ChemMedChem最新文献

The tandem Tudor domain (TTD) of UHRF1 is a compelling epigenetic target for novel cancer therapeutics. Here, we integrate theoretical simulations, sophisticated biophysical evaluations and cellular assays to characterize potent TTD binders. Screening of small drug- and fragment-like collections identifies several TTD ligands, with the most promising hit being the local anesthetic hydroxyprocaine. The ligand is characterized in terms of its binding requisites by calorimetry, affording a K_d of 1.46 μM and a well-balanced thermodynamic profile. Molecular dynamics simulations combined with heat capacity measurements and osmotic stress titrations confirm that hydroxyprocaine binds stably to the TTD by displacing approximately 26 interfacial water molecules upon complexation. A targeted follow-up screen focusing on sodium channel blockers yields two additional, although less promising hits, mexiletine and triamterene. In the DU145 prostate cancer cell line, hydroxyprocaine treatment significantly up-regulates key downstream targets including the tumor-suppressor p53 and, to a lesser degree, the stress and inflammation regulators p38 and p65, respectively, while exhibiting very low cytotoxicity. Finally, a previously undocumented interdomain interaction between TTD and its N-terminal adjacent Ubiquitin-like domain is reported, introducing a novel, potentially druggable UHRF1 regulatory feature. Together, these findings establish hydroxyprocaine as a highly viable chemical scaffold for TTD-targeted drug development.

Photodynamic therapy (PDT) is a clinically established approach that relies on the localized generation of reactive oxygen species (ROS) mediated by a photosensitizer (PS), light, and molecular oxygen. Protoporphyrin IX (PpIX) is an approved PS; however, its intracellular retention is limited, factor that can alter its overall photodynamic efficiency. In this study, we report how the design of PpIX derivatives bearing piperazine (PpIX-Pip) or morpholine (PpIX-Morp) substituents may modulate lipophilicity, cellular uptake, oxidative stress, and phototoxicity. The photodynamic activity of these derivatives was evaluated in the aggressive triple-negative human breast cancer cell line MDA-MB-231. Both derivatives showed greater time-dependent cellular retention and enhanced photodynamic activity compared to PpIX, promoting oxidative stress, and triggering loss of mitochondrial membrane potential and caspase-3 activation. These results highlight the impact of rational structural modification of PpIX on photodynamic efficiency and provide valuable structure–activity relationship insights for the development of improved porphyrin-based PS for PDT.

The S-phase kinase-associated protein 2 (Skp2)–cyclin-dependent kinase subunit 1 (Cks1) protein–protein interaction (PPI) plays a central role in recognition of phosphorylated p27 and therefore represents an attractive target for anticancer drug discovery. Herein, we sought to identify new small-molecule disruptors of the Skp2–Cks1 interface from a focused fumiquinazoline-scaffold library by combining virtual screening, molecular simulation, and experimental validation. Docking showed that all selected compounds occupied the Skp2–Cks1 interfacial hotspot. However, longer 1000-ns MD simulations, comparative MM/PBSA calculations, and interface-related metrics revealed distinct structural, energetic, and dynamic binding profiles among the selected compounds. Consistent with these analyses, comparative MM/PBSA evaluation of PPI stability showed that Fumiquinazoline D produced a positive $$, indicating weakening of the Skp2–Cks1 interface relative to the apo complex, whereas Ardeemin, Fiscalin A, and Fumiquinazoline F generally yielded negative $$ values consistent with interfacial stabilization. Free energy landscape analysis further supported a more weakly confined and dynamically disruptive binding mode for Fumiquinazoline- D. In vitro homogeneous time-resolved fluorescence assays validated these predictions: Fumiquinazoline D inhibited the Skp2–Cks1 interaction with an IC₅₀ of 6.33 ± 0.44 µM, whereas Ardeemin, Fiscalin A, and Fumiquinazoline F were substantially weaker. Although ADMET profiling identified substantial absorption and toxicity liabilities requiring future optimization, these findings identify Fumiquinazoline D as an early-stage biochemical hit for disruption of the Skp2–Cks1 interaction and as a potential scaffold for further mechanistic validation and medicinal-chemistry investigation.

