Eur J Med Chem [JOURNAL]
Sun
200 papers
An intrinsically hydrophilic linker enables a stable, high-DAR exatecan-based HER2 ADC with potent antitumor activity.
Heng X, Feng C, Wu C … +6 more , Yang T, Ni D, Ma J, Bao Y, Huang J, Zeng N
Eur J Med Chem · 2026 Jun · PMID 42296596 · Publisher ↗
Antibody-drug conjugates (ADCs) combine the targeting specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. However, ADC development using Exatecan, a potent topoisomerase I inhibitor...
Antibody-drug conjugates (ADCs) combine the targeting specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. However, ADC development using Exatecan, a potent topoisomerase I inhibitor, has been challenged by its hydrophobicity, leading to aggregation, rapid clearance, and off-target toxicity. Herein, we report the design of an intrinsically hydrophilic drug-linker platform (SMP-70067-L) that enables the construction of a homogeneous Exatecan-based HER2-targeted ADC (SMP-70067-X) with a high drug-to-antibody ratio (DAR of 7.92). Similar to Trastuzumab deruxtecan (DS-8201a), which achieves high DAR without PEG or polysarcosine chains through a hydrophilic self-immolative spacer, SMP-70067-L integrates minimal hydrophilic elements, including a glutamic acid residue and a modified aromatic self-immolative spacer, to balance hydrophilicity, stability, and efficient payload release. The resulting ADC exhibits low aggregation (<1%), favorable plasma and thermal stability, and sustained exatecan release. SMP-70067-X demonstrates potent cytotoxicity in HER2-positive tumor cells (sub-nanomolar IC values) and significantly enhanced antitumor efficacy compared to DS-8201a in HER2-moderate and HER2-low xenograft models. These results highlight the critical role of rational linker engineering in expanding the therapeutic window of hydrophobic topoisomerase I inhibitor-based ADCs.
Corrigendum to "Perillaldehyde-derived chromeno-dipyrimidines as multi-target-directed ligands: in vitro anticholinesterase and in vivo anti-inflammatory activities supported by molecular modeling" [Eur. J. Med. Chem. 315 (2026) 118958].
Bazine I, Maadadi R, Derbal S … +5 more , Litim B, Aissaoui M, Bensouici C, Saher L, Harakat D
Eur J Med Chem · 2026 Jun · PMID 42288435 · Publisher ↗
Abstract loading — click title to view on PubMed.
Cu-selective porphyrin probes with multifunctional anti-AD activities and the structural-activity insights from X-ray single crystal analysis.
Zhi J, Feng H, Xue Q … +4 more , Pang Z, Shen R, Yang A, Kou X
Eur J Med Chem · 2026 Jun · PMID 42288030 · Publisher ↗
Metal ions play an important role in the pathogenesis of Alzheimer's disease (AD). The aggregation of β-amyloid and oxidative stress caused by metal dyshomeostasis are important reasons for the progression of AD. Therefo...
Metal ions play an important role in the pathogenesis of Alzheimer's disease (AD). The aggregation of β-amyloid and oxidative stress caused by metal dyshomeostasis are important reasons for the progression of AD. Therefore, metal therapeutics have received increasing attention. In this work, two multifunctional near-infrared porphyrin probes (1 and 2) were designed and synthesized, and the single crystals of their Cu complexes (1-Cu and 2-Cu) were obtained. Comprehensive biological activity evaluations demonstrated that 1, 2 possessed strong multifunctional anti-AD activities, including metal chelating, self-/Cu- induced Aβ aggregation inhibition, and in vitro/in vivo reactive oxygen species (ROS) elimination. Especially after coordination with copper, the cholinesterase inhibition and ROS elimination abilities were significantly increased. Notably, X-ray single crystal diffraction of 1, 1-Cu and 2-Cu provided crucial molecular-level structural information. Combined with molecular docking, density functional theory (DFT) calculations, and molecular dynamics simulations, these crystallographic data fully elucidated the precise structure-activity relationships, revealing that the larger conjugated plane structure, differences in intermolecular forces and the picket-fence architecture significantly influenced the activities. Meanwhile, both probes exhibited highly selective fluorescence quenching responses to Cu with very low cytotoxicity, indicating their promising potential as both therapeutic and diagnostic agents for AD.
Synthesis, anti-tumor activity, and mechanistic study of triphenylphosphonium (TPP) conjugates of diosgenin.
Huang X, Ji X, Zhang J … +5 more , Zhao H, Shi X, Wang Y, Wang W, Dong W
Eur J Med Chem · 2026 Jun · PMID 42288029 · Publisher ↗
Diosgenin (DSG), a naturally occurring steroidal sapogenin, has attracted considerable attention because of its broad spectrum of pharmacological activities, including anti-cancer effects. However, its further developmen...
