Bacher F, Madejski C, Kuznetcova I
… +19 more, Dömötör O, Gyurcsik B, Nafaee ZH, Igaz N, Bocz C, Péntek B, Kiricsi M, Raptova P, Stoica AC, Hejl M, Jakupec MA, Alfadul SM, Babak MV, Rapta P, Reynisson J, Sindlerova L, Enyedy ÉA, Hamel E, Arion VB
Eur J Med Chem
· 2026 Oct · PMID 42184561
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Indoloquinolines are potent anticancer agents, but their poor aqueous solubility prevents clinical development. Indoloquinoline-based metal complexes offer an opportunity to circumvent this drawback. A series of new indo...Indoloquinolines are potent anticancer agents, but their poor aqueous solubility prevents clinical development. Indoloquinoline-based metal complexes offer an opportunity to circumvent this drawback. A series of new indolo[2,3-c]quinoline derivatives HL-HL and their copper(II) complexes were synthesized, comprehensively characterized and tested for antiproliferative activity against MDA-MB-231, MCF-7, MCF-7 KCR, A549 and DU-145 cancer cells and compared to known isomeric indolo[3,2-c]quinolines (HL-HL and 11-14). The Cu(II) complexes were generally as active, or slightly more so, than the proligands. Lead compounds HL and 8 showed superior anticancer activity compared to isomers HL and 14, respectively. Complex 8 was superior to HL in ROS generation in A549 cells, induced mitochondrial dysfunction as evidenced by JC-1 staining, induced lactate dehydrogenase release in medium, inhibited DNA synthesis and triggered apoptosis. DNA-binding studies, supported by molecular docking calculations, showed strong affinity of the compounds for double stranded DNA, to which they bind by intercalation.
Wang S, Wang X, Zhong Z
… +4 more, Liu Y, Lv X, Huang W, Pan Y
Eur J Med Chem
· 2026 Oct · PMID 42184560
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Conventional prodrug strategies, while innovative, are frequently hampered by off-target activation and systemic toxicity inherent to endogenous stimuli. Recently, bioorthogonal cleavage reactions have emerged as a signi...Conventional prodrug strategies, while innovative, are frequently hampered by off-target activation and systemic toxicity inherent to endogenous stimuli. Recently, bioorthogonal cleavage reactions have emerged as a significant alternative, utilizing exogenous and endogenous triggers to ensure high-fidelity in situ prodrug activation and release. Among these, the tetrazine-trans-cyclooctene (TZ-TCO) IEDDA reaction has emerged as a promising strategy for click-to-release prodrug activation. Furthermore, recent advances in transition-metal and photocatalytic systems have integrated drug activation with real-time imaging through simultaneous pro-fluorophore uncaging. This review systematically summarizes these bioorthogonal platforms and their dual therapeutic-diagnostic applications, providing a roadmap for their transition from experimental models to clinical practice. Furthermore, we offer perspectives on the future development of bioorthogonal prodrug activation.
Lo Mascolo F, Lipani A, Giuffrida S
… +11 more, Barreca M, Bivacqua R, Spanò V, Raimondi MV, Montalbano A, Borrelli A, Venturini A, Guidone D, Genovese M, Galietta LJV, Barraja P
Eur J Med Chem
· 2026 Oct · PMID 42184559
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Airway surface liquid (ASL) homeostasis is crucial for effective mucociliary clearance (MCC) and innate lung defense, both of which are severely compromised in cystic fibrosis (CF). Although CFTR modulators improved dise...Airway surface liquid (ASL) homeostasis is crucial for effective mucociliary clearance (MCC) and innate lung defense, both of which are severely compromised in cystic fibrosis (CF). Although CFTR modulators improved disease management, many patients remain ineligible due to mutations that cannot be targeted pharmacologically, highlighting the need for alternative therapeutic strategies. Among these, direct inhibition of the epithelial Na channel (ENaC) has emerged as a pharmacologically attractive approach to counteract airway dehydration. Due to adverse effects caused by systemic ENaC inhibition, and in particular related to potassium homeostasis, medicinal chemistry efforts have focused on inhaled, lung-restricted inhibitors. This review examines the evolution of direct ENaC blockers from early amiloride-like compounds to more advanced clinical candidates, emphasizing the medicinal chemistry principles that enabled improved airway selectivity. In particular, the optimization process progressively shifted to a multi-parameter strategy integrating persistent positive charge, increased polarity, reduced lipophilicity and low epithelial permeability, in order to decrease pulmonary absorption, prolong lung retention and reduce systemic exposure. In this context, special attention is given to positively charged acylguanidine mimetics, including quaternary amines and N-alkylated benzimidazoles. Overall, the field shows that for inhaled ENaC inhibitors, therapeutic success depends not only on nanomolar target potency, but on achieving sustained local airway exposure with minimal renal liability.
