Eur J Med Chem
· 2026 Jun · PMID 42364458
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Despite being appealing oncological targets, a majority of cancer-driving proteins with high biomedical relevance remain intractable to conventional small-molecule drug design due to several well-documented challenges. N...Despite being appealing oncological targets, a majority of cancer-driving proteins with high biomedical relevance remain intractable to conventional small-molecule drug design due to several well-documented challenges. Nonetheless, progress in drug design strategies and experimental techniques has produced far-reaching impact on our efforts in harnessing these undruggable, cancer-driving targets. The past few years have witnessed massive achievements in this field, including the approval of KRAS inhibitors, and the successful discovery of investigational new drugs and in vivo potent therapeutics. Herein, we comprehensively depict the strategic landscape for tackling the four classes of undruggable oncoproteins: transcription factors, GTPases, scaffolding proteins, and phosphatases, with a focus on the highly sought-after target(s) within each category. It is anticipated that this overview of strategic strides, along with the perspectives, will guide future innovative drug discovery targeting intractable oncoproteins.
Gu Z, Qi Z, Chen Z
… +10 more, Li J, Song S, Liu L, Wang J, Zheng W, Xie X, Liu H, Zhang X, Dai W, Bai F
Eur J Med Chem
· 2026 Jun · PMID 42364457
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How to efficiently explore chemical space to discover new compounds remains an important challenge in drug discovery. In this work, we introduce a Transformation strategy that enables efficient, scaffold-guided explorati...How to efficiently explore chemical space to discover new compounds remains an important challenge in drug discovery. In this work, we introduce a Transformation strategy that enables efficient, scaffold-guided exploration of sub-chemical space around known bioactive molecules to obtain broad-spectrum inhibitors capable of targeting multiple proteins with related binding pockets. The core concept is to retain a validated binding scaffold responsible for essential target interactions, while systematically modifying peripheral regions to rapidly access nearby chemical space associated with target variability and functional optimization. We applied this strategy to the 3C-like protease (3CL), a conserved enzyme present in multiple coronaviruses and a key target for broad-spectrum antiviral development. Key pharmacophoric features of the SARS-CoV-2 3CL inhibitor Leritrelvir were preserved as the core scaffold to maintain critical active-site interactions, while non-essential regions were iteratively transformed within a defined sub-chemical space to generate structurally diverse analogues. Using this, several novel compounds were designed, synthesized and evaluated. Compounds 7c and 7d exhibited potent inhibition of SARS-CoV-2 3CL. Notably, compound 7c showed broad-spectrum antiviral activity, maintaining potency comparable to Leritrelvir against β-coronavirus 3CL, while demonstrating improved inhibition against α-coronavirus HCoV-NL63 3CL. Its anti-SARS-CoV-2 activity was essentially equivalent to Leritrelvir, while its anti-HCoV-NL63 activity was superior. Overall, these results demonstrate that the Transformation strategy is an effective and generalizable framework for scaffold-guided chemical space exploration, particularly suitable for multi-target systems such as viral proteases, where conserved scaffolds maintain baseline activity, while sub-chemical space exploration enables optimization of potency, spectrum coverage, and resistance mitigation.
Eur J Med Chem
· 2026 Jun · PMID 42364456
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Respiratory syncytial virus (RSV) remains a leading cause of lower respiratory tract infections in infants, elderly individuals, and immunocompromised individuals, and poses a substantial global health burden. Despite th...Respiratory syncytial virus (RSV) remains a leading cause of lower respiratory tract infections in infants, elderly individuals, and immunocompromised individuals, and poses a substantial global health burden. Despite the clinical use of ribavirin and the monoclonal antibody palivizumab, their limitations in efficacy, safety, and cost necessitate the development of novel anti-RSV agents. This comprehensive review summarizes the progress in RSV therapeutics over the past decade (2015-2025), focusing on three major categories: small-molecule inhibitors, monoclonal antibodies, and vaccines. Small-molecule inhibitors, including fusion inhibitors targeting the F protein, nucleoside and non-nucleoside polymerase inhibitors, and nucleoprotein inhibitors, are discussed in detail. The review also covers approved and emerging monoclonal antibodies and vaccines, highlighting their mechanisms, clinical status, and limitations. Key challenges such as drug resistance, target specificity, and patient heterogeneity are addressed, and future directions-including structure-based drug design, host-targeted therapies, drug repurposing, and combination strategies-are proposed. This review aims to provide medicinal chemists with a structured update on RSV drug discovery and to accelerate the development of effective antiviral strategies.