Triple-negative breast cancer (TNBC) remains a major clinical challenge due to the absence of effective targeted therapies. In this study, thirty analogs of (S)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-3-carboxamide (A1–F5) were designed, synthesized, and evaluated for their cytotoxic activity against hormone receptor-positive breast cancer (MCF-7) and EGFR-overexpressing TNBC (MDA-MB-468) cell lines. Notably, compounds B1 and B3 exhibited potent growth inhibition toward MDA-MB-468 cells, with GI₅₀ values of 2.8 and 4.7 µM, respectively, surpassing the efficacy of the reference compound (Ref 2, GI₅₀: 7.6 µM) and gefitinib (GI₅₀: 16.5 µM). Flow cytometric analysis demonstrated significant apoptosis induction by compounds B1 and B3, with rates of 42.8% and 42.2%, respectively. Mechanistic investigations revealed that compounds B1 and B3 selectively inhibited Akt phosphorylation and enhanced JNK phosphorylation, suggesting a dual modulation of survival and apoptotic pathways. These findings support the development of N2-benzyl-(S)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-3-carboxamide analogs, particularly compound B1, as selective therapeutic candidates for triple-negative breast cancer.

Given its pivotal role in the viral life cycle, blocking integrase (IN) through IN strand transfer inhibitors (INSTIs) represented a breakthrough in the treatment of HIV infection, establishing these antiretroviral regimens as first-line options against AIDS. However, the onset of drug-resistant strains has challenged the efficacy of INSTIs, demanding new efforts in the search for therapeutic tools that work through alternative modes of action. In this context, the discovery of allosteric IN inhibitors (ALLINIs) has highlighted new opportunities to target IN beyond its active site, enhancing antiviral efficacy and the genetic barrier to resistance. Extensive drug discovery campaigns have resulted in the development of effective ALLINIs with both in vitro and in vivo efficacy, two of which are advancing in clinical trials as next-generation therapeutic tools. Nevertheless, advancements in structural biology have critically aided in elucidating the underlying effects of ALLINIs, highlighting a complex, multimodal mode of action that ultimately yields defects in virion maturation. This review focuses on ALLINIs, providing a comprehensive overview of major drug discovery efforts devoted to this field, with an emphasis on the medicinal chemistry and structural biology findings that have revealed unprecedented opportunities for developing innovative and effective anti-HIV drugs.

Tuberculosis (TB) remains a global epidemic, and Mycobacterium tuberculosis (Mtb), its etiological agent, continues to be the deadliest single infectious agent worldwide. Our inability to eradicate TB is strongly related to Mtb's ability to alternate between an active and latent disease state, and a lack of pharmacological agents that effectively target the heterogeneity of TB, which leads downstream to the emergence of drug resistance. The ongoing quest to discover novel effective chemical agents to improve anti-TB regimens remains a significant challenge. Multicomponent reactions (MCRs) have been shown to generate highly diverse chemical libraries in a time- and cost-efficient, sustainable manner, and thus have emerged as powerful tools to accelerate drug discovery and development. This review provides an overview of the chemical libraries of anti-TB agents developed by MCRs, highlighting the contributions of MCRs to advance anti-TB drug discovery through a medicinal chemistry approach.

In this study, we present a comprehensive structural analysis of four distinct chemical libraries: FDA-approved drugs, blood-brain barrier (BBB) permeable agents, natural products (UNPDA), and human metabolites. Our multidimensional profiling reveals fundamental divergences in molecular architecture. While synthetic drugs (FDA) and CNS-active agents (BBB) follow continuous, Gaussian-like distributions for carbon hybridization, natural products exhibit biosynthetic quantization, discrete, high-intensity abundance spikes at C19 and C30, corresponding to steroid and triterpene scaffolds. Stereochemical analysis identifies a chirality-structure lock in natural products, where stereoisomer density peaks significantly at these same integers (Avg. 3.53 isomers/mol), a complexity feature absent in the diffuse distribution of synthetic libraries. Topologically, we identify hyper-globularity as a distinct signature for CNS permeability. Radial distribution function (RDF) analysis demonstrates that BBB agents possess a highly compressed aliphatic core, packing 93.2% of their sp³ mass within a 3 Å radius, compared to 84.4% for general FDA therapeutics. Furthermore, elemental profiling reveals a heteroatom gap: synthetic drugs exhibit a high electronegative atom-to-carbon ratio (0.43), whereas BBB agents (0.33) converge with the lipophilic profile of natural products (0.32), suggesting that CNS penetration requires a biomimetic reduction in polarity. These findings establish new quantitative metrics for designing neuro-compatible and biomimetic pharmacophores.

