Zhang P, Qu S, Liu J
… +3 more, Zhan K, Yang X, Lei H
Eur J Med Chem
· 2026 Jun · PMID 42224938
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Dysregulation of the ATX-LPAR signaling axis is closely associated with idiopathic pulmonary fibrosis. However, many traditional ATX inhibitors tend to suffer poor druggability due to their acidic groups. In this study,...Dysregulation of the ATX-LPAR signaling axis is closely associated with idiopathic pulmonary fibrosis. However, many traditional ATX inhibitors tend to suffer poor druggability due to their acidic groups. In this study, starting from the previously reported benzoic acid ATX inhibitors 1 and 2, a series of 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one derivatives (3∼19) were designed and synthesized with preferred drug-likeness profiles. Following systematic structure-activity relationship (SAR) analysis, compound 16, a cyano-substituted N-methylacrylamide derivative, displayed the most promising inhibitory activity against ATX enzyme (IC = 13.7 nM), which was superior to that of the positive control PAT-409 (IC = 17.5 nM). Meanwhile, the salicylaldehyde derivative 19 was also identified with potent ATX inhibitory activity (IC = 27.3 nM). 16 not only retained the H-bond interactions with Val278 and Trp261, but also enhanced the aromatic interaction with Trp261. In the Bleomycin-induced mice lung fibrosis model, compounds 16 and 19 exerted appreciable antifibrotic effects accompanied by down-regulating the expression of the pro-fibrotic α-SMA. Notably, 60 mg/kg of compound 16 was significantly superior to PAT-409 in ameliorating lung tissue pathological damage and attenuating collagen deposition. Collectively, these findings may expand the repertoire of non-acidic ATX inhibitors and offer valuable experimental evidence for their utilization in fibrotic diseases.
Eur J Med Chem
· 2026 May · PMID 42224937
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Interleukin-2 inducible T-cell kinase (ITK) plays a major role in T cell signaling downstream of the T cell receptor (TCR) and is a promising therapeutic target for inflammatory diseases and T cell-related blood cancers....Interleukin-2 inducible T-cell kinase (ITK) plays a major role in T cell signaling downstream of the T cell receptor (TCR) and is a promising therapeutic target for inflammatory diseases and T cell-related blood cancers. Herein, a novel series of covalent ITK inhibitors was developed using a structure-based design. The optimized compound 19 demonstrated potent ITK inhibitory activity and effectively suppressed downstream protein phosphorylation as well as IL-2 secretion in Jurkat cells. It exhibits exceptional selectivity over BTK and other structurally related kinases. Moreover, compound 19 significantly inhibited IL-2 production in both a washout cellular assay and an anti-CD3 mAb-challenged mouse model, with sustained effects superior to its reversible counterpart. Thus, compound 19 represents a valuable tool for the further exploration of the potential benefits of ITK inhibition in basic and translational research.
Eur J Med Chem
· 2026 May · PMID 42224936
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Dengue is no longer confined to tropical and subtropical regions; due to climate change, urbanization, and vector expansion, it has now spread to several Western countries, emerging as a significant global public health...Dengue is no longer confined to tropical and subtropical regions; due to climate change, urbanization, and vector expansion, it has now spread to several Western countries, emerging as a significant global public health threat. A critical unmet need remains for the prevention and treatment of dengue and its complications. In addition to developing vaccines, substantial efforts are underway to discover prophylactic and therapeutic small-molecule inhibitors targeting viral proteins and host factors. This perspective article reviews discovery efforts from the past five years focused on inhibitors of nonstructural (NS) proteins and highlights key directions for future research.