Divoux G, Sautour M, Swiatek R
… +4 more, Moundanga S, Dupont S, Gros CP, Desbois N
Eur J Med Chem
· 2026 Jun · PMID 42364455
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The antifungal activity of acid-functionalized corroles, with and without ultra-high-intensity irradiation, was investigated. Their antifungal efficacy was evaluated against the yeast Candida albicans. Corroles functiona...The antifungal activity of acid-functionalized corroles, with and without ultra-high-intensity irradiation, was investigated. Their antifungal efficacy was evaluated against the yeast Candida albicans. Corroles functionalized with phosphonic acids exhibited MICs values of 25-50 μg/mL against Candida albicans. However, ultra-high-intensity irradiation significantly increased the antifungal activity of most of the tested corroles. The best results (3.12 μg/mL) were obtained with Cor4a-b diacid corroles functionalized with fluorine atoms after only 3 min of ultra-high-intensity irradiation (250 mW/cm, 405 nm). ROS production studies in the presence and absence of C. albicans confirmed that the antifungal mechanism of these corroles may be correlated with the production of reactive oxygen species (ROS) in cells.
Madia VN, Patacchini E, Saccoliti F
… +4 more, Zarbo L, Arpacioglu M, Costi R, Di Santo R
Eur J Med Chem
· 2026 Jun · PMID 42364454
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The SARS-CoV-2 pandemic highlighted the urgent need for antivirals targeting essential viral enzymes. Herein, we critically examine the current landscape of small molecule inhibitors targeting the highly conserved non-st...The SARS-CoV-2 pandemic highlighted the urgent need for antivirals targeting essential viral enzymes. Herein, we critically examine the current landscape of small molecule inhibitors targeting the highly conserved non-structural protein 12 (nsp12), the RNA-dependent RNA polymerase, and non-structural protein 13 (nsp13), the helicase, both critical for viral genome replication. Structural and mechanistic features that inform rational inhibitor design, including active sites and cofactor interactions, are discussed. For nsp12, nucleoside analogues derived from a drug repurposing strategy, as well as emerging non-nucleoside inhibitors targeting allosteric sites, are evaluated. Development of ATPase and helicase inhibitors for nsp13 is at an earlier stage, but promising scaffolds have been revealed through high-throughput and structure-based screening. An in-depth analysis of small molecule inhibitors from synthetic and natural sources is presented for both enzymes, highlighting key limitations and strategic directions to advance the development of next-generation antivirals against SARS-CoV-2 through targeted modulation of nsp12 and nsp13.
Labrano L, Primavera E, Rocchi M
… +8 more, Massuoli M, Ragni MG, Poletta L, Gargaro M, Fallarino F, Manfroni G, Barreca ML, Astolfi A
Eur J Med Chem
· 2026 Jun · PMID 42364453
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The increasing availability of large chemical libraries and bioactivity datasets has created a growing need for cheminformatics tools capable of extracting interpretable structure-activity relationship (SAR) information...The increasing availability of large chemical libraries and bioactivity datasets has created a growing need for cheminformatics tools capable of extracting interpretable structure-activity relationship (SAR) information across structurally diverse chemical series. However, many existing approaches rely on rigid scaffold definitions, descriptor-based clustering, or manually curated groupings, often limiting the identification of SAR trends spanning partially overlapping chemotypes. Here, we present SARgate, an open-source cheminformatics platform designed to organize chemical libraries into structurally coherent subsets and facilitate multi-level SAR exploration within a unified graphical environment. Starting from Bemis-Murcko scaffolds, SARgate applies automated aggregation procedures to derive generalized cores based on minimal shared substructures, enabling flexible R-group decomposition and improved recognition of chemically related series. Developed in Python using RDKit as the core cheminformatics engine, SARgate integrates dataset curation, scaffold organization, R-group analysis, matched molecular pair analysis (MMPA), stereochemical evaluation, similarity assessment, and structure-activity landscape visualization into a single interactive workflow accessible to users with different levels of computational expertise. The utility of SARgate is demonstrated through representative case studies involving AKT1 and IL4I1 inhibitor datasets derived from public repositories, externally curated collections, and manually assembled patent-derived libraries. These applications show that SARgate can recover known SAR determinants, identify activity-driving substituents and stereochemical constraints, reveal context-dependent effects, and support mechanistically interpretable medicinal chemistry insights directly from large-scale bioactivity data.
