MedChemComm最新文献

To achieve covalent CDK7 inhibitors with superior antiproliferative activity and enhanced selectivity, we designed and synthesized a series of covalent CDK7 inhibitors bearing diverse warheads based on the THZ1 scaffold. Experimental validation confirmed that 2-chloroacrylamide-based covalent inhibitors possess potent CDK7 kinase inhibitory activity. HRMS results revealed that the interaction between these compounds and the cysteine residue of CDK7 extends beyond a simple Michael addition, potentially involving nucleophilic substitution at the covalent warhead. Among them, compound B19 exhibited potent CDK7 kinase inhibition with an IC₅₀ value of 0.370 ± 0.0200 nM, as well as strong anti-proliferative activity against MV-4-11 (IC₅₀ = 0.820 ± 0.0500 nM), Molm-13 (IC₅₀ = 1.14 ± 0.0900 nM) and MDA-MB-231 (IC₅₀ = 20.2 ± 1.34 nM) cells. Furthermore, B19 strongly suppressed CDK7-mediated downstream signaling and induced apoptosis and G0/G1 phase arrest in MV-4-11 cells, supporting its potent antitumor effects. Wash-out assays indicated that compound B19 possesses a prolonged activity profile compared with THZ1. Additionally, B19 displayed favorable selectivity across a panel of other kinases. Collectively, these results identify B19 as a promising lead compound for targeting CDK7.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. A key feature of AD is the accumulation of amyloid beta (Aβ) peptides in the form of extracellular plaques. The amyloid cascade hypothesis suggests that the pathogenesis of AD is initiated by the cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Numerous therapeutic approaches have been pursued to target BACE1 due to its crucial role in AD. However, the complexity of AD and the localization of BACE1 in the brain have posed challenges, leading to the failure of clinical trials and, in some cases, even exacerbating disease progression. Specifically, the blood–brain barrier (BBB) prevents the entry of many molecules, making BACE1 a difficult target to approach. Recent advancements in BACE1 therapy have shifted the focus from traditional enzyme inhibitor-based therapeutics to modulators, antibody therapy, and gene therapy. These approaches offer several advantages, including the ability to efficiently cross the BBB and provide targeted treatment. In this review, we explore the latest developments in modulators, antibody therapy, and gene therapy targeting BACE1 to combat AD. These approaches offer a promising avenue to mitigate the progression of AD and provide a novel therapeutic strategy.

Heterocyclic derivatives of steroids have emerged as promising anticancer agents by concurrently targeting multiple pathways, including apoptosis induction, cell cycle arrest, and mitochondrial dysfunction. Here, we report novel pregnenolone-isoxazole hybrids as selective anticancer agents targeting mitochondrial apoptosis. Starting from 20-vinyl pregnenes, nitroisoxazole-substituted pregnenolone derivatives were synthesized and subjected to nucleophilic aromatic substitution, yielding a variety of pregnenolone-isoxazole hybrids bearing azido, phenylthio, and amino groups. In total, 33 new compounds were prepared and evaluated for their in vitro antiproliferative activity against breast cancer cells. The lead compound, 20-[3′-(5″-nitro)isoxazole]-pregna-5-ene-3β-ol-20-one, demonstrated IC₅₀ values of 2.8 μM or lower against MCF7, MCF7/HT2, MDA-MB-231, and HCC1954 breast cancer cell lines under both normoxic and hypoxic conditions. This compound induced mitochondria-dependent apoptosis in MCF7 cells in a concentration-dependent manner. Modulation of key proliferation pathways, including the PI3K/Akt and ERK cascades, further supported the antiproliferative potential of these derivatives. Considering its high cytotoxicity and antiproliferative activity in breast cancer cells, the lead compound has been identified as a promising candidate for further development.

N-Acetylcysteine (NAC) is the established antidote for acetaminophen toxicity and an approved mucolytic agent. Beyond these traditional uses, increasing evidence highlights its broader role as a modulator of thiol–redox biology. Rather than functioning as a nonspecific antioxidant, NAC modulates glutathione metabolism, redox-sensitive signaling, immune checkpoints, thiol-based post-translational modifications, ferroptosis susceptibility, and glutamatergic neurotransmission. This review synthesizes mechanistic, preclinical, and clinical evidence across pulmonary, hepatic, neuropsychiatric, metabolic, cardiovascular, and oncologic disorders, emphasizing how variability in baseline redox state, pharmacogenetics, and delivery contributes to heterogeneous outcomes. Strategies to improve pharmacokinetics and tissue targeting include structural derivatives such as N-acetylcysteine amide (NACA), and combination regimens such as NAC with probenecid or GlyNAC. Emerging applications span long COVID, neurodegeneration, psychiatric disorders, microbiome–redox interactions, environmental toxicology, and cancer immunotherapy. NAC and NACA exemplify the evolution of redox-targeted therapeutics. NAC is well established for safety and clinical utility, but its pharmacokinetic and tissue distribution properties constrain broader efficacy. NACA, a lipophilic amide derivative, enhances membrane permeability and cellular uptake, suggesting it may achieve higher tissue exposure at lower doses. Future progress will rely on biomarker-guided, precision approaches that optimize dosing, formulation, and delivery while exploring rational combinations across disease contexts defined by redox biology.