Wang J, Xu K, Zhu P
… +7 more, Zhao Z, Wen S, Zhao J, Xin Y, You Q, Jiang Z, Lu M
Eur J Med Chem
· 2026 May · PMID 42224935
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Myeloid cell leukemia 1 (Mcl-1) is a pivotal anti-apoptotic protein, whose overexpression drives tumorigenesis, progression and drug resistance in multiple hematological malignancies. Herein, guided by a bioisosteric des...Myeloid cell leukemia 1 (Mcl-1) is a pivotal anti-apoptotic protein, whose overexpression drives tumorigenesis, progression and drug resistance in multiple hematological malignancies. Herein, guided by a bioisosteric design, we replaced the sulfonyl group with a drug-like sulfonimide linker and synthesized a novel series of Mcl-1 inhibitors based on our previous lead compound DDO-8201. Among them, compound 52 displayed potent and selective Mcl-1 inhibition (K = 0.024 μM) with at least 400-fold selectivity over other Bcl-2 family proteins. It showed an IC of 0.45 μM against Mcl-1-sensitive Molm-13 cells, superior to A1210477, and retained good activity against Venetoclax-resistant Molm-13 cells (Molm-13_VenR, IC = 1.16 μM). Moreover, 52 exhibited favorable drug-like properties, including good membrane permeability (Pe = 11.11 × 10 cm/s), water solubility (78.5 μg/mL), high stability (HLM, t = 1.83 h) and oral bioavailability (F% = 32%). This study provided a new strategy for Mcl-1 inhibitor development, and 52 represents a promising candidate for overcoming Venetoclax resistance.
Zhang T, Zhang H, Zhong X
… +4 more, Yan Y, Chen H, Zhang Y, Yin H
Eur J Med Chem
· 2026 May · PMID 42224934
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Ubiquitin-specific protease 15 (USP15) plays a critical role in the pathogenesis of various malignancies, including breast cancer, by virtue of its specific deubiquitinating functions. However, small-molecule inhibitors...Ubiquitin-specific protease 15 (USP15) plays a critical role in the pathogenesis of various malignancies, including breast cancer, by virtue of its specific deubiquitinating functions. However, small-molecule inhibitors targeting USP15 have not been reported to date. In the present study, we established a novel high-throughput screening (HTS) platform based on USP15, which led to the identification of a class of active compounds characterized by a 1-(azetidin-3-yl)-triazole scaffold. Following extensive structure-activity relationship (SAR) investigations and structural optimization, we identified TH-407a as a potent small-molecule inhibitor of USP15. Using TH-407a as a chemical probe, we investigated its mechanism of action and anticancer activity. Our findings demonstrate that TH-407a functions as a reversible, non-competitive inhibitor of USP15. It potently and dose-dependently suppressed the growth, proliferation, clonogenicity, and migratory capacity across a panel of breast cancer cell lines. TH-407a was shown to modulate p53 cancer-associated signaling pathways and reduce the stability of Poly (ADP-ribose) polymerase 1 (PARP1). In breast cancer xenograft mouse models, TH-407a exhibited potent anti-tumor activity. Collectively, these results highlight TH-407a as a promising candidate for the development of novel anticancer therapeutics.
Eur J Med Chem
· 2026 May · PMID 42224933
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Fragment-based drug design (FBDD) has become a key approach for mapping chemical space by starting with small, low-affinity fragments and building them into potent leads. Although these fragments bind weakly, strategies...Fragment-based drug design (FBDD) has become a key approach for mapping chemical space by starting with small, low-affinity fragments and building them into potent leads. Although these fragments bind weakly, strategies like fragment merging and linking can convert them into high-affinity molecules. More recently, Artificial Intelligence (AI) and Machine Learning (ML) have sped up this workflow by powering structure-guided optimization and generative design of new compounds. This review presents the state of FBDD: from biophysical screening and rapid structure elucidation to fragment growing, merging, and linking that elevate affinity while preserving ligand efficiency and drug-like properties. In particular, this review focuses on the integration of AI/ML approaches within these workflows. We compare experimental and computational strategies, summarize representative case studies, and assess how AI/ML now supports hit triage, compound priorization, and efficient exploration of chemical space. By emphasizing the role of AI-driven methods within established FBDD pipelines, we aim to provide a perspective on how these approaches complement traditional strategies. Limitations, common artifacts, and validation practices are discussed to clarify what reliably works and where open challenges remain in FBDD.