Diosgenin (DSG), a naturally occurring steroidal sapogenin, has attracted considerable attention because of its broad spectrum of pharmacological activities, including anti-cancer effects. However, its further development as an anti-tumor agent has been hindered by its limited potency. In this study, thirteen triphenylphosphonium (TPP)-conjugated DSG derivatives were designed and synthesized to enhance mitochondrial targeting and improve anti-tumor activity. The in vitro anti-proliferative activities of these compounds were evaluated against five cancer cell lines (PC-3, A549, MCF-7, HeLa, and HCT116) and one normal human liver cell line (L02) using the CCK-8 assay. Notably, compound 11f exhibited an IC value of 0.1 μM in HeLa cells, representing up to a 226-fold increase in cytotoxicity compared to DSG (IC = 22.6 μM). Additionally, compound 11f showed relatively low toxicity toward L02 cells (IC = 39.0 μM), indicating good selectivity. Further biological studies demonstrated that compound 11f depolarizes the mitochondrial membrane potential (Δψm), reduces ATP production, and results in an abnormal increase in intracellular reactive oxygen species (ROS). In addition, compound 11f promoted apoptosis, as evidenced by Annexin V/PI staining and modulation of apoptosis-related proteins, including upregulation of Bax, cytochrome c, cleaved caspase 9, cleaved caspase 3, and cleaved PARP-1, together with downregulation of Bcl-2. Moreover, in vivo experiments showed that compound 11f inhibited the proliferation of HeLa cells in a zebrafish xenograft model. These findings suggest that TPP conjugation is an effective strategy for enhancing the anti-tumor activity of DSG and that compound 11f deserves further investigation as a lead compound for cervical cancer therapy.
Novel captopril-valproic acid platinum(IV) hybrids with potent antiproliferative and antimetastatic activities targeting fibrosis and DNA-repair.
Chen Y, Feng S, Liu Z … +3 more , Zhao Y, Ji C, Wang Q
Eur J Med Chem · 2026 Jun · PMID 42288028 · Publisher ↗
Fibrosis and DNA repair are crucial factors for cancer development and metastasis. Here, three-component platinum(IV) hybrids with captopril (CTP) and valproic acid (VPA) functional ligands were developed as antiprolifer...
Fibrosis and DNA repair are crucial factors for cancer development and metastasis. Here, three-component platinum(IV) hybrids with captopril (CTP) and valproic acid (VPA) functional ligands were developed as antiproliferative and antimetastatic agents. These agents exerted effects by inducing DNA damage, suppressing fibrosis and inhibiting DNA repair. Upon activation, the platinum core bound to DNA and caused mitochondria-mediated apoptosis through the Bcl-2/Bax/caspase-3 pathway. The VPA moiety inhibited the key enzyme HDAC3, disrupted DNA-repair by modulating the proteins P-gp, PARP, and PTEN, and further overcame multidrug resistance (MDR). Furthermore, the TGF-β1/Smad2 and MMPs cascades were inhibited by CTP, while tumor inflammation was also inhibited through downregulating COX-2, TNF-α, and IL-6. These combined actions displayed a synergistic role in attenuating tumor fibrosis, and further reversed EMT. In addition, decreased PD-L1 expression and increased infiltration of CD3 and CD8 T cells were observed, leading to the initiation of antitumor immunity in tumors.
Design, synthesis and biological evaluation of EZH2/HDAC dual inhibitors for the treatment of lymphomas.
Sun Y, Yang J, Guo Z … +9 more , Zhang M, Luo B, Zhang Q, Lu W, Wu Z, Fan Z, Huang P, Liu R, Wen S
Eur J Med Chem · 2026 May · PMID 42288027 · Publisher ↗
As the most common hematologic malignancy, lymphoma poses a significant threat to human health and contributes substantially to the global cancer burden. It has been reported that the combination of EZH2 and HDAC inhibit...
As the most common hematologic malignancy, lymphoma poses a significant threat to human health and contributes substantially to the global cancer burden. It has been reported that the combination of EZH2 and HDAC inhibitors may be a promising strategy to enhance their anticancer efficacy and even treat tumors being insensitive to EZH2 inhibitors. In our current work, two series of EZH2/HDAC dual inhibitors were designed and synthesized, where YM1240 was discovered as the most potent compound by the SAR studies. Compound YM1240 exhibited superior anti-proliferative effects compared to combination therapy across multiple lymphoma cell lines. Further mechanism studies showed that YM1240 inhibited cell proliferation and induced apoptosis and cell cycle arrest. Moreover, YM1240 exhibited in vivo antitumor efficacy in lymphoma xenograft models, in which both EZH2 and HDAC pathways were sufficiently inhibited as indicated by decreased H3K27me3 and increased H3K9ac and H4ac in immunohistochemical stained tumor tissues. Therefore, YM1240 was a potential EZH2/HDAC dual inhibitor that may pave a new approach for treating lymphomas.