Yang K, Cui M, Bejoma T
… +4 more, Lv J, Li A, Peng X, Zhao Q
Eur J Med Chem
· 2026 Jun · PMID 42361483
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Dihydroartemisinin (DHA) attracts considerable attention as a promising antineoplastic agent against colorectal cancer. However, its suboptimal antitumor efficacy and its C-10 configurational lability driven by hemiaceta...Dihydroartemisinin (DHA) attracts considerable attention as a promising antineoplastic agent against colorectal cancer. However, its suboptimal antitumor efficacy and its C-10 configurational lability driven by hemiacetal-mediated epimerization collectively impede its clinical development. In this context, a library of 52 DHA-cinnamic acid (DHA-CA) hybrid derivatives with defined C-10 stereochemistry was constructed via stereocomplementary esterification: Mitsunobu conditions selectively afforded 10β-configured esters, whereas HATU-mediated acylation preferentially furnished 10α-isomers. Structure-activity relationship (SAR) exploration revealed that structural modifications, including double-bond saturation, the introduction of electron-withdrawing groups, or altered phenyl substitution patterns, substantially attenuated antiproliferative activity. These findings established that a 10β-configured CA (α,β-unsaturated ester linkage) combined with a bulky, electron-donating meta-substituent (e.g., tBu) constituted the optimal pharmacophore. Guided by this SAR framework, compound 12b-meta was identified as the most potent derivative against colorectal cancer cell lines, exhibiting IC values of 0.057 ± 0.014 μM (HT-29) and 0.067 ± 0.016 μM (HCT 116), with a selectivity index (SI) exceeding 447 against NCM460 normal colon mucosal epithelial cells. This profile represents a 52- and 86-fold enhancement in potency relative to DHA. Mechanistic studies showed that 12b-meta suppressed colony formation and DNA synthesis, induced G0/G1 arrest, and was accompanied by reduced Cyclin D1/CDK4 expression. Quantitative proteomic profiling revealed downregulation of proteins related to DNA replication and mitochondrial translation, and immunoblot analysis confirmed RRM2 downregulation. Moreover, 12b-meta showed moderate human plasma stability, with 53.4% remaining after 240 min. These findings established the meta-tBu CA-DHA scaffold as a platform for a potential preclinical optimization in colorectal cancer drug discovery.