Lv X, Huang X, Tian L
… +6 more, Xu S, Zhan Y, Hou H, Zhang D, Wang L, Xu S
Eur J Med Chem
· 2026 Oct · PMID 42176658
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Cyclin-dependent kinase 4/6 (CDK4/6) plays a pivotal role in cell cycle regulation, and its abnormal activation is closely associated with the initiation and progression of breast cancer.1 However, the limited number of...Cyclin-dependent kinase 4/6 (CDK4/6) plays a pivotal role in cell cycle regulation, and its abnormal activation is closely associated with the initiation and progression of breast cancer.1 However, the limited number of clinically available CDK4/6 inhibitors restricts treatment options. This study focuses on the design, synthesis, and antitumor activity investigation of novel CDK4/6 inhibitors.Employing computer-aided drug design (CADD) strategies and utilizing drug-like and bioisostere principles, we innovatively introduced pyridine-2-aminopyrimidine, thieno[3,2-d]pyrimidine, and pyrazolo[1,5-a]pyrimidine as core skeletal structures to design and screen 250 compound molecules. Based on computational results, including molecular docking and MM/GBSA binding free energy, 40 potential novel CDK4/6 inhibitors were selected for synthesis.Cellular assays validated that compound 3c exhibited the strongest inhibitory activity against CDK4/6 in breast cancer cell lines, with IC values of 0.11 ± 0.01 μM (MCF-7), 0.21 ± 0.01 μM (4T1), and 0.12 ± 0.01 μM (MDA-MB-231). And compound 3c demonstrated favorable CDK4/6 inhibition rates and showed a certain degree of selectivity among 23 kinases. In vitro mechanistic studies revealed that 3c consistently inhibited cell colony formation and migration. Furthermore, 3c effectively arrested the MCF-7 cell cycle at the G1 phase and induced apoptosis. In the MCF-7 xenograft model, compound 3c achieved a tumor inhibition rate of 45.20%, highlighting its significant potential as a therapeutic CDK4/6 inhibitor.
Huang S, Lv Y, Wang Y
… +8 more, Duan Y, Li S, Guo Y, Xie S, Dong C, Yang Y, Sun SK, Xuan C
Eur J Med Chem
· 2026 Oct · PMID 42176657
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PROteolysis TArgeting Chimeras (PROTACs) represent a novel therapeutic strategy that leverages the ubiquitin-proteasome system for targeted protein degradation. Aptamers, with their high specificity and binding affinity,...PROteolysis TArgeting Chimeras (PROTACs) represent a novel therapeutic strategy that leverages the ubiquitin-proteasome system for targeted protein degradation. Aptamers, with their high specificity and binding affinity, have recently been explored as alternative recognition elements in PROTAC design. Here, we developed an aptamer-based PROTAC targeting SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), an epigenetic regulator implicated in breast cancer progression. The SETDB1-specific aptamer identified in our previous work was conjugated to a CRBN E3 ligase ligand via click chemistry, generating a serum-stable PROTAC, designated as P-SETDB1-4. P-SETDB1-4 effectively recruits CRBN to SETDB1, inducing proteasome-dependent degradation of SETDB1 in breast cancer cells. Consequently, P-SETDB1-4 significantly inhibits the proliferation and migration of breast cancer cells. Moreover, P-SETDB1-4 enhances the CD8 T cells cytotoxicity against breast cancer cells and suppresses tumor growth in vivo. RNA sequencing analysis elucidates the molecular mechanism underlying P-SETDB1-4-mediated tumor suppression and promotion of CD8 T cell-mediated killing. This study provides a promising therapeutic strategy for breast cancer and highlights the potential of aptamer-CRBNL PROTACs for targeting other challenging oncogenic proteins.