From virtual screening to reality: Identifying potent PI3Kγ inhibitors for inflammation treatment by harnessing machine learning and biological validation.
Jia L, Cai Y, Chen Y … +4 more , Xu L, Yu L, Jin J, Zhu J
Eur J Med Chem · 2026 Jun · PMID 42288026 · Publisher ↗
Research increasingly shows that excessive activation of phosphoinositide 3-kinase gamma (PI3Kγ) is linked to numerous inflammatory factors, highlighting its potential as a drug target for inflammatory disorder treatment...
Research increasingly shows that excessive activation of phosphoinositide 3-kinase gamma (PI3Kγ) is linked to numerous inflammatory factors, highlighting its potential as a drug target for inflammatory disorder treatment. Nonetheless, few inhibitors have advanced to clinical trials for inflammation treatment. One of the major reasons for this is the extreme difficulty in developing selective PI3Kγ inhibitors due to the high homology among kinase structures. Therefore, the development of new PI3Kγ inhibitors is still urgently needed. We developed a machine learning-driven virtual screening (VS) approach that integrates a Naïve Bayesian classification model, molecular descriptors, pharmacophore mapping, and molecular docking to discover novel PI3Kγ inhibitors. The VS method was validated for its exceptional predictive accuracy by successfully identifying marketed and clinically studied PI3K inhibitors. Additionally, this strategy was applied to screen the Bioactive Compounds Library Max, followed by enzyme inhibition assays, leading to the identification of three compounds with definitive PI3Kγ inhibitory activity. Notably, Cpd13 demonstrated an IC value of 656 ± 171 nM. In vitro and in vivo studies showed that Cpd13 inhibited the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β by blocking the PI3K/Akt signaling pathway in LPS-stimulated RAW264.7 macrophages and a mouse model of acute lung injury (ALI). Cpd13 significantly inhibited nitric oxide production and decreased inflammatory cell infiltration in lung tissues. Ultimately, the administration of Cpd13 provided substantial protection against LPS-induced ALI. This study provides a validated virtual screening pipeline for the hit discovery of PI3Kγ inhibitors, and lays a preclinical foundation for the application of these inhibitors in the treatment of inflammatory diseases.
Chemical methodologies for Direct-to-Biology library synthesis.
Wu G, Lu X, Zhu B … +2 more , Cheng W, Wei H
Eur J Med Chem · 2026 Jun · PMID 42284636 · Publisher ↗
The Direct-to-Biology (D2B) paradigm represents a transformative shift in drug discovery, bypassing traditional purification to enable direct biological screening of crude reaction mixtures. Successful D2B implementation...
The Direct-to-Biology (D2B) paradigm represents a transformative shift in drug discovery, bypassing traditional purification to enable direct biological screening of crude reaction mixtures. Successful D2B implementation demands a holistic strategy that moves beyond yield to assess biocompatibility, miniaturized operational feasibility, and analytical validation. This review first outlines critical factors for D2B library setup, then systematically categorizes reported chemical methodologies into single-step reactions (such as amide couplings, click chemistry, multicomponent reactions, and nucleophilic substitutions, among others) and multi-step approaches (including telescoped liquid-phase sequences as well as solid-phase and solid-liquid combined strategies). By dramatically accelerating the "design-make-test" cycle, D2B platforms are poised to unlock unprecedented chemical space and establish intelligent, self-optimizing discovery ecosystems, ultimately expediting the delivery of novel therapeutics.
Synthetic heterocyclic scaffolds relevant to human 15-lipoxygenase-2 (h15-LOX-2) inhibition: Scaffold diversity, structure-activity relationships, selectivity challenges, and future directions.
Imran S
Eur J Med Chem · 2026 Jun · PMID 42284635 · Publisher ↗
Human 15-lipoxygenase-2 (h15-LOX-2), encoded by the ALOX15B gene, is a non-heme iron-containing dioxygenase implicated in the pathophysiology of atherosclerosis, cancer, and chronic inflammatory disorders through stereos...