Recognizing the strong interconnection between human, animal, and environmental health, the "One Health" perspective listed by WHO promotes cross-disciplinary integration as a key strategy to address global challenges. Within this framework, this perspective article summarizes the key themes and future directions emerging from the conference "Medicinal and Crop Protection Chemistry: Breaking Barriers, Building Synergies," held in Como, Italy, in October 2025. The meeting highlighted the strong conceptual and technological convergence between medicinal and crop protection science, two disciplines that share common goals in the discovery and development of bioactive compounds despite traditionally evolving as separate sectors. Emphasis was particularly placed on providing an updated overview of the latest advances in drug and agrodrug development through those strategies discussed during the congress, which ranged from established approaches in bioactive molecule discovery, such as bioisosterism and covalent ligand design, to emerging modalities including AI-assisted discovery and targeted protein degradation technologies. We believe that the congress represented an important opportunity to catalyze dialog across both sectors, encouraging the exchange and adaptation of innovative strategies rather than their simple transfer, with the hope that this interdisciplinary initiative will continue to grow and stimulate future collaborations toward sustainable solutions for global health and food security.

The development of highly effective antibiotics and antimicrobials over the centuries has greatly improved human life. However, the irresponsible use of these substances and their release into the environment have led to the emergence of resistant microorganisms. Quaternary ammonium salts (QAS), due to their high efficacy as antibacterial agents and their wide spectrum of activity as disinfectants and antiseptics, represent a possibility to avoid antibiotic resistance. In this work, new bis-cationic QAS, having as common precursor 2,4,6-trichloro-1,3,5-triazine, were synthetized showing high antimicrobial properties (bis-TQAS). The compounds obtained were characterized by ¹H NMR, ¹³C NMR, COSY, HSQC, HMQC, ESI-MS, elemental analysis, and Log P determination. Their antibacterial activity was evaluated against Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes. Significant growth inhibition was achieved for all tested strains. Specifically, for the bis-TQAS with C₁₀ alkyl chain, a Log reduction of >5.70 against S. aureus and L. monocytogenes was observed, while the antibacterial Log reduction exceeded 3.60 Log for K. pneumoniae and E. coli strains. In contrast, the performance of the C₁₂ alkyl chain derivative varied; nevertheless, it still demonstrated strong efficacy, with Log reductions exceeding 3.63 for the Gram-positive strains and 4.00 for the Gram-negative strains.

Cancer remains a major global health challenge, and the limited efficacy, systemic toxicity, multidrug resistance, and tumor recurrence associated with current therapies continue to drive the development of novel targeted anticancer agents. Quinoline-based heterocyclic scaffolds have emerged as valuable structural frameworks in anticancer drug discovery owing to their structural diversity and ability to interact with multiple oncogenic targets. This review provides a target-oriented overview of quinoline-based anticancer agents reported between 2019 and 2025, covering quinoline, quinazoline, quinoxaline, and a few selected nonquinoline nitrogen-containing heterocyclic derivatives. Recent advances in quinoline-based derivatives targeting ER, CDK4/6, topoisomerase I/II, epidermal growth factor receptor, PLCγ1, PI3K/AKT, and VEGFR-2/P-glycoprotein pathways are discussed with respect to their synthetic strategies, in vitro anticancer assay, and structure–activity relationships (SAR). This review integrates comparative SAR trends across diverse quinoline-based scaffolds, highlighting the influence of scaffold planarity, ring fusion, substitution patterns, linker architecture, and metal complexation on anticancer activity. In addition, clinically approved quinoline-based anticancer drugs, representative patents, and future perspectives are summarized to emphasize the translational potential of these scaffolds. Collectively, this review provides a comprehensive overview of recent advances to guide the rational design of next-generation quinoline-based anticancer agents.