Liu J, Dou X, Liu Z
… +3 more, Wang C, Wu X, Wang Y
Eur J Med Chem
· 2026 Jun · PMID 42361482
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The escalating crisis of antimicrobial resistance necessitates the development of novel antibacterial agents with distinct mechanisms of action. Inspired by the membrane-disruptive properties of antimicrobial peptides, a...The escalating crisis of antimicrobial resistance necessitates the development of novel antibacterial agents with distinct mechanisms of action. Inspired by the membrane-disruptive properties of antimicrobial peptides, a series of amphiphilic cinnamamide-pyridine quaternary ammonium derivatives were rationally designed and synthesized. The optimal derivative, compound 9c, featuring a bis-cationic scaffold with hexyl chains, exhibited potent and broad-spectrum antibacterial activity against Gram-positive pathogens (MICs = 0.5-1 μg/mL), along with good safety profiles characterized by low hemolytic activity (HC = 482.4 μg/mL) and low cytotoxicity (CC = 32.92 μg/mL). Other notable attributes included exceptional plasma stability, rapid bactericidal kinetics, a low tendency to induce resistance, and strong antibiofilm activity. Mechanistic investigations revealed that compound 9c selectively target bacterial membranes via specific interaction with phosphatidylglycerol, leading to membrane depolarization, increased permeability, and subsequent leakage of intracellular components. More importantly, 9c significantly reduced bacterial burden and mitigated tissue inflammation, outperforming vancomycin in a murine skin abscess model. Collectively, these findings establish 9c as a promising membrane-active antibacterial candidate worthy of further development.
Zhang Y, Lin S, Chen H
… +7 more, Wang X, Ye XY, Gao Y, Tang C, Luo L, Hui Z, Xie T
Eur J Med Chem
· 2026 Jun · PMID 42361481
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Fungal-derived natural products, with their structural diversity and broad biological activity, hold great potential in drug discovery and biomedical research. This systematic review summarizes the research progress on f...Fungal-derived natural products, with their structural diversity and broad biological activity, hold great potential in drug discovery and biomedical research. This systematic review summarizes the research progress on fungal-derived bioactive natural products from 2020 to 2025, covering major structural types such as polyketides, alkaloids, terpenoids, steroids and phenolics. We systematically discuss their chemical diversity, biological activities, mechanisms of action, structure-activity relationships, as well as key translational challenges in the field, aiming to provide research insights for further exploration of fungal resources and the development of novel drugs.
Zhou Y, Feng K, Jin H
… +4 more, Xue H, Yin Y, Wang K, Zhao W
Eur J Med Chem
· 2026 Jun · PMID 42361480
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Sepsis is a life-threatening disorder with high mortality and limited host-targeted treatments. Heparanase (HPA) mediates endothelial glycocalyx degradation and represents a key therapeutic target for sepsis. Our previou...Sepsis is a life-threatening disorder with high mortality and limited host-targeted treatments. Heparanase (HPA) mediates endothelial glycocalyx degradation and represents a key therapeutic target for sepsis. Our previously reported pentasaccharide CV122 showed potent HPA inhibition and anti-inflammatory efficacy, yet its complex structure, dense sulfation, and low synthetic yield hindered further development. Herein, we rationally designed and synthesized a series of structurally defined sulfated tetrasaccharides by truncating and optimizing the CV122 scaffold. Compound 5 displayed the most potent HPA inhibition with an IC of 11.27 μM. In a Cecal Ligation and Puncture (CLP) induced mouse sepsis model, compound 5 significantly improved survival, reduced pro-inflammatory cytokines, and preserved organ morphology. Molecular docking confirmed favorable binding to the HPA active site. This work showed that rationally modified tetrasaccharides derived from CV122 retained strong inhibitory activity with better synthetic accessibility, offering a promising glycan-based strategy for sepsis intervention.