Human 15-lipoxygenase-2 (h15-LOX-2), encoded by the ALOX15B gene, is a non-heme iron-containing dioxygenase implicated in the pathophysiology of atherosclerosis, cancer, and chronic inflammatory disorders through stereospecific oxygenation of arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid, which is subsequently reduced to 15(S)-hydroxyeicosatetraenoic acid. Despite its considerable therapeutic relevance, h15-LOX-2 remains a profoundly underexplored drug target relative to its closely related isozyme, 15-lipoxygenase-1 (15-LOX-1), with which it shares only approximately 38-40% amino acid sequence identity. This fundamental sequence divergence translates into distinct active site architectures, substrate binding profiles, and tissue distribution patterns that strongly justify the pursuit of isoform-selective inhibitor development. Critically, while zileuton remains the sole clinically approved lipoxygenase-targeting drug, it is clinically used as a 5-LOX inhibitor for asthma and is not an h15-LOX-2-targeted therapy. A focused survey of the literature from 2015 to 2025 reveals that no dedicated synthetic medicinal chemistry review exclusively addressing heterocyclic scaffold-based h15-LOX-2 inhibitors currently exists. To address this gap, the present review examines synthetic heterocyclic chemotypes reported as h15-LOX-2 inhibitors or as structurally relevant 15-LOX inhibitory scaffolds, including imidazoles, thiazolidinone-thiadiazole hybrids, triazoles, quinoline-based dual inhibitors, pyrazoles, indoles, benzimidazole hybrids, xanthenones, thienopyrimidines, and isoniazid derivatives. For each scaffold class, synthetic methodologies, in vitro inhibitory potencies, structure-activity relationship analyses, isoform selectivity profiles, and computational docking findings are comprehensively discussed. Cross-scaffold analysis suggests that lipophilicity, a central heteroaromatic anchoring core capable of interacting with His373 and His378, and a geometrically constrained hydrogen-bonding feature oriented toward Ile676 may represent recurring pharmacophoric features associated with potent 15-LOX/h15-LOX-2 inhibition. Among the evaluated chemotypes, imidazole-based derivatives currently demonstrate the strongest h15-LOX-2-directed profile, with IC values as low as 0.34 μM and greater than 50-fold selectivity over related lipoxygenase and cyclooxygenase isoforms. Outstanding challenges including the scarcity of ex vivo validated compounds, species-specific translational barriers arising from divergent murine ortholog function, and the absence of wild-type inhibitor co-crystal structures are critically evaluated. Future directions encompassing covalent inhibitor strategies, PROTAC-based targeted degradation, and selective modulation of the pro-ferroptotic h15-LOX-2/PEBP1 complex are discussed as promising avenues to fully realize the therapeutic potential of this target.
First-in-class nonsteroidal anti-inflammatory drug and carbonic anhydrase inhibitor hybrid compounds as effective antimycobacterial agents.
Parkkinen J, Akgul Ö, Berrino E … +9 more , Carta F, Selleri S, Hammarén M, Aspatwar A, Bartolucci G, Capasso C, Parikka M, Parkkila S, Supuran CT
Eur J Med Chem · 2026 Jun · PMID 42284634 · Publisher ↗
We investigated the in vitro effects of nonsteroidal anti-inflammatory drug-carbonic anhydrase inhibitor hybrids (NSAID-CAIs) on β-carbonic anhydrases 1-3 expressed by Mycobacterium tuberculosis, as well as their antimyc...
We investigated the in vitro effects of nonsteroidal anti-inflammatory drug-carbonic anhydrase inhibitor hybrids (NSAID-CAIs) on β-carbonic anhydrases 1-3 expressed by Mycobacterium tuberculosis, as well as their antimycobacterial efficacy in a zebrafish infection model. The primary aims were to investigate whether these enzymes represent valid therapeutic targets and whether NSAID-CAIs constitute potential drug candidates for tuberculosis. In vitro inhibition activity against the carbonic anhydrases was evaluated with a CO-hydration assay. Antimycobacterial properties of the NSAID-CAIs were assessed via screening assays based on bioluminescence and colony-forming units. Larval and adult zebrafish were used for in vivo experiments. NSAID-CAIs strongly inhibited Mycobacterium tuberculosis β-carbonic anhydrase 2 and human carbonic anhydrases IX and XII in vitro. They exhibited high efficacy against Mycobacterium marinum and attenuated Mycobacterium tuberculosis in biofilm environments, outperforming their coadministered constitutive fragments. Compounds 11, 19, and 24 showed bactericidal properties against Mycobacterium marinum, and 12 was able to potentiate the effects of rifampicin. The experimental data provides solid in vitro evidence for the use of NSAID-CAIs as antimycobacterial agents by means of Mycobacterium tuberculosis β-carbonic anhydrase inhibition along with the possible suppression of the host immune response through the induction of host-directed therapeutic effects.
Artemisinin oligomers from a natural product to multivalent antimalarial and anticancer agents: Overcoming drug resistance and expanding therapeutic potential.
