MedChemComm最新文献

Fungal pathogens have emerged as one of the most significant threats to global public health. Invasive fungal infections, characterized by high morbidity and mortality rates, have become one of the most severe diseases, posing a substantial threat to human health. In this study, a rational drug design strategy was employed, targeting lanosterol 14α-demethylase (CYP51). Using SCZ-14, a CYP51 inhibitor with moderate antifungal activity, as the lead compound, 27 novel 2-phenylthiazole derivatives were designed and synthesized through two rounds of structural optimization. Among these compounds, compound B9 exhibited potent inhibitory activity against seven common clinically susceptible fungal strains and moderate activity against six fluconazole-resistant fungi strains, and it demonstrated low cytotoxicity. In addition, the preferred compound B9 had good drug-like properties according to the prediction software. In addition, molecular dynamics studies were conducted on compound B9. All the results of the above research show that the target compound B9 is valuable for further study.

The Ku70–Ku80 (Ku) heterodimer complex plays a central role in the non-homologous end joining (NHEJ) double-strand break (DSB) repair pathway and the DNA damage response (DDR). Like DNA–PK, Ku is a promising drug target for cancer treatment when combined with radiotherapy or DSB-inducing agents. We have previously reported the first-in-class, early-generation, highly potent, and specific Ku–DNA binding inhibitors (Ku-DBi's) that block the Ku interaction with DNA and inhibit DNA-PK kinase activity. These early-generation Ku-DBi's also inhibit cellular DNA-PK, NHEJ-catalyzed DSB repair, sensitize non-small cell lung cancer (NSCLC) cells to DSB-inducing agents, and potentiate the cellular effects of these agents via p53 phosphorylation through the activation of the ATM pathway. In this study, we report a comprehensive structure–activity relationship (SAR) analysis around the initial X80 hit molecule to develop highly potent Ku-DBi's. Early generation Ku-DBi's display a potent Ku–DNA binding inhibitory activity with a range of 2 to 6 μM, and DNA-PK inhibitory activity in the nanomolar range of approximately 110 nM. Microscale thermophoresis assay shows that these compounds inhibit Ku70–Ku80 binding to DNA with a Kd value of 0.4–6.4 μM. The thermal stability analysis also supports the notion that these Ku-DBi's bind to the Ku as measured by nanoDSF (Differential Scanning Fluorimetry), which is consistent with the observed SAR trends. These Ku-DBi's may serve as candidate compounds for further modification and development as anticancer therapeutics in combination with radiotherapy or DSB-inducing agents to treat certain DNA repair-deficient cancers.

Leishmaniasis represents a significant threat to global health as a neglected tropical disease. While therapeutic options exist, their high cost, safety concerns, and significant adverse effects necessitate the discovery of safer and more efficacious alternatives. Natural products, possessing diverse biological activities including inherent anti-leishmanial properties, constitute a vital resource for drug development. However, the intrinsic activity of these compounds is frequently suboptimal. Structural modification offers a potent strategy to significantly enhance their efficacy. This comprehensive review summarizes advances from 2010 to 2024 in the structural modification of natural products to improve anti-leishmanial activity, with particular emphasis on phenylpropanoid derivatives and other natural product classes, and provides detailed synthetic routes for each derivative. The findings demonstrate that strategic structural modifications can substantially increase potency, achieving IC₅₀ values in the nanomolar range for some derivatives. Furthermore, these optimized compounds exhibit promising safety profiles and favorable pharmacokinetic properties, underscoring their considerable potential for further development. These advancements not only offer promising avenues for novel anti-leishmanial drug discovery but also provide valuable insights applicable to natural product-based therapies for other diseases. Future research should prioritize elucidating mechanisms of action and conducting further structure–activity relationship optimization to develop more potent and less toxic anti-leishmanial agents.

Staphylococcus aureus is a highly virulent Gram-positive pathogen implicated in a wide spectrum of severe infections, including pneumonia, endocarditis, osteomyelitis, and bacteremia. In 2024, the World Health Organization (WHO) designated S. aureus as a high-burden, drug-resistant bacterial pathogen of global priority, reinforcing the urgent need for innovative antibacterial strategies. Spirocyclic scaffolds, defined by their rigid three-dimensional architectures and diverse pharmacological properties, have emerged as versatile and privileged frameworks in medicinal chemistry. In this review, we provide a comprehensive account of natural and synthetic spirocyclic derivatives active against S. aureus, with an in-depth discussion of their structural diversity, structure–activity relationships (SARs), and classification into distinct spirocyclic categories. Particular emphasis is placed on the molecular targets modulated by these scaffolds, highlighting their mechanistic relevance in combating S. aureus infections. The therapeutic significance of FDA-approved spiro-based drugs is also discussed in the context of antibacterial drug discovery. By consolidating recent advances, mechanistic insights, and SAR trends, this review aims to guide the rational design and development of next-generation spirocyclic antibacterials with enhanced potency, selectivity, and safety profiles.

Chordoma is a special malignant tumor that lacks effective therapeutic targets, which can lead to incomplete treatment and metastasis. Inflammation plays an important role in chordoma progression and malignant phenotype. Inflammatory factors such as NF-kappaB and STAT3 are continuously activated in many tumors and contribute to the malignant phenotype of tumors and are potential therapeutic targets. This study suggest TNF-alpha and NF-kappaB signaling pathways were consistently activated in chordomas. Long-term TNF-alpha treatment induces chordoma resistance to EGFR family inhibitors. The underlying mechanism is realized by the key molecules HS3ST3A and HS3ST3B1. These two enzymes are potential targets for chordoma treatment, as well as for combination drugs treatment. It should be emphasized that the above analysis lacks experimental verification.