Wang L, Yang J, Liu Y
… +5 more, Yan J, Huang Q, Gan W, Wang T, Tian Y
Eur J Med Chem
· 2026 Oct · PMID 42176656
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Curcumin, a natural polyphenolic compound extracted from the rhizome of Curcuma longa, has emerged as a research hotspot in medicinal chemistry owing to its unique diarylheptadienone skeleton (C6-C7-C6), broad-spectrum b...Curcumin, a natural polyphenolic compound extracted from the rhizome of Curcuma longa, has emerged as a research hotspot in medicinal chemistry owing to its unique diarylheptadienone skeleton (C6-C7-C6), broad-spectrum bioactivities, and multi-target mode of action. However, its inherent drawbacks, including poor water solubility, low in vivo stability, and rapid metabolic rate, have severely hindered its clinical translation and application. In recent years, breakthrough progress has been made in the structural modification and scaffold reconstruction of the curcumin nucleus. Through diverse strategies including monocarbonyl modification, heterocyclic fusion, metal coordination, halogen substitution, and pharmacophore hybridization, a series of derivatives with improved druggability and enhanced bioactivity have been successfully developed. This review systematically collates relevant research literature from 2020 to April 2026, summarizes the latest research advances of curcuminoids in core fields including anticancer, antibacterial, antiviral, anti-inflammatory, antioxidant, and neuroprotective activities by bioactivity classification, and focuses on the structural characteristics, activity advantages, structure-activity relationships (SARs), and molecular mechanisms of representative derivatives. Furthermore, key SAR insights, including the modification of the β-diketone group, regulation of aromatic ring substituents, and the synergy of scaffold fusion with metal coordination, are further refined, and future research directions are prospected. This review aims to provide systematic SAR guidance and insights for the rational design of innovative drugs based on the curcumin scaffold.
Mocka S, Modica MN, Pittalà V
… +5 more, Salerno L, Romeo G, Marrazzo A, Siracusa L, Intagliata S
Eur J Med Chem
· 2026 Oct · PMID 42176655
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Antimetabolites are anticancer drugs designed to mimic endogenous substrates, thereby inducing irreversible damage that ultimately leads to tumor cell death. 5-Fluorouracil (5-FU) belongs to this class, as it is an uraci...Antimetabolites are anticancer drugs designed to mimic endogenous substrates, thereby inducing irreversible damage that ultimately leads to tumor cell death. 5-Fluorouracil (5-FU) belongs to this class, as it is an uracil analog capable of interfering with both DNA and RNA. Despite its widespread use in the treatment of several solid tumors, such as pancreatic, stomach, lung, breast, esophageal, and colorectal cancers, 5-FU suffers from limitations such as poor bioavailability, a short half-life, and low selectivity. This review aims to discuss the main medicinal chemistry strategies developed to overcome these drawbacks, and to highlight emerging trends over the past five years. Unlike recently published reviews, which predominantly focus on single strategies, this work aims to offer a comparative analysis of structural modifications performed on 5-FU to develop its analogs, hybrid compounds, and prodrugs. Collectively, the available evidence identifies mutual prodrugs as a leading strategy to address the long-standing clinical challenges associated with 5-FU therapy, with future efforts likely to focus on improved tumor targeting and translational potential.