Tian Z, Tian L, Li X … +1 more , Wang C
Eur J Med Chem · 2026 Jun · PMID 42284633 · Publisher ↗
This review conducts a critical assessment of artemisinin oligomers as multivalent agents against pharmacokinetic resistance, rather than presenting a simple literature summary. Dimerization and trimerization are hypothe...
This review conducts a critical assessment of artemisinin oligomers as multivalent agents against pharmacokinetic resistance, rather than presenting a simple literature summary. Dimerization and trimerization are hypothesized to strengthen the binding ability to limited heme within PfKelch13-mutant parasites through the mechanism of 'heme hijacking'. This mode of action relies on affinity-driven molecular capture. Nevertheless, direct biophysical evidence that integrates stoichiometric ratios with kinetic and thermodynamic data is still absent. Three key scientific issues remain insufficiently clarified. First, it remains unclear whether multivalence can effectively reverse drug resistance or only enhance binding affinity in drug-susceptible strains. Second, relevant ADME research on higher-order oligomers is far from adequate. Third, the imprecise definition of multitarget pharmacology leads to ambiguous differentiation between antimalarial and anticancer mechanisms. Notably, no existing research has validated the antimalarial potency of artemisinin trimers. This review evaluates mainstream hypotheses with current research findings and highlights critical knowledge gaps in this field. It thereby provides a solid foundation for rational molecular design. It also helps transform relevant research paradigms. Research focus can shift from empirical linker optimization to the verification of target binding behaviors and comprehensive pharmacokinetic characterization.
Discovery of novel chalcone-benzenesulfonamide conjugates as PPARγ agonists: Design, synthesis, and biological evaluation.
Ali IH, Hassan RM, El Kerdawy AM … +3 more , Abo-Elfadl MT, Abdallah HMI, Ghannam IAY
Eur J Med Chem · 2026 Jun · PMID 42275932 · Publisher ↗
In the present study, a series of novel chalcone-benzenesulfonamides 7a-w was designed and synthesized. Compounds 7a-w were evaluated for their PPARγ ligand binding compared to pioglitazone, and their IC (μM) values were...
In the present study, a series of novel chalcone-benzenesulfonamides 7a-w was designed and synthesized. Compounds 7a-w were evaluated for their PPARγ ligand binding compared to pioglitazone, and their IC (μM) values were determined. The 4-methoxybenzyloxy (unsubstituted)benzenesulfonamide 7o revealed as the most potent PPARγ ligand (IC = 1.752 ± 0.04 μM), and high binding affinity (K = 54.81 nM). Eleven compounds 7a, 7f, 7g, 7i-l, 7n, 7o, 7t, and 7w were further selected, and evaluated for their PPARγ agonistic activity compared to pioglitazone, and their EC (μM) values were reported. Compound 7o displayed PPARγ agonistic activity comparable to pioglitazone with EC values of 0.273 ± 0.01, and 0.197 ± 0.007 μM, respectively. Selected compounds 7g, 7l, and 7o were further examined to determine their PPARα/δ agonistic activities compared to fenofibrate, and bezafibrate, respectively. Compounds 7l, and 7o demonstrated a higher selectivity towards PPARγ than PPARα by 24.8-fold, and 12.1-fold, respectively, while 7g showed a realtively equipotent dual PPARγ/α agonistic activity, however, the three tested compounds displayed a weak PPARδ agonistic activity. Moreover, compounds 7g, 7l, and 7o enhanced PPARγ protein expression in HepG-2 cells in a dose-dependent manner, whereas, 7g increased the PPARα expression level. In vivo studies revealed that compound 7o at a dose 72 mg/kg possessed antidiabetic activity better than that of pioglitazone. Furthermore, molecular docking studies and molecular dynamic simulations were carried out for the newly synthesized compounds to study their predicted binding modes and energies in the PPARγ/α binding sites.
Discovery of a borylated aza-arene chemotype as a direct HSF1 inhibitor targeting the DNA-binding domain.
Pan X, Huang WH, Liu Y … +6 more , Zhang ZP, Ye JM, Wu YF, Huang ZS, Wang HG, Huang SL
Eur J Med Chem · 2026 Jun · PMID 42275931 · Publisher ↗
Heat shock transcription factor 1 (HSF1) is a master regulator of proteostasis and a compelling yet challenging anticancer target because of the scarcity of direct small-molecule inhibitors and the lack of canonical liga...