Jahan K, Glatfelter G, Sanchez J
… +13 more, Maitland AD, Bonifazi A, Saab E, Keegan BM, Rais R, Bi GH, Gomez JL, Michaelides M, Xi ZX, Lane JR, Canals M, Baumann MH, Newman AH
Eur J Med Chem
· 2026 Jun · PMID 42361479
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The development of opioid analgesics with low abuse liability remains a challenge. As dopamine D receptor (DR) antagonists/partial agonists can reduce opioid self-administration and reinstatement in animals while augment...The development of opioid analgesics with low abuse liability remains a challenge. As dopamine D receptor (DR) antagonists/partial agonists can reduce opioid self-administration and reinstatement in animals while augmenting antinociceptive effects, a dual-target ligand strategy was investigated. Here, the high affinity mu opioid receptor (MOR) agonist etonitazene was modified by incorporating various DR pharmacophores with varying linking chains. N-substituted etonitazene analogs 31 (MOR K = 33.4 nM; DR K = 90.6 nM), 35 (MOR K = 29.7 nM; DR K = 53.8 nM), and 43 (MOR K = 89.6 nM; DR K = 45.4 nM) achieved balanced binding affinities and were chosen as lead molecules. In vitro bioluminescent resonance energy transfer (BRET) assays confirmed that all three compounds functioned as MOR agonists and DR antagonists/partial agonists. Notably, compound 31 demonstrated metabolic stability and maximal antinociceptive effects (ED = 29.1 mg/kg s.c.) with reduced motor stimulation in C57BL/6J mice. Although compound 31 produced respiratory depression at the analgesic dose of 30 mg/kg, this was comparable to morphine which has lower intrinsic efficacy and a safer profile compared to etonitazene. Overall, our findings support the feasibility of developing MOR-DR dual-target ligands, based on etonitazene, as efficacious analgesics that may have reduced addictive liability.
Ren C, Wang X, Yao Y
… +3 more, Liang S, Liao W, Yao Z
Eur J Med Chem
· 2026 Jun · PMID 42361478
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Butyrylcholinesterase (BuChE) plays a crucial role in maintaining neurotransmission homeostasis as a key complementary hydrolase to acetylcholinesterase (AChE), making it an essential target for addressing neurodegenerat...Butyrylcholinesterase (BuChE) plays a crucial role in maintaining neurotransmission homeostasis as a key complementary hydrolase to acetylcholinesterase (AChE), making it an essential target for addressing neurodegenerative diseases, neuroinflammation, and chemical toxin metabolism. A variety of selective BuChE inhibitors have been developed; however, their clinical translation remains constrained by insufficient efficacy, off-target effects, and poor blood-brain barrier (BBB) permeability. Recently, dual-target inhibitors have emerged as a promising strategy to circumvent these limitations. By integrating BuChE inhibition with complementary targets, researchers have designed multifunctional ligands through rational structural fusion and hybridization strategies and combinatorial library screening. These inhibitors exhibit enhanced neuroprotective efficacy, improved selectivity, and reduced side effects. This review highlights recent advances in the rational design, structure-activity relationship (SAR), and preclinical efficacy of novel BuChE dual-target inhibitors, focusing on their therapeutic potential for Alzheimer's disease (AD).
Fageeri MF, Ramadan WS, Kawaf RR
… +4 more, Alqedra S, Msallam YA, Alniss HY, El-Awady R
Eur J Med Chem
· 2026 Jun · PMID 42349363
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Minor groove binders (MGBs) are a distinctive class of potential anticancer agents that are characterized by high sequence-selectivity interactions with the DNA minor groove. Their effects extend beyond the cytotoxic con...Minor groove binders (MGBs) are a distinctive class of potential anticancer agents that are characterized by high sequence-selectivity interactions with the DNA minor groove. Their effects extend beyond the cytotoxic consequences to profound effects on gene transcription, epigenetic modulation, and DNA repair. Advances in the design and development of MGBs have expanded their spectrum to include cancer management, with recent pharmacological studies being indicative of their promising anticancer characteristics. This review provides a comprehensive overview of the MGBs and their DNA binding mechanisms. It integrates the current knowledge on how sequence-specific DNA recognition translates into downstream biological responses relevant to cancer therapy. It also highlights how their sequence-specific interactions disrupt the function of essential proteins involved in critical cellular processes, including polymerases, transcription factors, and topoisomerases. Furthermore, the review discusses how MGBs perturb the cellular microenvironment, induce DNA damage, and alter epigenetic regulation, collectively influencing cell cycle progression and ultimately triggering apoptotic pathways. Particular emphasis is placed on the molecular determinants of reduced sensitivity and resistance to MGBs, including alterations in DNA sequence, epigenetic landscape, and DNA repair pathways, addressing an important gap in understanding the therapeutic effects of these compounds at the cellular levels. Finally, the review highlights future advances in this field and the requirement for integrating DNA sequence specificity with a system-level understanding of cellular responses to minor groove binding.