Xu J, Zhan M, Tong M
… +3 more, Liu G, Tang Y, Li W
Eur J Med Chem
· 2026 Oct · PMID 42176654
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Prediction of intrinsic clearance (CL), a key parameter of metabolic stability, is critical for pharmacokinetic assessment and early drug candidate screening. However, existing predictive models for CL are often constrai...Prediction of intrinsic clearance (CL), a key parameter of metabolic stability, is critical for pharmacokinetic assessment and early drug candidate screening. However, existing predictive models for CL are often constrained by the quality of publicly available data and insufficient biological interpretability. In this study, CL data were systematically collected from public databases and manually verified against original experimental records. A pragmatic filtering step was employed as part of the data curation process to mitigate the influence of potentially inconsistent measurements. Based on the curated data set, we developed traditional machine learning (ML) models and a dual-branch deep learning (DL) architecture that integrates molecular fingerprints with graph-based structural features. Furthermore, we proposed an ensemble strategy that dynamically combines ML and DL predictions according to molecular similarity. The ensemble model achieved the best overall performance, with an R of 0.634 on the test set. To elucidate the biochemical determinants underlying these predictions, we conducted interpretability analyses that linked model outputs to molecular physicochemical properties and potential metabolic sites, revealing a complementary representation pattern between the ML and DL models. Together, the proposed modeling framework and its mechanistic insights provide a biologically informed tool for early pharmacokinetic screening and contribute to a deeper understanding of structure-metabolism relationships. An interactive web server has been developed to facilitate the practical application of the proposed model and is publicly available at https://lmmd.ecust.edu.cn/clint/.
Bourg S, Place M, Copin C
… +10 more, Chaikuad A, Robert T, Holzmann H, Müller S, Bach S, Ruchaud S, Knapp S, Buron F, Routier S, Bonnet P
Eur J Med Chem
· 2026 Oct · PMID 42176653
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CLK1 is one of the four human isoforms of the cdc2-like (CLK) kinases that has been suggested as a therapeutic target in diverse diseases based on its important role regulating mRNA splicing. For example, CLKs and closel...CLK1 is one of the four human isoforms of the cdc2-like (CLK) kinases that has been suggested as a therapeutic target in diverse diseases based on its important role regulating mRNA splicing. For example, CLKs and closely related kinases such as DYRK1A have been targeted in Alzheimer's disease and other diseases in which splice site selection contributes to the disease development. Here we have developed an efficient in silico fragment-based ligand design approach to identify novel CLK1 inhibitors with excellent ligand efficiency based on an imidazo[2,1-b][1,3,4]thiadiazole fragment. More than one million docking poses were generated from 26,225 unique virtual compounds, and after applying several filtering steps, 11 compounds were selected, synthesized and their CLK1 inhibition and cellular potency were evaluated. Gratifyingly, inhibitor potencies were in excellent agreement with predicted values and crystallographic data of an inhibitor bound to CLK1 confirmed the unusual binding mode of the compounds.
Eur J Med Chem
· 2026 Oct · PMID 42176652
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Tyrosinases are copper-containing enzymes involved in melanin biosynthesis and represent key targets for treating hyperpigmentation disorders. This review focuses on tyrosinase inhibitors bearing carboxylate- and thiocar...Tyrosinases are copper-containing enzymes involved in melanin biosynthesis and represent key targets for treating hyperpigmentation disorders. This review focuses on tyrosinase inhibitors bearing carboxylate- and thiocarboxylate-based moieties, with particular emphasis on their metal-chelating properties and interaction with the dicopper active site. We provide a comparative analysis of major scaffold families, including thioureas, thiosemicarbazones, and hydroxamic acids, highlighting structure-activity relationships and key determinants of binding affinity. Beyond simple copper coordination, kinetic studies reveal complex inhibition mechanisms, often involving mixed or noncompetitive behaviors, which are critically discussed in light of recent structural insights. Particular attention is given to limitations associated with the use of non-human tyrosinases and to strategies aimed at improving relevance to human systems. By integrating available biochemical, kinetic, and structural data, this work identifies current limitations and outlines strategies for the rational design of next-generation inhibitors with improved translational relevance.