Heat shock transcription factor 1 (HSF1) is a master regulator of proteostasis and a compelling yet challenging anticancer target because of the scarcity of direct small-molecule inhibitors and the lack of canonical ligand-binding pockets. Here, we report the discovery of compound 1168, a borylated aza-arene identified by differential scanning fluorimetry (DSF)-based screening against the HSF1 DNA-binding domain (DBD). Orthogonal biophysical validation by microscale thermophoresis (MST) demonstrated direct binding of 1168 to HSF1-DBD with a dissociation constant (Kd) of 23.8 μM, while electrophoretic mobility shift assay (EMSA) showed that 1168 effectively disrupted HSF1-DBD/HSE complex formation and nearly completely abolished DNA binding at 12.5 μM under the assay conditions. Functionally, 1168 suppressed proliferation across multiple cancer cell lines and showed enhanced sensitivity in androgen-dependent prostate cancer cells. Mechanistically, 1168 inhibited HSF1 signaling, reduced the expression of downstream effectors including HSP70 and HSP90, and attenuated HSE-driven transcriptional activity. Furthermore, 1168 reduced the expression of HSF1 and impaired heat shock-induced HSF1 Ser326 phosphorylation and trimerization, thereby suppressing HSF1 activation. Importantly, the inhibitory effect of 1168 on HSP70 expression was markedly attenuated upon HSF1 knockdown, supporting HSF1-dependent activity in cells. Collectively, these findings identify 1168 as a direct HSF1-DBD-binding inhibitor and establish borylated aza-arenes as a promising chemotype for the development of HSF1-targeted anticancer agents.
From farm to clinic? Exploring the anticancer potential of monensin and its semisynthetic derivatives.
Antoszczak M, Sulik M, Huczyński A
Eur J Med Chem · 2026 Jun · PMID 42275930 · Publisher ↗
Natural products have traditionally played a pivotal role in the field of drug discovery, offering chemists and biologists an abundant source of inspiration regarding a variety of structures and functions. Notably, the i...
Natural products have traditionally played a pivotal role in the field of drug discovery, offering chemists and biologists an abundant source of inspiration regarding a variety of structures and functions. Notably, the identification of anticancer activities in several renowned antibiotics over the past years has opened new therapeutic avenues and highlighted the significance of drug repurposing strategies. In this context, we provide a comprehensive review of monensin (MON), a natural polyether ionophore antibiotic, delineating its biological and chemical properties and summarizing various approaches, particularly structural modifications, employed to explore its potential in cancer-related research. Preclinical investigations have demonstrated that MON effectively targets a wide range of cancer cells, including those exhibiting stem cell-like properties. Its combination with standard chemotherapeutics appears especially promising in this context. While nanotechnology may help address some clinical limitations of MON, extensive research over the past decade has focused on the derivatization of its most reactive functional groups, such as C1 carboxyl and C26 hydroxyl, to produce semisynthetic derivatives with improved anticancer activity compared to the native structure. We hope that the findings presented in this review will inspire and motivate researchers to initiate, sustain, and broaden studies of the off-label use of MON in the ongoing battle against cancer.
Discovery of a novel cinnamoyl piperazinyl alepterolic acid hybrid as a TrxR1 inhibitor for inducing ROS/ER stress-mediated apoptosis in breast cancer.
Liu Z, Mao X, Jin X … +8 more , Xia C, Wang C, Zhao H, Hu J, Wu Y, Huang G, Chen H, Ma L
Eur J Med Chem · 2026 Jun · PMID 42269567 · Publisher ↗
Targeting thioredoxin reductase 1 (TrxR1) to induce reactive oxygen species (ROS)-mediated apoptosis represents a promising anticancer strategy. However, whether TrxR1-targeted therapy holds broad-spectrum antitumor prom...
Targeting thioredoxin reductase 1 (TrxR1) to induce reactive oxygen species (ROS)-mediated apoptosis represents a promising anticancer strategy. However, whether TrxR1-targeted therapy holds broad-spectrum antitumor promise for breast cancer remains to be determined. Alepterolic acid is an attractive natural scaffold for drug development, yet its therapeutic potential is hampered by low potency and an undefined molecular target profile. In this work, a novel series of cinnamoyl piperazinyl alepterolic acid hybrids containing the Michael acceptor scaffolds were designed and synthesized via molecular hybridization, and their anti-breast cancer effects and TrxR1 inhibitory activity were evaluated. Among these compounds, 6m displayed the strongest antiproliferative activity against diverse breast cancer subtypes, including triple-negative breast cancer (TNBC). Importantly, 6m exhibited low cytotoxicity toward normal human breast epithelial MCF-10A cells (IC = 26.79 ± 0.24 μM), with a selectivity index (SI) exceeding 10 for each of the breast cancer cell lines tested. Mechanistic exploration validated that 6m directly targets TrxR1, elevating intracellular ROS, inducing ER stress, and activating caspase-dependent apoptosis. In vivo xenograft experiments further demonstrated that 6m significantly inhibited tumor growth. This study identifies 6m as a promising anti-breast cancer agent and provides novel insights into TrxR1-based targeted therapy strategies for breast cancer.