Chen H, Song L, Dai Y
… +3 more, Ma Y, Liang J, Lin W
Eur J Med Chem
· 2026 May · PMID 42218838
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Tumor necrosis factor-α (TNF-α) is a central driver of chronic inflammatory diseases, yet the development of non-biologic TNF-α inhibitors remains challenging due to the large, shallow nature of its protein-protein inter...Tumor necrosis factor-α (TNF-α) is a central driver of chronic inflammatory diseases, yet the development of non-biologic TNF-α inhibitors remains challenging due to the large, shallow nature of its protein-protein interface. Peptides offer a promising alternative to small molecules; however, rational optimization of complex peptide architectures such as branched or cyclic scaffolds remains a major bottleneck, as conventional approaches often rely on empirical screening or low-resolution mutagenesis. Here, we report a deterministic, branch-selective optimization strategy for a lysine-centered branched peptidomimetic TNF-α inhibitor using On-Demand Array Synthesis and Screening (ODAST). Through three iterative rounds of hypothesis-driven diversification, we systematically resolved the roles of charge identity, charge density, and cooperative aromatic interactions across distinct branches of the scaffold. This process led to the identification of a conserved bidentate anionic recognition motif, paired with aromatic and hydrogen-bonding elements that cooperatively stabilize TNF-α binding. The optimized peptides exhibited >10-fold improvements in apparent affinity and effectively inhibited TNF-α-induced cytotoxicity, with a lead compound displaying low-micromolar cellular IC values. Collectively, this work establishes a generalizable framework for rationally optimizing multivalent peptide architectures against challenging protein surfaces and provides design principles applicable beyond TNF-α to other cytokines and protein-protein interaction targets.
Li X, Kasireddy HR, Mishra CB
… +2 more, Moku BK, Song Y
Eur J Med Chem
· 2026 May · PMID 42218837
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Transcription cofactor ENL is a novel target for MLL-rearranged (MLL-r) leukemia and other blood cancers. We designed and synthesized several series of ENL-degrading compounds. Cereblon-recruiting, proteolysis targeting...Transcription cofactor ENL is a novel target for MLL-rearranged (MLL-r) leukemia and other blood cancers. We designed and synthesized several series of ENL-degrading compounds. Cereblon-recruiting, proteolysis targeting chimera (PROTAC) compounds 1-6 and 14 can efficiently degrade and deplete ENL with DC as low as 4.2 nM, but not its paralog AF9. Mechanistic studies showed that the lysine residues of ENL(173-190) are critical for selective ENL degradation. These compounds selectively inhibited proliferation of MLL-r leukemia and multiple myeloma cells with ECs as low as 130 nM. Depletion of ENL mimicked ENL-knockdown and significantly suppressed expression of MYC and its target genes, causing inhibited cell proliferation. Combination treatment with a BRD4 inhibitor was synergistic. Compound 14 underwent rapid metabolic degradations when exposed to human microsomes. More medicinal chemistry optimization is therefore needed in the perspective of drug discovery targeting MLL-r leukemia and other blood cancers.