Huang L, Shu C, Lai W
… +7 more, Qiu Y, Wang X, Wei P, Xia J, Zou Y, Zhu Q, Shi S
Eur J Med Chem
· 2026 Oct · PMID 42176651
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PROTAC has emerged as a promising strategy in the field of drug discovery, offering several advantages such as high target selectivity and the potential to overcome drug resistance et al. However, there have been few rep...PROTAC has emerged as a promising strategy in the field of drug discovery, offering several advantages such as high target selectivity and the potential to overcome drug resistance et al. However, there have been few reports on ATR-PROTACs to date. In this study, we developed a series of novel ATR-PROTAC molecules, among which compound I-1 demonstrated effective and selective degradation of ATR in ATM-deficient LoVo cells, with DC and D values of 6.18 μM and 71.42%, respectively. Preliminary in vitro mechanistic studies revealed that compound I-1 can downregulate the expression of ATR protein, which leads to nuclear envelope breakdown, resulting in genome instability and extensive DNA damage, ultimately triggering cell apoptosis. In addition, I-1 had acceptable pharmacokinetic properties and exhibited significant anti-tumor activity in the LoVo xenograft tumor mouse model. Collectively, these findings suggest that ATR degraders may represent a promising strategy for the treatment of cancer with deficient in ATM.
Eur J Med Chem
· 2026 Oct · PMID 42172932
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Autophagy strategies have seen clinical or preclinical studies underway to combat cancer therapeutic resistance, but the on-target effects in normal tissues necessitate new selective approaches. Based on the antitumor ef...Autophagy strategies have seen clinical or preclinical studies underway to combat cancer therapeutic resistance, but the on-target effects in normal tissues necessitate new selective approaches. Based on the antitumor efficacy and low toxicity of matrine, a traditional Chinese medicine component, we designed and synthesized 24 matrine derivatives with higher in vitro activities. Among these compounds, A1 demonstrated the highest activity and selectivity against the HeLa cell line, with a half maximal inhibitory concentration of 0.43 μM and a selective index of 3.5. Subsequently, a label-free target fishing method using size exclusion chromatography was developed to separate proteins binding to A1. Surprisingly, TBC1 domain family member 2 (TBC1D2) emerged as the selective target of compound A1, which promotes Ras-related protein Rab-7a (RAB7A) accumulation on the lysosomal membrane and facilitates autophagy by inhibiting TBC1D2-mediated guanosine triphosphate (GTP) hydrolysis on RAB7A-GTP. Further mechanistic studies show that low-dose compound A1 induced reversible cell cycle arrest and anastasis through autophagy. Finally, A1 proved to be more efficient than matrine in HeLa-infected nude mice and was well-tolerated. These findings provide new insights into target identification techniques, ultimately leading to the discovery of first-in-class TBC1D2 inhibitors and paving the way for a novel therapeutic strategy for cervical carcinoma and beyond.
Liu W, Li X, Han Y
… +7 more, Wu L, Wang M, Xuan W, Xu Z, Liu W, Zhao Q, Hao S
Eur J Med Chem
· 2026 Oct · PMID 42172931
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In 2025, the Center for Drug Evaluation and Research (CDER) approved 46 new drugs, comprising 34 new molecular entities (NMEs) and 12 new biologicals. Small molecules dominated (31 drugs, 67.4%), with kinase inhibitors (...In 2025, the Center for Drug Evaluation and Research (CDER) approved 46 new drugs, comprising 34 new molecular entities (NMEs) and 12 new biologicals. Small molecules dominated (31 drugs, 67.4%), with kinase inhibitors (10 drugs) remaining prominent and expanding beyond oncology. Therapeutic areas were led by oncology (35%), cardiovascular (11%), and allergy/inflammatory diseases (9%). The approvals sustained the recent approval rate and showed diverse modalities including proteins and oligonucleotides. This review systematically summarizes the 31 approved small molecules, focusing on their target mechanisms, clinical indications, and synthesis processes. Furthermore, the non-small-molecule therapeutics are evaluated regarding their target mechanisms, and clinical impacts. It aims to inspire the development of efficient synthetic methods and provide practical references for future drug design targeting complex and rare diseases.