Pharmacological activities, SARs and targets of heterocyclic derivatives as QSIs against bacteria multidrug resistance.
Cui Z, Guo T, Xu K … +4 more , Xie Z, Emam M, Wang H, Yang Z
Eur J Med Chem · 2026 Jun · PMID 42269566 · Publisher ↗
The escalating global crisis of bacterial multidrug resistance (MDR), particularly the recalcitrant infections caused by Pseudomonas aeruginosa, underscores an urgent need for novel therapeutic strategies. In contrast to...
The escalating global crisis of bacterial multidrug resistance (MDR), particularly the recalcitrant infections caused by Pseudomonas aeruginosa, underscores an urgent need for novel therapeutic strategies. In contrast to conventional bactericidal antibiotics, antivirulence approaches targeting the quorum sensing (QS) system offer a promising paradigm by attenuating pathogenicity without exerting lethal selective pressure, thereby potentially mitigating resistance development. This review provides a comprehensive and systematic analysis of the research progress on heterocyclic derivatives as QS inhibitors reported between 2020 and 2025. It is specifically focused on two principal structural classes: nitrogen-containing heterocycles (e.g., quinolines, (inhibition rate: 40.3%-87.4%), quinazolines (IC = 0.3-6.9 μM), pyridines (IC = 0.3-6.6 μM), indoles (IC = 0.2-0.3 μM), thiazoles (IC = 0.4-131.5 μM)) and oxygen-containing heterocycles (e.g., furans (inhibition rate: 53.0%-86.8%), flavonoids (inhibition rate: 32.0%-90.9%), coumarins (inhibition rate: 50.0%-73.0%)). For these compounds, biological activities, structure-activity relationships, and targets are critically discussed. This work aims to consolidate recent advances and offer valuable insights for the rational design and development of next-generation anti-infective agents targeting bacterial communication pathways.
Design, synthesis and anti-inflammatory activity on N-(4-(pyridin-4-yloxy)phenyl)-1,4-dihydropyridazine-3-carboxamide derivative z18 for acute lung injury, sepsis and ulcerative colitis models in mice.
Zhang K, Xu Y, Fu D … +10 more , Yang J, Liao J, Chen T, Dai Q, Zhang A, Liang G, Tang Q, Gao Y, Wu D, Mo Y
Eur J Med Chem · 2026 Jun · PMID 42269565 · Publisher ↗
The pathogenesis of acute lung injury (ALI), sepsis, and ulcerative colitis (UC) is closely interrelated. As inflammatory diseases, they are all characterized by the excessive production of inflammatory cytokines. Theref...
The pathogenesis of acute lung injury (ALI), sepsis, and ulcerative colitis (UC) is closely interrelated. As inflammatory diseases, they are all characterized by the excessive production of inflammatory cytokines. Therefore, suppression of these cytokines represents a promising therapeutic strategy. Herein, we designed and synthesized a series of N-(4-(pyridin-4-yloxy)phenyl)-1,4-dihydropyridazine-3-carboxamide derivatives based on integrating three structural fragments relating to anti-inflammation. The anti-inflammatory activities of these compounds were evaluated in J774A.1 macrophages, and most compounds effectively inhibited interleukin-6 (IL-6) release in vitro. Compound z18 was identified as the most promising candidate and was further investigated for its dose-dependent effects. Preliminary mechanistic studies indicated that compound z18 suppresses c-Kit kinase activity and subsequently inhibits the NF-κB signaling pathway. z18 exhibited significant anti-inflammatory effects in vivo in LPS-induced ALI, sepsis, and UC mouse models. The preliminary drug-like properties of z18 were also evaluated. z18 demonstrated favorable stability in body fluid stability studies, and its favorable safety profile was further confirmed by subacute toxicity studies. In summary, this study offers novel insights into the design of anti-inflammatory agents and presents z18 as a promising candidate for the treatment of ALI, sepsis, and UC.
OralAbsPredict: A data-driven framework to predict human intestinal absorption (HIA) and human oral bioavailability (HOB) from chemical structures.
Pore S, Roy K
Eur J Med Chem · 2026 Jun · PMID 42263584 · Publisher ↗
Oral absorption is a key pharmacokinetic process for orally administered drugs, determining therapeutic efficacy and influencing distribution, metabolism, and excretion. One of the major reasons a drug fails in early dev...