Zhao B, Ning M, Cao T
… +5 more, Wu J, Leng J, Hu D, Kong L, Yin Y
Eur J Med Chem
· 2026 May · PMID 42217374
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The tubulin and PARP protein are two crucial therapeutic targets in cancer treatment. Simultaneous targeting of these two targets can disrupt cancer cell proliferation, enhance DNA damage, and thereby exert a synergistic...The tubulin and PARP protein are two crucial therapeutic targets in cancer treatment. Simultaneous targeting of these two targets can disrupt cancer cell proliferation, enhance DNA damage, and thereby exert a synergistic antitumor efficacy. Herein, we designed and synthesized a series of nitrogen-containing heterocyclic derivatives based on the natural product deoxypodophyllotoxin. Among which compound C2R exhibited the prominent antitumor activity. By targeting the tubulin colchicine-binding site and PARP1 protein, C2R effectively inhibited the proliferation of HT-29 colorectal cancer cells with an IC value of 44 nM, arrested the cell cycle at the G2/M phase, enhanced DNA damage, and induced cell apoptosis. Further studies demonstrated that C2R possessed the favorable pharmacokinetic properties and exerted antitumor activity in vivo through a combined mechanism of "inhibiting tumor cell proliferation, blocking tumor angiogenesis, and inducing tumor cell DNA damage", while showing a certain level of safety. Furthermore, C2R exerted the potent activity against lung metastasis of colorectal cancer, markedly reducing cancer cell colonization and dissemination in mice. Although C2R only exhibits moderate inhibitory activity against PARP1 that fell short of our initial expectations and its antitumor activity may be primarily derived from its potent tubulin inhibitory effect, our findings still demonstrated that the design of dual-target inhibitors targeting both tubulin and PARP1 is a feasible strategy for the development of novel anticancer agents.
Al-Zoubi RM, Farhan A, Hanbali B
… +6 more, Al-Zoubi SR, Khan A, Shkoor M, Bani-Yaseen AD, Al Zoubi MS, Agouni A
Eur J Med Chem
· 2026 May · PMID 42217373
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The repurpose of established antiparasitic agents for oncological applications represents a promising and cost-effective strategy in the search for novel anticancer therapeutics. Drugs originally developed to treat paras...The repurpose of established antiparasitic agents for oncological applications represents a promising and cost-effective strategy in the search for novel anticancer therapeutics. Drugs originally developed to treat parasitic infections, including ivermectin, mebendazole, niclosamide, albendazole, artesunate, flubendazole, and other antiparasitic agents, have demonstrated compelling anticancer properties across a wide range of preclinical models. Their mechanisms of action are multifaceted, encompassing disruption of microtubule dynamics, induction of apoptotic signaling cascades, inhibition of key oncogenic pathways (including Wnt/β-catenin, PI3K/Akt/mTOR, and Hedgehog signaling), immunomodulation, and targeting cancer stem cell populations. Ivermectin, a macrocyclic lactone, has shown potent activity against breast, ovarian, and colorectal cancer models through modulation of the P-glycoprotein drug efflux pump, activation of chloride ion channels, and inhibition of oncogenic signaling. Mebendazole, a benzimidazole antiparasitic, exerts anticancer effects primarily through inhibition of tubulin polymerization, mirroring mechanisms of conventional taxane and vinca alkaloid chemotherapeutics, and has additionally demonstrated anti-angiogenic and immunostimulatory properties. Emerging preclinical and early clinical data support anticancer activity for niclosamide (STAT3/Wnt inhibitor), artesunate (reactive oxygen species induction), and pyrvinium pamoate (Wnt pathway blockade). Despite substantial in-vitro and in-vivo evidence, the clinical translation of these agents faces significant challenges, including pharmacokinetic limitations, heterogeneous dosing regimens, and the paucity of adequately powered randomized clinical trials. This review systematically examines the current mechanistic understanding, experimental evidence, and clinical data supporting the repositioning of antiparasitic drugs as anticancer agents, while critically evaluating the limitations of existing evidence and outlining future research priorities.