A series of fifteen novel zerumbone-amide-triazole hybrids 12a–i and 15a–f were successfully designed and synthesized from azazerumbone II (2) via click reaction. The cytotoxicity of these derivatives was evaluated against four human cancer cell lines: gastric carcinoma (AGS), hepatocellular carcinoma (HepG2), lung carcinoma (A549), and acute leukemia (HL-60). Most derivatives displayed significantly improved cytotoxicity compared with the parent compound 9, and several hybrids showed low-micromolar potency. These results highlight the crucial role of the simultaneous incorporation of secondary amide and 1,2,3-triazole pharmacophores into the zerumbone scaffold in enhancing anticancer activity. In particular, compound 12g was the most active derivative, exhibiting IC₅₀ values of 3.25 μM (AGS), 2.21 μM (HepG2), 3.84 μM (A549) and 2.43 μM (HL-60), while 15e also demonstrated consistently strong activity across all cell lines. Molecular docking suggested that the hybrids preferentially associate with non-canonical surface regions within the Rel homology domain (RHD) of NF-κB p65, rather than occupying the DNA-binding groove, with key contacts involving residues such as Phe298, Phe301, Pro303, Lys337 and Lys318. To further assess interaction stability, 50 ns molecular dynamics simulations and MM-GBSA calculations were performed, supporting productive surface binding for the most active ligands and helping discriminate less active candidates. Mechanistically, Western blot analysis in HepG2 cells showed that compound 12g reduced NF-κB p65 and phospho-p65 (Ser536) levels, together with phospho-IκB-α (Ser32), predominantly at 2× IC₅₀, suggesting attenuation of NF-κB activation at higher effective concentrations. Overall, the combined experimental and computational results support zerumbone-amide-triazole hybrids as promising cytotoxic leads, with NF-κB p65 modulation likely contributing to their biological effects.

Two series of compounds were designed and synthesized based on a glycine methyl ester-quinoline core scaffold combined with a fragment containing nitrogen using either an isoxazole or a piperidine carboxamide fragment as a linker as dual inhibitors targeting both chitin synthase (CHS) and glucosamine-6-phosphate synthase (GlmS). The inhibition percentage (IP) values of these compounds against CHS ranged from 29.9% to 84.5%, while their inhibition percentages against GlmS spanned 38.1% to 86.9% at the concentration of 300 μg mL⁻¹. The IC₅₀(CHS)/IC₅₀(GlmS) ratios of compounds 8c, 9, 14c, 14g, and 14i, which were approximately equal to 1 (between 0.97 and 1.15), demonstrated that these compounds were dual inhibitors targeting both CHS and GlmS. Kinetic analysis revealed that compounds 8c (K_i = 0.109 mM) and 14e (K_i = 0.125 mM) acted as noncompetitive inhibitors of CHS, exhibiting stronger binding affinities for CHS than that of UDP-GlcNAc (K_m = 4.11 mM). Similarly, 8c (K_i = 0.227 mM) and 14e (K_i = 0.248 mM) displayed higher binding affinities for GlmS than that of UDP-GlcNAc (K_m = 6.28 mM). Antifungal activity assays in vitro demonstrated that compounds 8c, 8i, 9, 14d, 14e, and 14g exhibited potent antifungal effects comparable to those of fluconazole or polyoxin B. The results of antifungal activity experiments against drug-resistant fungal strains and sorbitol protection assays, coupled with the results of drug combination studies, further indicated that the target of these compounds is the chitin in the cell wall. Molecular docking showed that compounds had good affinities with both CHS and GlmS. Furthermore, ADME (absorption, distribution, metabolism, excretion) profiling revealed that these compounds possess favorable pharmacokinetic properties and drug-likeness, representing viable lead compounds for the development of novel antifungal agents.

