoparticles within bovine serum albumin (BSA) and cloaking them with a red blood cell membrane (RM). Subsequently, the physicochemical properties, drug loading, stability, and release profiles of Pt@BSA-RM were comprehensively characterized. Next, we assessed the radiosensitizing effect of Pt@BSA-RM in 4T1 BC cells by EdU incorporation, CCK-8, and apoptosis assays, explored the mechanism by ROS generation and γ-H2AX staining, and assessed the effect of Pt@BSA-RM on energy metabolism by GFAAS and JC-1 staining and metabolic flux analysis (OCR/ECAR). A subcutaneous 4T1 tumor model in BALB/c mice was established to assess the in vivo antitumor efficacy and biosafety of Pt@BSA-RM combined with radiotherapy. We found that Pt@BSA-RM nanoparticles possess excellent physical and chemical properties. In vitro studies showed that Pt@BSA-RM significantly enhanced radiation-induced cytotoxicity, inhibited cell proliferation, promoted apoptosis and DNA damage, disrupted mitochondrial membrane potential, and altered glycolytic and oxidative metabolisms. In vivo studies indicated that Pt@BSA-RM combined with X-ray irradiation markedly suppressed tumor growth compared with monotherapy, with reduced systemic toxicity. These results indicated that the red blood cell membrane-coated Pt@BSA nanoparticles effectively improve radiotherapeutic outcomes in breast cancer by enhancing the cellular radiosensitivity and minimizing the adverse effects. This biomimetic nanoplatform holds promise for further translational research in cancer radiotherapy.

The success of antibody-drug conjugates has demonstrated the value of targeted delivery strategies for cytotoxic molecules. However, many oncogenic drivers remain inaccessible to antibodies due to their intracellular location, and these drivers are currently mainly addressed using small molecule inhibitors. This work explores repurposing such inhibitors for the intracellular delivery and controlled release of cytotoxic payloads. Using click-to-release chemistry, a pre-targeting strategy was developed where inhibitor-tetrazine conjugates enable selective activation of systemically administered trans-cyclooctene (TCO) caged prodrugs. This concept was demonstrated using the epidermal growth factor receptor (EGFR), a key therapeutic target in non-small cell lung cancer. An afatinib-tetrazine conjugate achieved sufficient intracellular retention in EGFR-overexpressing cells to enable toxicity recovery from a TCO-protected monomethyl auristatin E (MMAE) derivative. Successful intracellular targeting and controlled payload release establish a foundation for expanding the scope of targeted drug delivery to previously inaccessible oncogenic drivers.