Sun M, Shao R, Chen H
… +7 more, Guo T, Chen H, Song W, Liang C, Cheng R, Li T, Ye J
Eur J Med Chem
· 2026 Oct · PMID 42172930
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The efficient construction of structurally diverse and drug-like compound libraries remains a major bottleneck in modern drug discovery. To address this, we developed a fully automated modular flow synthesis platform tha...The efficient construction of structurally diverse and drug-like compound libraries remains a major bottleneck in modern drug discovery. To address this, we developed a fully automated modular flow synthesis platform that integrates continuous flow chemistry and automation technologies. This system enables rapid, high-throughput synthesis of complex molecules without intermediate purification. For the quinolone synthesis presented here, the platform achieved a 60-fold acceleration over conventional batch methods. To demonstrate the platform's versatility, we constructed a 409-member quinolone-based library through systematic structural diversification. Screening identified highly active candidates, including (S)-C-9-21 and C-1-13, which exhibited potent activity against multidrug-resistant bacterial strains, excellent safety profiles, and negligible cytotoxicity. In a murine thigh infection model, a 10 mg/kg dose of (S)-C-9-21 reduced bacterial load by 100-fold, matching the efficacy of vancomycin at 40 mg/kg. Beyond the discovery of promising antibiotic candidates, this work establishes a scalable, automated, and machine learning-ready platform that bridges the critical gap between synthetic chemistry and biological screening. Our approach provides a versatile blueprint for next-generation drug discovery, enabling rapid exploration of chemical space and accelerating the development of novel therapeutic agents.
Peng X, Hossain A, Ma P
… +6 more, Guo S, Mottamal M, Zhang C, Zheng S, Kang B, Wang G
Eur J Med Chem
· 2026 Oct · PMID 42172929
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Degradation of estrogen receptor has been clinically proven effective in treating ER+ breast cancer. Proteolysis-Targeting Chimeras (PROTACs) can degrade a target protein by engaging both the target protein and the E3 li...Degradation of estrogen receptor has been clinically proven effective in treating ER+ breast cancer. Proteolysis-Targeting Chimeras (PROTACs) can degrade a target protein by engaging both the target protein and the E3 ligase, bringing them into close physical proximity to effect ubiquitination and proteasomal degradation. We report the design and construction of ER PROTACs that link tamoxifen derivatives to a CRBN E3 ligand to achieve ER protein degradation. The ER degrading efficacy of the synthesized PROTACs was found to depend on the ER binding affinity, the linker structure, and the E3 ligand. Tamoxifen-4-boronic acid conjugated to lenalidomide through a rigid piperidine-methylene-piperazine linker was found to yield degraders that show nanomolar antiestrogenic potency and excellent oral bioavailability. The most active ER degrader with good pharmacokinetic profile, 4r, showed remarkable in vivo efficacy in blocking ER+ (both non-mutant and Y537S mutant) breast tumor growth as a monotherapy or in combination with CDK4/6 inhibitors.