A series of D-galactose-conjugated pyrimidine-based thioureas 8a–l was efficiently synthesized using an environmentally benign ionic liquid–microwave protocol. Optimal conditions employing [BMIM][BF₄] under microwave irradiation (100 W) afforded excellent yields (up to 96%) within 60 s, with the ionic liquid showing good recyclability. The synthesized compounds were evaluated for antibacterial and antifungal activities against a broad panel of pathogenic microorganisms. Several derivatives exhibited potent antimicrobial effects, with MIC values comparable to or superior to reference drugs. Structure–activity relationship analysis revealed that ortho-hydroxyl substitution and synergistic hydroxyl/methoxy patterns significantly enhanced biological activity. Among the series, compound 8l (2-OH-4-OMe) emerged as the most potent and broad-spectrum candidate. In silico ADMET analysis suggested favourable drug-like characteristics for non-oral antimicrobial applications. Molecular docking studies supported the experimental results, demonstrating strong and stable binding of compound 8l within bacterial and fungal enzyme active sites. Overall, these findings highlight D-galactose-conjugated pyrimidine thioureas as promising antimicrobial scaffolds.

Cancer, due to its high morbidity and mortality rate, coupled with the dose-restricted toxicity of many chemotherapy drugs, is still a major challenge in the global health field. In order to meet this challenge, we report the design and synthesis of 16 benzoyl hydrazone derivatives using molecular hybridization to identify potent anticancer candidates. Biological evaluation revealed that compound Q-11 exhibited pronounced antiproliferative activity at nanomolar concentrations, with an IC₅₀ value of 12.5 nM against SGC-7901 gastric cancer cells, and showed broad inhibitory effects across multiple human cancer cell lines. Notably, compound Q-11 displayed markedly lower cytotoxicity toward non-cancerous HK-2 renal epithelial cells, indicating a favorable in vitro selectivity profile. Mechanistic studies demonstrated that compound Q-11 induces early intracellular ROS accumulation, mitochondrial membrane depolarization, and caspase-dependent apoptosis. In addition, immunofluorescence analysis revealed significant disruption of microtubule organization following compound Q-11 treatment. Taken together, these findings identify compound Q-11 as a highly potent nanomolar-level anticancer lead, supporting its further investigation in anticancer drug discovery.

Obesity and type 2 diabetes have reached pandemic proportions, largely driven by sedentary lifestyles and unhealthy dietary habits. According to the World Obesity Atlas 2024, by 2035 more than 4 billion adults and children are expected to be living with overweight or obesity, up from 2.2 billion in 2020. These alarming trends contribute substantially to morbidity and mortality from noncommunicable diseases, underscoring the urgent need for innovative and effective therapeutic strategies. The present study aimed to design and develop a novel GLP-1/GIP/GCG receptors triagonist with high and balanced efficacy across all three biological targets. Advanced computer-aided drug design approaches were employed to optimize pharmacological activity and identify promising multi-receptor agonists rationally. Integrated bioinformatics analyses enabled identification of key sequence determinants and optimal modification sites, while molecular dynamics simulations elucidated the impact of stapling and staple positioning on α-helical stability and conformational rigidity in incretin-like peptides. Guided by these insights, 22 novel triagonistic structures were designed, synthesized, and evaluated in vitro using fluorescence membrane potential assays. Relative agonist activity was assessed using a balanced triagonism score, defined as the standard deviation of Δlog(E_max/EC₅₀) values across GLP-1R, GCGR, and GIPR. Most compounds exhibited highly balanced pharmacological profiles, demonstrating comparable activity across receptors. The most active analogue, P2-L4, exhibited low-nanomolar potency across all three targets, with efficacy comparable to reference incretin therapeutics. The developed triagonists demonstrated potent in vitro activity, providing a solid foundation for further optimization and the future development of innovative therapies for obesity and diabetes.

Ataxia telangiectasia and Rad3-related (ATR) kinase plays a critical role in the DNA damage response (DDR), making it a promising target for cancer therapy. Herein, a series of dihydrospiro[cyclopropane-1,7′-pyrrolo[3,4-d]pyrimidine] derivatives have been identified as a novel class of ATR inhibitors. Among them, compound 10h exhibited the most excellent ATR kinase inhibitory activity, with an IC₅₀ value of 6.89 nM. In vitro, 10h demonstrated potent anti-tumor activity and effectively inhibited niraparib-induced CHK1 phosphorylation in Granta-519. Pairwise drug combinational antiproliferative assays revealed that 10h and niraparib synergistically enhanced antiproliferative effects against Granta-519. These results suggested that 10h holds promise for further development as a lead compound for the design of ATR kinase-targeted therapies.