Eur J Med Chem
· 2026 May · PMID 42217372
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The feature that makes it easier to identify and optimize orthosteric inhibitors-their reliance on a well-defined active site-also limits their selectivity and leads to off-target effects. An example of this is found in...The feature that makes it easier to identify and optimize orthosteric inhibitors-their reliance on a well-defined active site-also limits their selectivity and leads to off-target effects. An example of this is found in the orthosteric inhibitors for the serine/threonine-protein kinase PIM-1. PIM-1 is a pro-oncogenic protein involved in tumor progression and drug resistance development, making it a prime therapeutic target. Indeed, several orthosteric PIM-kinase inhibitors have been developed, however, they interfere with off-target kinases, leading to toxicity. While non-orthosteric inhibitors are challenging to identify, we aimed to discover such an inhibitor for PIM-1 to improve selectivity over current orthosteric inhibitors. Therefore, we designed a luciferase reporter assay to identify potential non-orthosteric PIM-1 inhibitors from a specifically designed 41-compound library. Taking hit compounds through in vitro experiments, in-silico study, and BLI-analysis indicated that our identified inhibitors physically interact with PIM-1, do not inhibit PIM-1 kinase function, and decrease PIM-1 concentration under cellular conditions. These findings suggest these compounds interact with PIM-1 via a non-orthosteric binding site. In vivo study of the top three compounds in the EMT6 mouse tumor model indicated one compound, 6d, significantly reduced tumor burden. With these promising initial findings, we introduce novel non-orthosteric PIM-1 inhibitors as new strategy to target PIM-1 with high potential for low toxicity and, further down the road, for use in combination therapy to overcome resistance caused by PIM-1.
Lee IJ, Li Q, Raskar T
… +5 more, Pellegrino J, Ecker AK, Howard SY, Fraser JS, Seiple IB
Eur J Med Chem
· 2026 May · PMID 42214237
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Natural products and their derivatives have long served as powerful tools for treating bacterial infections, but the rise of antibiotic resistance threatens their continued effectiveness. Targeted structural modification...Natural products and their derivatives have long served as powerful tools for treating bacterial infections, but the rise of antibiotic resistance threatens their continued effectiveness. Targeted structural modification of existing classes of antibiotics is an effective strategy to overcome resistance and extend clinical utility. The development of group A streptogramins that overcome acetyltransferase resistance, a pervasive resistance mechanism to the class, is an example of successful implementation of this strategy. However, the synthetic chemistry to reach these new analogs was limited in its ability to access modifications at the C4 position on the scaffold, a promising modification site that produced the most potent streptogramin to date. Here, we report the development of a modified route to group A streptogramins that enables access to a broad diversity of functionality at C4. Using cryo-EM data to guide structural modifications, we synthesize several series of C4-modified group A streptogramins with sidechains designed to make binding contacts with the exit tunnel of the ribosome. We identify multiple analogs that are active against multidrug-resistant bacteria, including strains that are resistant to macrolides, β-lactams, vancomycin, and first-generation streptogramins. We structurally characterize the binding of two analogs to the bacterial ribosome, revealing new π-stacking interactions between the C4 sidechain and the non-canonical U1782-U2586 base pair. These findings demonstrate how structure-guided drug design can drive the development of next-generation antibiotics and increase the therapeutic potential of the streptogramin class.
Kong H, Yang S, Fu Y
… +6 more, Ma Y, Zhang M, Shen Y, Li ZH, Zhang E, Li YY
Eur J Med Chem
· 2026 May · PMID 42208370
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The rise of multidrug-resistant bacterial infections severely endangers human health. Herein, we prepared two classes of di-amino acid antimicrobial peptide mimetics bearing either simple alkyl chains or heteroatom-incor...The rise of multidrug-resistant bacterial infections severely endangers human health. Herein, we prepared two classes of di-amino acid antimicrobial peptide mimetics bearing either simple alkyl chains or heteroatom-incorporated alkyl chains as linkers. The mimetics bearing simple alkyl chains as linkers all exhibited high hemolytic toxicity, whereas the compounds with heteroatom-containing alkyl chains as linkers displayed both potent antibacterial activity and low hemolytic toxicity. Among them, 7d exhibited potent antibacterial effects against S. aureus and MRSA (MIC = 0.5-1 μg/mL), along with low hemolytic toxicity. Moreover, 7d was characterized by rapid bactericidal kinetics and a low potential for resistance emergence. Furthermore, 7d both prevented S. aureus biofilm formation and disrupted established biofilms. Mechanistic and transcriptomic analyses indicated that 7d kills bacteria by disrupting the cell membrane, causing ROS accumulation and metabolic disturbances. Importantly, 7d showed strong in vivo antibacterial activity in a mouse subcutaneous infection model. Collectively, these results suggest that 7d is a promising lead compound for treating bacterial infections.