Du J, Ren X, Meng J
… +8 more, Li Z, Zhao J, Yu Y, Deng Y, Liu J, Han J, Huang J, Yan W
Eur J Med Chem
· 2026 Jun · PMID 42349362
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Antimicrobial peptides are promising alternatives to conventional antibiotics, but their translational development is often limited by the difficulty of simultaneously optimizing antibacterial potency, mammalian-cell com...Antimicrobial peptides are promising alternatives to conventional antibiotics, but their translational development is often limited by the difficulty of simultaneously optimizing antibacterial potency, mammalian-cell compatibility, and formulation-relevant properties. Here, using Jelleine-I (J1) as a representative scaffold, we developed a multi-task learning and reinforcement learning-based framework for the multi-objective optimization of antimicrobial peptides across antibacterial activity, hemolytic toxicity, and self-assembly propensity. Experimental validation of AI-designed analogues identified YB18 (RFRLILRL-NH) as a balanced Gram-negative-directed lead, with improved antibacterial potency relative to the parent peptide Jelleine-I and MIC values of 8-16 μM against reference Gram-negative strains. YB18 showed low hemolytic activity, acceptable cytocompatibility at antibacterial-relevant concentrations, and membrane-associated bactericidal behavior involving membrane permeability and membrane potential disruption. In an E. coli-infected wound model, topical administration of YB18 reduced the bacterial burden in vivo. Importantly, YB18 retained formulation-relevant self-assembly and formed a viscoelastic hydrogel at 12 mM in 0.8× PBS. The YB18 hydrogel further reduced bacterial counts in infected wounds and showed favorable preliminary local tolerability after repeated topical administration. These findings identify YB18 as a promising peptide lead for local anti-infective applications and support AI-guided multi-objective optimization as an effective strategy for antimicrobial peptide lead discovery.
Wu Y, Wu M, Wei J
… +5 more, Tao G, Jia Y, Yang H, Huang Q, Shi Y
Eur J Med Chem
· 2026 Jun · PMID 42349361
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Necroptosis is closely associated with a variety of inflammatory diseases, with receptor-interacting serine/threonine-protein kinase 1 (RIPK1) serving as a key regulator of this signaling pathway. RIPK1 inhibitors based...Necroptosis is closely associated with a variety of inflammatory diseases, with receptor-interacting serine/threonine-protein kinase 1 (RIPK1) serving as a key regulator of this signaling pathway. RIPK1 inhibitors based on the 5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide scaffold have demonstrated potent anti-inflammatory activity, and two representatives, GSK2982772 and GSK3145095, advanced into Phase II clinical trials. However, their clinical development encountered significant challenges, highlighting the need for structurally novel RIPK1 inhibitors with improved pharmacological properties. Herein, GSK2982772 was selected as the starting point for rational optimization. Systematic structural modifications, including removal of the methylene linker in the benzyl moiety and replacement of the five-membered nitrogen-containing heterocycle with a phenyl ring, led to the design and synthesis of a series of novel biphenyl-based RIPK1 inhibitors. Importantly, our results demonstrate that the methylene linker is dispensable for anti-necroptosis activity and is not an essential pharmacophoric element in this scaffold. Among the synthesized compounds, W-1 exhibited approximately threefold stronger binding affinity toward RIPK1 than GSK2982772 (Kd = 21 nM vs. 60 nM). In addition to potent inhibition of necroptosis in vitro, W-1 significantly attenuated inflammatory responses in a mouse systemic inflammatory response syndrome (SIRS) model. Furthermore, W-1 displayed lower cytotoxicity and reduced predicted interactions with more than 70 toxicity-associated targets, suggesting a potentially improved safety profile. Although its pharmacokinetic properties remain to be further optimized, W-1 represents a promising starting point for the development of next-generation RIPK1 inhibitors.