Inhibition of the NLRP3 inflammasome has emerged as a high potential treatment paradigm for the treatment of neuroinflammation, with demonstrated anti-neuroinflammatory effects in Parkinson's disease patients and a strong rationale in Alzheimer's disease and amyotrophic lateral sclerosis. To facilitate further progress in this field, brain penetrant NLRP3 inflammasome inhibitors as leads and tool compounds are required. We discovered a small molecule NLRP3 inflammasome inhibitor, NT-0527 (11), and extensively profiled this to reveal a highly potent, selective and brain penetrant compound. This was shown to be orally bioavailable, efficacious in an in vivo model of inflammation, and with good developability characteristics. However, NT-0527 exhibited CYP 2C19 time-dependent inhibition, which halted development, but this molecule could be employed as a valuable tool compound for the investigation of neuroinflammatory conditions where NLRP3 inflammasome activation is implicated.

Challenges in cancer treatment lie in the identification and development of novel agents with potent anti-tumor activity. A series of novel dehydroabietylamine–pyrimidine derivatives 3a–3s were designed and synthesized based on the principles of molecular hybridization. The inhibitory activities of the target compounds against the proliferation of four different human cancer cell lines (HepG2, A549, HCT116 and MCF-7) were evaluated. Among them, compound 3r, which contains a bicyclic quinuclidine ring, was identified as a potent apoptotic inducer, with a better IC₅₀ value of 1.15 ± 0.31 μM on MCF-7 cells and a favorable selectivity index (SI = 27.7) on human normal mammary epithelial cells (MCF-10A). Cell clonogenic and migration assays further demonstrated that 3r not only effectively inhibited colony formation but also suppressed the cell migratory capacity. Further mechanistic studies revealed that 3r significantly elevates reactive oxygen species (ROS) levels and reduces mitochondrial membrane potential (MMP), thereby inducing cancer cell apoptosis and causing G2 phase cell cycle arrest.

Biofilm formation on medical devices and the rise of antibiotic resistance have undermined conventional antibiotics such as cephalexin (CEX), which is effective against Gram-positive infections but has limited activity against Gram-negative pathogens and biofilms. To overcome these limitations, we developed a hybrid nitric oxide (NO)-releasing conjugate (SNAP_CEX) by covalently attaching the NO donor S-nitroso-N-acetylpenicillamine (SNAP) to CEX. SNAP_CEX exhibited a sustained NO release profile over 30 days, indicating enhanced stability compared to SNAP's rapid degradation, even though the Griess assay showed NO release from SNAP over 30 days. The hybrid maintained strong antibacterial activity against Staphylococcus aureus (S. aureus; MIC₅₀ = 7 μM vs. 2.5 μM for CEX) and dramatically improved efficacy against Pseudomonas aeruginosa (P. aeruginosa; MIC₅₀ = 3 mM vs. 16 mM for CEX). SNAP_CEX also significantly disrupted established biofilms, reducing S. aureus biofilm biomass by ∼75% (vs. ∼33% by CEX) and viable cells by ∼99%, and achieving ∼67% biomass reduction and 77% killing in P. aeruginosa biofilms (vs. ∼25% and 18% by CEX). These effects demonstrate that SNAP_CEX combines NO's biofilm-disruptive action with antibiotic therapy to combat biofilm-associated resistant infections, while remaining cytocompatible at therapeutic concentrations.

Proteolysis-targeting chimeras (PROTACs) are emerging as powerful tools for targeted protein degradation. Among the key factors influencing their efficacy, linker design plays a critical role by affecting membrane permeability, ternary complex formation, and degradation potency. In this study, we conducted a comparative analysis of three novel PROTACs targeting hematopoietic prostaglandin D synthase (H-PGDS), each incorporating linkers with distinct degrees of rigidity—including methylene modifications and spirocyclic structures. Although all compounds exhibited similar binding affinities and degradation activities, the most rigid derivative (PROTAC-3) showed markedly higher intracellular accumulation but formed the least stable ternary complex. These results reveal a trade-off between cell permeability and complex stability, emphasizing the importance of comprehensive linker optimization. Our findings highlight the value of integrating conformational rigidity and spatial design in the rational development of next-generation PROTACs.

Invasive fungal infections caused by Candida albicans are becoming increasingly severe, creating an urgent need to explore new antifungal drugs. Compound YW01 is a structurally novel CYP51 inhibitor that was screened by our research group in the preliminary stage. To enhance its activity, three rounds of structural optimization and modification were conducted in this study. Through in vitro antifungal activity testing and time-kill curve analysis, it was found that compound B3 exhibited potent antifungal activity, which was superior to that of the positive control drug fluconazole. Further research on the antifungal mechanism revealed that compound B3 could effectively inhibit the yeast-to-hypha transition of Candida albicans and possessed the ability to kill fungi. Cytotoxicity experiments demonstrated that compound B3 had no significant inhibitory effects on MCF-7, A549 and BEAS-2B cell lines, indicating moderate safety. In summary, as a CYP51 inhibitor with a novel structural type, compound B3 is highly worthy of further investigation.