Nguyen HN, Ranasinghe PS, Ilesinghe IKRS
… +17 more, Dampalla CS, Rathnayake AD, Liska Z, Jesri AM, Azmi Z, Nevonen DE, Kim Y, Ung AR, Taylor KE, Cooper A, Liu L, Battaile KP, Thurman HA, Gusachenko E, Lovell S, Groutas WC, Chang KO
Eur J Med Chem
· 2026 May · PMID 42208369
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Constant changes in SARS-CoV-2 in human populations as well as potential future spillovers from animal coronaviruses have provided the impetus for the development of additional direct-acting antivirals. We describe herei...Constant changes in SARS-CoV-2 in human populations as well as potential future spillovers from animal coronaviruses have provided the impetus for the development of additional direct-acting antivirals. We describe herein the discovery of a new class of broad-spectrum inhibitors of coronavirus 3C-like protease (3CLpro), a cysteine protease essential for viral replication and a validated drug target, that incorporate in their structure a 1,3,2-oxazaphospholidin-3-one scaffold. Inhibitors 1 and 2 potently inhibited SARS-CoV-2 3CLpro (IC = 0.34 and 0.23 μM) and MERS-CoV 3CLpro (IC = 0.12 and 0.09 μM), and displayed antiviral activity against SARS-CoV-2 (EC = 60 and 50 nM) with low cytotoxicity (CC > 100 μM). Importantly, several of the synthesized compounds inhibited recombinant human cathepsin L with IC values in the low nM to sub-nM range. Thus, the compounds can potentially exhibit high antiviral potency by abrogating viral entry via the inhibition of cathepsin L and viral replication by inhibition of 3CLpro. High resolution cocrystal structures were determined to elucidate the mechanism of action, identify the molecular determinants associated with binding, and to inform the optimization process.
Zorman M, Minovski N, Zajec Ž
… +6 more, Anderluh M, Golob M, Radakovic N, Atanaskovic M, Senerovic L, Hrast-Rambaher M
Eur J Med Chem
· 2026 May · PMID 42208368
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Antibiotic-resistant Staphylococcus aureus poses a major global health challenge as current therapies lose effectiveness. Because most S. aureus infections are biofilm-associated, there is a critical need for new agents...Antibiotic-resistant Staphylococcus aureus poses a major global health challenge as current therapies lose effectiveness. Because most S. aureus infections are biofilm-associated, there is a critical need for new agents capable of targeting biofilm-embedded cells, and not just their planktonic form. Novel bacterial type II topoisomerase inhibitors (NBTIs) are known for their excellent antibacterial properties, against planktonic bacteria, and could also possess anti-biofilm activity. To investigate this, we designed and synthesized a new series of NBTIs featuring alternative linker scaffolds and a modified DNA-intercalating moiety to improve antibacterial and antibiofilm activity. Comprehensive MIC profiling against clinically relevant Gram-negative and Gram-positive bacteria revealed clear structure-activity trends, with compounds 20 and 40 emerging as the most promising candidates. Compound 20 showed exceptional potency against S. aureus and multiple MRSA strains (MICs 0.004-0.008 μg/mL), while compound 40 displayed the most balanced broad-spectrum activity. Both compounds exhibited dual inhibition of DNA gyrase and topoisomerase IV, maintained high selectivity over human topoisomerase IIα. In vivo evaluation in zebrafish embryos demonstrated robust protection against lethal S. aureus infection within a well-tolerated concentration range. Kinetic studies demonstrated dose-dependent bactericidal activity and measurable post-antibiotic effects. Additionally, both compounds inhibited biofilm formation at 1/2 MIC and reduced metabolic activity within mature biofilms at 2 × MIC, outperforming gepotidacin, an FDA-approved NBTI, in several assays. Together, these findings identify new NBTI chemotypes with enhanced potency and promising antibiofilm activity, providing a strong foundation for future antibacterial development.