Oral absorption is a key pharmacokinetic process for orally administered drugs, determining therapeutic efficacy and influencing distribution, metabolism, and excretion. One of the major reasons a drug fails in early development is poor oral absorption. Therefore, it is important to determine the oral absorption properties of drugs during early development, even before synthesis. Human intestinal absorption (HIA) and human oral bioavailability (HOB) are two important pharmacokinetic properties of orally administered drugs that provide a good measure of drug absorption through the oral route. The experimental determination of the HIA and HOB required substantial time, resources, and money. Therefore, an alternative approach is needed to quickly screen the HIA and HOB of orally administered compounds. In this study, we introduce a Python-based software tool, "OralAbsPredict," that predicts HIA and HOB from chemical structures provided as SMILES strings. This tool returns three predicted values, HIA and HOB at two different experimental cutoffs, i.e., 50% and 20%, based on the developed machine learning models. The tool is based on the developed machine learning models showing good performance not only on the training set (accuracy > 0.9) but also on the test set (accuracy > 0.7). These models are developed using Functional-Class Fingerprints (FCFP) and Mordred descriptors: a count-based FCFP2 fingerprint for the HIA model, a Mordred descriptor for HOB_50% model, and a count-based FCFP4 fingerprint for the HOB_20% model. One of the major drawbacks of existing models is that they do not adequately address class imbalance in the modeled data. However, we have addressed the class imbalance problem in this work using hyperparameters like class_weight. Here, we have identified and interpreted the important features using the SHAP method. Additionally, we have performed a substructure analysis to identify key substructures present in most of the active molecules. From this analysis, we have found that most of the orally active compounds contain the aromatic ring system with chlorine, fluorine, and amine groups. A comparative analysis with the benchmark expert systems was also conducted, demonstrating that our models achieved similar test performance.
Single versus dual EGFR/PARP inhibition: Mechanistic rationale, synthetic approaches, pharmacophoric features, structure-activity relationships, and therapeutic perspectives.
Elkafoury EM, El-Moselhy TF, El-Hamamsy MH … +4 more , El-Bastawissy EA, Rabea EY, Afarinkia K, Sidhom PA
Eur J Med Chem · 2026 Jun · PMID 42263583 · Publisher ↗
Cancer remains a major global health challenge, driving the need for more effective targeted therapies. Simultaneous inhibition of the epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) has em...
Cancer remains a major global health challenge, driving the need for more effective targeted therapies. Simultaneous inhibition of the epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) has emerged as a promising strategy due to the strong interplay between oncogenic signaling and DNA repair pathways. Although EGFR inhibitors, PARP inhibitors, and multitarget-directed ligands have been widely reviewed individually, a focused medicinal chemistry perspective on dual EGFR/PARP inhibitors remains limited. This review specifically highlights the rational design of dual EGFR/PARP inhibitors, emphasizing pharmacophore fusion, linker engineering, scaffold optimization, and structure-activity relationship (SAR) studies governing balanced dual-target activity. Particular attention is given to quinazoline-, quinoline-, pyrimidine- and nicotinamide-based scaffolds, synthetic strategies for hybrid molecule construction, and the molecular determinants influencing potency, and selectivity. In addition, molecular docking and computational studies are discussed to clarify dual binding interactions within EGFR and PARP active sites. Emerging multifunctional systems integrating EGFR inhibition, PARP suppression, and DNA-damaging capabilities are also summarized as advanced anticancer approaches.
SENSAAS-Bioisostere: A computational method for 3D shape-guided bioisosteric replacements and scaffold-hopping.
Somme L, Saim YE, Payan F … +1 more , Douguet D
Eur J Med Chem · 2026 Jun · PMID 42263582 · Publisher ↗
We introduce SENSAAS-Bioisostere, a computational method for identifying bioisosteric replacements or scaffold-hopping. Our process utilizes the matching and sub-matching properties of the method SENSAAS to compare fragm...
We introduce SENSAAS-Bioisostere, a computational method for identifying bioisosteric replacements or scaffold-hopping. Our process utilizes the matching and sub-matching properties of the method SENSAAS to compare fragments. SENSAAS has been initially developed to align and calculate the similarity between the colored shapes of two molecules. The latest feature, SENSAAS-Bioisostere, specifically identifies fragments that are similar in shape and pharmacophore to a query fragment. It then builds and aligns new molecules on the query molecule. In SENSAAS-Bioisostere, a fragment is represented by a colored 3D point cloud with openings, which characterizes its shape, pharmacophoric features, but also the position of its substituents, all in a single representation. Alignments are achieved through 3D point set registration, a process widely used in computer graphics to align multiple point clouds, by minimizing the distances between pairs of points. SENSAAS-Bioisostere currently uses two data sets: one containing over 9500 fragments extracted from approved drugs, and another containing over 27,000 fragments extracted from co-crystallized molecules. A retrospective analysis of successful scaffold-hoppings confirmed the effectiveness of our approach in the search of new molecules.
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