Czarnota-Łydka K, Kucwaj-Brysz K, Cios A
… +21 more, Mordyl B, Głuch-Lutwin M, Jastrzębska-Więsek M, Partyka A, Honkisz-Orzechowska E, Karcz T, Pakulska J, Satała G, Żesławska E, Dąbrowska M, Starek M, Więcek M, Kurowska K, Pyka P, Brunetti L, Leuci R, Piemontese L, Nitek W, Wesołowska A, Carrieri A, Handzlik J
Eur J Med Chem
· 2026 Oct · PMID 42166820
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The clinical failure of selective serotonin 5-HT receptor (5-HTR) antagonists in Alzheimer's disease (AD) highlights the need for multitarget therapeutic strategies addressing the multifactorial nature of neurodegenerati...The clinical failure of selective serotonin 5-HT receptor (5-HTR) antagonists in Alzheimer's disease (AD) highlights the need for multitarget therapeutic strategies addressing the multifactorial nature of neurodegeneration. Building upon our pioneering discovery of the first-in-class dual 5-HTR/FAAH (fatty acid amide hydrolase) modulators among O-ether triazine compounds, we here report a comprehensive lead-optimization campaign centered on the triazine-based compound MR3b, identified as a promising lead in the search for AD treatment. Structural modifications based on scaffold contraction and chalcogen bioisosterism generated a focused library of 1,3,5-triazine derivatives with diversified GPCR and FAAH profiles. Several compounds displayed nanomolar affinities for 5-HTR, 5-HTR, and DR, alongside improved FAAH inhibition and antioxidant properties. Sulfur and selenium substitutions markedly enhanced receptor affinity and reduced cytotoxicity compared to the oxygen-containing lead. Selected compounds demonstrated significant neuroprotective effects in cellular models of AD-related pathology, including mitochondrial dysfunction, amyloid-β, and glutamate-induced toxicity. Furthermore, the thio-analogue 4c effectively reversed memory deficits in vivo, showing superior CNS penetration (Kp,brain = 0.78), an expanded therapeutic window (NOR test), and improved safety relative to MR3b. This study identified compound 4c as a second-generation lead and underscores the potential of multitarget triazine-based ligands combining serotonergic modulation and FAAH inhibition as potential disease-modifying candidates for AD and related neurodegenerative disorders.
Bazine I, Maadadi R, Derbal S
… +5 more, Litim B, Aissaoui M, Bensouici C, Saher L, Harakat D
Eur J Med Chem
· 2026 Oct · PMID 42166819
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In this work, eight novel chromeno-dipyrimidine derivatives were designed and synthesized through a green, catalyst-free one-pot hemisynthetic approach starting from the natural perillaldehyde, barbituric acid and substi...In this work, eight novel chromeno-dipyrimidine derivatives were designed and synthesized through a green, catalyst-free one-pot hemisynthetic approach starting from the natural perillaldehyde, barbituric acid and substituted anilines. All prepared polycyclic heterocycles were isolated in high yields (74-94%), and were fully characterized by IR, H, C, 2D NMR spectroscopy and elemental analysis. Interestingly, the synthesized compounds underwent an unexpected intramolecular cyclization, leading exclusively to the formation of novel heterocyclic products, highlighting the structural versatility and reactivity of this system. The synthesized derivatives exhibited overall promising biological activity; notably, compounds BI-1, BI-2, and BI-3 emerged as the most active, displaying potent acetylcholinesterase inhibition (IC = 15.08-17.45 μM) together with moderate butyrylcholinesterase inhibition, while in vivo evaluation BI-3, BI-5, and BI-6 showed most significant anti-inflammatory effects (≤ 4.62%). Furthermore, docking studies performed on the chromeno-dipyrimidine derivatives suggest that the studied molecules exhibit inhibitory activity toward AchE and BchE, supported by their calculated docking scores. The findings from the docking analysis were further confirmed by 100 ns molecular dynamics simulations. The best-scoring complexes showed favorable dynamic behavior and stability when bound to both AChE and BChE during MD simulations.