Houngbedji PA, Bachtíková A, Boháčová J
… +12 more, Tabarestani P, Janďourek O, Konečná K, Ősterreicher J, Paterová P, Novák M, Bárta P, Záhorszká M, Korduláková J, Mori M, Meneghetti F, Zitko J
Eur J Med Chem
· 2026 Jun · PMID 42341628
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A series of pyrazinamide-derived 1,2,3-triazoles featuring systematic chlorination of the pyrazine ring and diverse aryl substituents was synthesized and evaluated for antimycobacterial activity. Biological activity scre...A series of pyrazinamide-derived 1,2,3-triazoles featuring systematic chlorination of the pyrazine ring and diverse aryl substituents was synthesized and evaluated for antimycobacterial activity. Biological activity screening revealed broad-spectrum antimycobacterial activity and good selectivity toward mycobacteria over other pathogens, with 11 of the prepared compounds showing activity against Mycobacterium tuberculosis (Mtb) H37Ra and/or Mtb H37Rv (MIC ≤62.5 μg/mL). Structure-activity relationship analysis showed that 5-Cl substitution on the pyrazine ring was associated with improved antimycobacterial activity, with the best MIC values observed for compound 7 against Mtb H37Ra (MIC = 1.98 μg/mL) and compound 37 against Mtb H37Rv (MIC = 1.56 μg/mL). The tested compounds retained activity against drug-resistant Mtb isolates and partially against naturally resistant Mycobacterium abscessus, while showing low in vitro cytotoxicity in the HepG2 cell line and favorable selectivity indices. During advanced cytotoxicity testing, both compounds 7 and 37 displayed substantially lower hemolytic activity than bedaquiline, indicating a favorable erythrocyte safety profile within the tested concentration ranges. In vivo toxicity testing on Galleria mellonella showed low acute toxicity for both compounds. Mechanistic studies on compounds 7, 27, 31, and 37 revealed reduced biosynthesis of fatty acids and derived lipids, a phenotype consistent with interference with the Fatty Acid Synthase I (FAS I) system.
Chen Y, Ding T, Li J
… +9 more, Lu W, Tuvey A, Hao H, Huang X, Ding L, Yang L, Singh I, Zhu Y, Zhang Q
Eur J Med Chem
· 2026 Jun · PMID 42341627
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Amphiphilic aminoglycosides offer a promising approach to combat antibiotic resistant Gram-negative bacteria. Here, a series of neamine-based amphiphiles bearing alkyl chains of varying lengths (C4-C16) was synthesized v...Amphiphilic aminoglycosides offer a promising approach to combat antibiotic resistant Gram-negative bacteria. Here, a series of neamine-based amphiphiles bearing alkyl chains of varying lengths (C4-C16) was synthesized via a concise route through selective modification at the 6'-amino position of neamine. Antibacterial evaluation revealed a chain length-dependent activity, with the C14- and C15-alkyl neamine amphiphiles exhibiting the most potent antibacterial activity against ESKAPE pathogens. The C15 derivative displayed superior activity compared to neamine and synergized with multiple clinical antibiotics against P. aeruginosa. Mechanistic studies indicated that this synergy results from enhanced outer membrane permeability, and cytotoxicity assays confirmed low toxicity at therapeutically relevant concentrations.
Frojuello Costa Bernstorff Damião MC, Souza Gama FH, Ferreira MA
… +4 more, Teodoro BVM, Guimarães CRW, Mascarello A, Azevedo H
Eur J Med Chem
· 2026 Jun · PMID 42341626
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Dual muscarinic antagonists and β-agonists (MABAs) represent a promising therapeutic class for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We report the discovery and optimization of MABAs b...Dual muscarinic antagonists and β-agonists (MABAs) represent a promising therapeutic class for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We report the discovery and optimization of MABAs by integrating a diarylsulfone scaffold with the hydroxyquinoline moiety of indacaterol 2 to achieve dual M and β activity. Through SAR studies to optimize the linker design and M-targeting features, a novel MABA series was realized with excellent affinity at M/β receptors. Lead compounds 150 and 160 showed high-affinity and long-lived binding to M (K: 1.95 nM and 1.75 nM, respectively, at 24 h) and subnanomolar β-agonist potency, along with excellent (EC < 10 nM) smooth muscle relaxant activity in carbachol-stimulated guinea pig trachea rings. Moreover, after intratracheal administration, both compounds exhibited sustained in vivo bronchoprotection for 24 h in the modified Einthoven model of acute bronchoconstriction, with equivalent efficacy to the clinical-stage MABA batefenterol 9. Further development of these compounds is warranted as inhaled bronchodilators.