Jula DT, Badea M, Maxim C
… +11 more, Marinas IC, Gaboreanu MD, Rostas AM, Suciu M, Ruta L, Farcasanu I, Tirsoaga A, Iorgulescu EE, Chifiriuc MC, Iordanescu V, Olar R
Eur J Med Chem
· 2026 May · PMID 42208367
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A new series of complexes [Cu(N-N)(dmtp)](ClO) (N-N = 2,2'-bipyridine (Cu1)/ 1,10-phenanthroline (Cu2) and dmtp = 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine) was developed as biologically active species. The compounds...A new series of complexes [Cu(N-N)(dmtp)](ClO) (N-N = 2,2'-bipyridine (Cu1)/ 1,10-phenanthroline (Cu2) and dmtp = 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine) was developed as biologically active species. The compounds were characterized using elemental analyses, IR, UV-Vis-NIR, EPR spectroscopy, electrochemistry, and single-crystal X-ray diffraction. Both complexes crystallize in the triclinic system, space group P-1, with two moieties in the unit cell. Both compounds exhibited varying antimicrobial efficacy, with (Cu2) demonstrating superior efficacy against Gram-positive bacteria and yeast strains. Complex (Cu2) also shows superior performance in inhibiting microbial adherence, which is crucial for preventing biofilm-related infections, particularly in the case of the E. coli strain. The study reveals that both complexes, at subinhibitory concentrations, increase intracellular nitric oxide levels, thereby inducing oxidative stress and protein oxidation, ultimately reducing microbial viability. In addition, the complexes exhibit selective superoxide-scavenging activity and interaction with DNA. In vitro cytocompatibility assays showed that compound (Cu1) induces apoptosis or cell cycle arrest in malignant melanoma (A375) and lung adenocarcinoma (A549), whereas compound (Cu2) induces necrosis, particularly at concentrations above 1 μM. The most potent effects were observed on lung adenocarcinoma cells. The docking data indicate that both complexes can interact with essential biomolecules involved in microbial pathogenesis and cancer progression.
D'Aniello A, Folliero V, Bello-Madruga R
… +17 more, Mazzarella V, Del Bene A, Dell'Annunziata F, Cosimato I, Salzano F, De Chiara I, Della Gala M, Cutolo R, Torino M, Mottola S, Messere A, Muscariello L, Cosconati S, Andreu D, Burgas MT, Franci G, Di Maro S
Eur J Med Chem
· 2026 May · PMID 42203594
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Li Y, Wen X, Liu R
… +6 more, Wang L, Feng Q, Wang Y, Zhao S, Zhao M, Zhang X
Eur J Med Chem
· 2026 Oct · PMID 42190433
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The AAA + ATPase p97/VCP is a central regulator of protein homeostasis and has emerged as an attractive anticancer target. However, first-generation ATP-competitive inhibitors have faced clinical setbacks due to off-targ...The AAA + ATPase p97/VCP is a central regulator of protein homeostasis and has emerged as an attractive anticancer target. However, first-generation ATP-competitive inhibitors have faced clinical setbacks due to off-target toxicity and sensitivity to ATP concentrations. Herein, we report the design, synthesis, and systematic structure-activity relationship (SAR) study of a novel series of diphenylmethyl-based non-competitive p97/VCP inhibitors derived from the allosteric hit MSC1094308. SAR optimization revealed that conversion of the amide linker to a secondary amine, coupled with the introduction of a tetrahydropyrido[3,4-b]indole scaffold and fluorine substitution on the biphenylmethyl group, dramatically enhanced p97/VCP inhibitory activity. The lead compounds, 10a and 10b, exhibited potent non-competitive inhibition (IC = 1.04 μM and 17 nM, respectively) and maintained efficacy independent of ATP concentration. Microscale thermophoresis (MST) confirmed strong binding affinity of 10a to p97/VCP (Kd = 14.99 μM), and limited proteolysis-mass spectrometry (LiP-MS) identified p97/VCP as a direct cellular targ et of 10a. Mechanistically, 10a induced mitochondrial membrane depolarization, leading to concurrent regulation of both apoptotic (caspase-3, PARP cleavage) and autophagic (LC3-II, p62) pathways. In vitro, 10a demonstrated broad-spectrum antiproliferative activity across multiple cancer cell lines and completely suppressed the growth of patient-derived colorectal cancer organoids. In an MC38 colorectal cancer xenograft mouse model, 10a achieved 55% tumor growth inhibition with manageable toxicity. Collectively, this study identifies 10a as a promising lead compound for colorectal cancer therapy and establishes allosteric p97/VCP inhibition via mitochondrial stress as a viable therapeutic strategy.