Eur J Med Chem
· 2026 Oct · PMID 42166818
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Phosphodiesterase 4 (PDE4) is a validated target for chronic inflammatory diseases such as COPD, asthma, and psoriasis. Although four PDE4 inhibitors have received FDA approval (roflumilast, apremilast, crisaborole, and...Phosphodiesterase 4 (PDE4) is a validated target for chronic inflammatory diseases such as COPD, asthma, and psoriasis. Although four PDE4 inhibitors have received FDA approval (roflumilast, apremilast, crisaborole, and ensifentrine), all suffer dose-limiting gastrointestinal side effects due to insufficient PDE4B/PDE4D selectivity. Plant-derived natural products offer complementary chemical space for discovering inhibitors with novel binding modes and improved isoform selectivity. This review systematically surveys plant-derived PDE4 inhibitors reported from 1979 to 2024, spanning seven major scaffold classes: flavonoids (∼40%), terpenoids, coumarins, xanthones, benzofurans, fluorenones, and alkaloids. Structure-activity analyses reveal that hydroxylation patterns, C2C3 unsaturation, and B-ring substitution govern flavonoid potency. Structure-guided optimization of toddacoumalone ultimately yielded compound 33a (IC = 3.1 nM, PDE4D), the fluorenone selaginpulvilin K (IC = 11 nM, 30-909-fold family selectivity), and a semi-synthetic α-mangostin derivative (IC = 17 nM). Despite promising potencies, critical gaps persist in subtype selectivity profiling, pharmacokinetic characterization, and metabolic stability. We propose that integrating AI-guided optimization, structure-informed isoform-selective design, nanodelivery systems, and biotechnology-enhanced production can accelerate clinical translation of these scaffolds.
Eur J Med Chem
· 2026 Oct · PMID 42166817
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The diseases induced by these parasites in humans and animals span a broad spectrum, ranging from mild diarrhea to death, with outcomes heavily dictated by the interplay of parasite traits and host characteristics. This...The diseases induced by these parasites in humans and animals span a broad spectrum, ranging from mild diarrhea to death, with outcomes heavily dictated by the interplay of parasite traits and host characteristics. This review systematically evaluates the antiprotozoal potential of aldehyde-based compounds through a comprehensive analysis of natural products, synthetic derivatives, and endogenous lipid peroxidation-derived species. A structured literature search was conducted across Web of Science, SciFinder, PubMed, Google Scholar, ACS, and ScienceDirect. The findings are organized into a conceptual framework covering four key areas: sources of antiprotozoal aldehydes, activity profiles against major protozoan taxa (including Plasmodium, Toxoplasma, Leishmania, and Trypanosoma), and emerging broad-spectrum candidates. The mechanistic landscape of aldehyde-based antiprotozoals is multifaceted, frequently involving covalent engagement with parasitic targets. This Janus-faced nature presents a trade-off: covalent inhibition on one hand versus metabolic instability, non-selective cytotoxicity, and suboptimal pharmacokinetics on the other. To address this challenge, we delineate four interconnected strategies. Together, these strategies provide a framework that transforms the intrinsic reactivity of aldehydes-from a barrier to drug development-into a precision tool for overcoming resistance and addressing the limitations of current protozoan therapies.
Eur J Med Chem
· 2026 Oct · PMID 42166816
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The inhibition of PI3K has only a limited therapeutic effect and often leads to drug resistance. Combining PI3K and BRD4 inhibition results in a beneficial antitumor effect in MYC-driven hematological malignancies and so...The inhibition of PI3K has only a limited therapeutic effect and often leads to drug resistance. Combining PI3K and BRD4 inhibition results in a beneficial antitumor effect in MYC-driven hematological malignancies and solid tumors, underlying the significance of developing dual kinase/epigenetic inhibitors. In this study, we report the design, synthesis, and biological evaluation of novel dual PI3K/BRD4 inhibitors. A series of benzopyranone (BP) based analogs were synthesized and subjected to structure activity relationship analysis (SAR). LCI40 displayed significant enzymatic inhibitory activity against PI3K, BRD4 proteins and demonstrated a remarkable selectivity profile against a 468 panel of kinases and 31 bromodomains. It exhibited favorable in vitro and in vivo pharmacokinetics in a mouse model. In a mantle cell lymphoma cell line (Mino), LCI40 inhibited the phosphorylation of pAKT (S473) and suppressed c-MYC levels. Further, LCI40 displayed immunomodulatory capacity with minimal toxicity to normal mouse immune cells. LCI40 is a promising lead candidate for development as a dual PI3K/BRD4 inhibitor for cancer therapy.