Eur J Med Chem
· 2026 Jun · PMID 42341625
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The widespread use and abuse of antibiotics have led to an increase in antibiotic resistance, and new methods and approaches are needed to combat bacterial infections. One promising alternative is to intervene early stag...The widespread use and abuse of antibiotics have led to an increase in antibiotic resistance, and new methods and approaches are needed to combat bacterial infections. One promising alternative is to intervene early stage in the infection process. Adhesion is a prerequisite for bacteria to colonize on the cell surface. Various pathogenic Escherichia coli strains utilize carbohydrate-specific lectins to bind to specific glycoconjugate receptors on host cells for cell adhesion. The most important and best-studied bacterial lectins are FimH and PapG. Therefore, blocking the adhesion of bacteria to cells mediated by FimH and PapG through high-affinity carbohydrate antagonists is an extremely attractive therapeutic target. This paper systematically reviews the research progress of FimH and PapG inhibitors over the past two decades. For FimH-targeted mannoside antagonists, we elaborate the effects of glycosidic linkage types, aromatic substituent modification, conformational rigidification and multivalent structural design on binding affinity, metabolic stability and in vivo performance. Meanwhile, we outline the research framework of high-affinity PapG inhibitors based on galactose scaffolds. Classical optimization strategies, including terminal aromatic group modification, selective hydroxyl substitution and hydrophobic moiety incorporation, can effectively improve the binding affinity and isoform selectivity of PapG ligands. In addition, multivalent modification acts as a universally effective strategy for both FimH and PapG inhibitors. Furthermore, we prospect the rational design directions of anti-adhesive agents in the future, providing systematic theoretical reference and practical guidance for the subsequent structural optimization, pharmacological evaluation and clinical translation of FimH and PapG inhibitors.
Shi H, Tang H, Li Y
… +9 more, Shen X, Fan T, Weng W, Chen D, Chen L, Wang Y, Ding J, Xie H, Xiong B
Eur J Med Chem
· 2026 Jun · PMID 42335717
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Hematopoietic progenitor kinase 1 (HPK1) is an intracellular negative regulator of immune responses, particularly in T cell receptor (TCR) signaling. Compelling genetic evidence indicates that HPK1 impairs multiple stage...Hematopoietic progenitor kinase 1 (HPK1) is an intracellular negative regulator of immune responses, particularly in T cell receptor (TCR) signaling. Compelling genetic evidence indicates that HPK1 impairs multiple stages of antitumor immunity largely via its kinase activity, thereby positioning it as a promising target for cancer immunotherapy. Starting from two 3-aminopyrazole hits identified through in-house screening, we initiated a structure-guided medicinal chemistry campaign. Through multi-stage optimization to enhance potency by engaging the Asp101 residue and to improve kinase selectivity via molecular hybridization, we developed a novel series of 1H-pyrazolo[3,4-c]pyridin-3-amine derivatives, from which D5 emerged as a key representative. Compound D5 exhibited potent HPK1 inhibitory activity (IC = 26.3 nM), and inhibited SLP76 phosphorylation and promoted IL-2 secretion in cell-based assays. Importantly, D5 showed favorable selectivity across diversity and immune-focused kinase panels, representing a marked improvement over its earlier analogue C4. Furthermore, D5 significantly suppressed tumor growth in the CT26 syngeneic mouse model without causing observable body weight loss. Overall, this work provides both a promising lead and a novel chemical scaffold, offering valuable insights and a concrete starting point for HPK1-targeted drug discovery.