Hassan NW, Afifi OS, El-Attar MAZ
… +19 more, Kamel YN, Yassin HA, Nomeir HM, Angeli A, Labib HF, Elsheikh MA, Zewail M, Gerges EM, El-Yazbi AF, Spagnuolo R, Naldi M, Ashmawy MI, Zahra WK, Hammad SF, Supuran CT, Bartolini M, Elzahhar PA, Belal ASF, Abd El Wahab SM
Eur J Med Chem
· 2026 Oct · PMID 42190432
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In this study, a series of tacrine-celecoxib hybrid compounds was designed and synthesized to modulate key molecular targets implicated in metabolic dysfunction-associated mild cognitive impairment, including cyclooxygen...In this study, a series of tacrine-celecoxib hybrid compounds was designed and synthesized to modulate key molecular targets implicated in metabolic dysfunction-associated mild cognitive impairment, including cyclooxygenase-2 (COX-2), carbonic anhydrases, and cholinesterases. Among the investigated derivatives, compound 10b was identified as the most balanced multitarget candidate, exhibiting selective inhibition of human butyrylcholinesterase (BuChE, IC: 470 nM), potent COX-2 inhibitory activity (IC: 50 nM), and low nanomolar Ki towards human carbonic anhydrase IX (hCA IX). Importantly, 10b showed lower neurotoxicity in neuronal cell models compared with tacrine and staurosporine. In a high-fat diet (HFD)-induced rat model of metabolic dysfunction and cognitive impairment, administration of 10b either orally or via intranasal nanoformulation significantly improved hippocampus-dependent cognitive performance as assessed by a composite behavioral z-score. Administration of 10b was also associated with improvements in glucose homeostasis, insulin sensitivity, lipid profile, together with a reduction of HFD-induced hepatological stress. Consistent with its multitarget profile, biochemical analyses showed significant attenuation of oxidative stress and neuroinflammatory markers in the hippocampus. Finally, docking and molecular dynamics simulation studies provided a structural rationale for the observed in vitro activities of 10b, highlighting favorable binding modes within the active sites of COX-2, BuChE, and hCA IX.
Li B, Wang X, Yu J
… +7 more, Xie Q, Shi Q, Li S, Geng M, Huang X, Wang Y, Yang H
Eur J Med Chem
· 2026 Oct · PMID 42190431
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The PRMT5·MTA complex has been recognized as a potential drug target for the treatment of MTAP-deleted cancers, especially for the brain tumors. Although several MTA-cooperative PRMT5 synthetic lethal inhibitors have bee...The PRMT5·MTA complex has been recognized as a potential drug target for the treatment of MTAP-deleted cancers, especially for the brain tumors. Although several MTA-cooperative PRMT5 synthetic lethal inhibitors have been advanced into clinical trials, only one of them (TNG908) showed brain permeability in the preclinical evaluation but failed to achieve the anticipated therapeutic exposure levels in glioblastoma in clinical trials. In this study, we reported the discovery of compound 21, which showed much higher brain permeability than TNG908. More importantly, compound 21 achieved significant tumor growth inhibition in an orthotopic U87MG brain tumor model, supported by its enhanced distribution and penetration within brain tissue. These results indicate the potential clinical advantages of compound 21 for treating MTAP- deleted tumors and support its potential utility against intracranial malignancies.