Based on the scaffold of brigatinib, we designed and synthesized a series of novel EGFR tyrosine kinase inhibitors, followed by the evaluation of their activity against the L858R/T790 M/C797S mutant EGFR kinase. Compound...Based on the scaffold of brigatinib, we designed and synthesized a series of novel EGFR tyrosine kinase inhibitors, followed by the evaluation of their activity against the L858R/T790 M/C797S mutant EGFR kinase. Compound 8c showed significantly higher inhibitory activity (IC = 0.48 nM) than brigatinib (IC = 3.41 nM), and preferred to inhibit the L858R/T790 M/C797S mutant EGFR kinase rather than other subtypes and ALK. In the proliferation inhibition assays, compound 8c also exhibited significantly greater potency (IC = 0.249 μM) and selectivity against BaF3-EGFR(L858R/T790 M/C797S) cell line compared to brigatinib (IC = 0.751 μM). Furthermore, cell cycle arrest assay, apoptosis induction assays, Western blot assay, colony formation inhibition assay, cell migration inhibition assays, tube formation assay, and docking analysis were carried out to study the action mechanism of compound 8c. All these results indicated that compound 8c has the potential for further evaluation of in vivo efficacy and druggability.
Depletion of the splicing factor RBM39 disrupts spliceosome function and induces widespread RNA splicing defects, leading to antiproliferative effects in susceptible cancer cells. Here, we report the discovery and charac...Depletion of the splicing factor RBM39 disrupts spliceosome function and induces widespread RNA splicing defects, leading to antiproliferative effects in susceptible cancer cells. Here, we report the discovery and characterization of a new series of biphenyl-containing RBM39 degraders. The lead compound 42 promotes RBM39 degradation through formation of a ternary complex with RBM39 and DCAF15/DDB1 in a Cullin-RING E3 ligase- and proteasome-dependent manner, consistent with a molecular glue mechanism. Transcriptomic analyses in HCT-116 and K562 cells revealed extensive alternative splicing alterations and suppression of cell-cycle-associated pathways, resulting in G2/M-phase arrest without apoptosis. Comparative cellular profiling identified 41 (YSA64) as a potent analog in acute myeloid leukemia MV4-11 cells and Ewing sarcoma A673 cells, disease contexts that have been minimally explored for RBM39 degraders. Notably, 41 exhibited favorable oral pharmacokinetics and significant antitumor efficacy in MV4-11 xenograft models. Collectively, this work expands the chemical space of RBM39 degraders and supports their continued development as RNA splicing-targeted anticancer agents.
Hepatitis B virus (HBV) remains a major global health challenge, where current therapies offer limited functional cure rates and are often burdened by adverse effects. HBV capsid assembly modulators (CAMs) represent a pr...Hepatitis B virus (HBV) remains a major global health challenge, where current therapies offer limited functional cure rates and are often burdened by adverse effects. HBV capsid assembly modulators (CAMs) represent a promising therapeutic approach by targeting viral nucleocapsid formation. Compounds GLP-26 and b were reported as CAMs exhibiting potent antiviral activity. A series of HBV CAMs featuring the core of 2-amino-5-(2-amino-2-oxoacetyl)-4-methylthiophene-3-carboxamide were designed and synthesized by integrating the acetamide fragment of GLP-26 with the pentavalent aromatic amine of b. Among them, compound 14Bc exhibited potent inhibitory activity on HBV DNA replication in HepG2.2.15 cells, alongside notable metabolic stability. Further biological evaluations indicated that 14Bc is an effective regulatory factor for capsid assembly, exhibiting strong antiviral properties that surpasses that of a CAM currently undergoing advanced clinical evaluation for chronic hepatitis B treatment. Moreover, 14Bc showed improved metabolic and pharmacokinetic profiles and in vivo distribution relative to GLP-26, thereby augmenting its potential as a therapeutic candidate for managing chronic hepatitis B.
Cutaneous squamous cell carcinoma (cSCC) is a common and potentially aggressive skin cancer, with limited therapeutic options for advanced disease. The Hedgehog/GLI (HH/GLI) signaling pathway has emerged as a potential t...Cutaneous squamous cell carcinoma (cSCC) is a common and potentially aggressive skin cancer, with limited therapeutic options for advanced disease. The Hedgehog/GLI (HH/GLI) signaling pathway has emerged as a potential therapeutic target in cSCC. Itraconazole (ITZ), a repurposed antifungal agent, exhibited HH/GLI pathway inhibition but suffers from unfavorable physicochemical properties. Herein, we report the rational design and evaluation of truncated-ITZ analogues as novel HH/GLI pathway inhibitors for cSCC treatment. Starting from the metabolite-inspired lead compound A-26, two series of analogues were synthesized and optimized through structure-based drug design and ligand-lipophilicity efficiency-driven optimization. Among them, compound 16 demonstrated potent HH/GLI pathway inhibition and enhanced aqueous solubility. Compound 16 selectively inhibited proliferation of A431 SCC cells, suppressed colony formation, and induced cell apoptosis. In an A431 xenograft model, 16 significantly suppressed tumor growth with downregulation of GLI1, Ki67, and SOX2. Preliminary safety evaluation revealed no significant hematological or organ toxicity. These results established truncated-ITZ analogues as promising HH/GLI pathway inhibitors and support further development of compound 16 as a potential therapeutic agent for cSCC.
This work describes the hit-to-lead optimization of the 2-ethyl-4-phenylthiazole class against Trypanosoma cruzi, the causative agent of Chagas disease. Compound LC-6 (1), previously identified in silico and in vitro aga...This work describes the hit-to-lead optimization of the 2-ethyl-4-phenylthiazole class against Trypanosoma cruzi, the causative agent of Chagas disease. Compound LC-6 (1), previously identified in silico and in vitro against epimastigotes, was confirmed here as an antichagasic hit due to its sub-micromolar potency against intracellular amastigotes. The ensuing structure-activity relationship identified five additional derivatives with promising activity against the Tulahuen strain, and subsequent assessment against strains from several Trypanosoma cruzi DTUs revealed that 1, 2 and 16 exerted nanomolar potency against the CL-Brener strain. The potency of these three compounds was complemented with a trypanocidal mechanism of action against the Dm28c-Luc and CL-Brener strains, highlighted by washout assays. However, assessing the pharmacokinetic profile of this series revealed a metabolic liability for 1 and most 2-ethyl-4-phenylthiazoles, despite an otherwise satisfactory ADME profile. Compound 2 was able to overcome this liability, displaying a sevenfold improvement in metabolic stability over 1. Therefore, 2 was selected for in vivo studies in a murine model of acute Chagas disease, in which it ultimately achieved an 84% reduction of the parasitemia in BALB/c mice. Thus, 2 was successfully identified as a new lead compound against Chagas disease.
Organophosphorus compounds (OP), like pesticides and nerve agents, are potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) due to the phosphylation of their catalytic serine. Current treatme...Organophosphorus compounds (OP), like pesticides and nerve agents, are potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) due to the phosphylation of their catalytic serine. Current treatment is limited, as approved oximes lack broad-spectrum efficacy and are poor reactivators of inhibited BChE. An alternative approach is pseudo-catalytic OP bioscavenging in which BChE and an efficient reactivator rapidly degrade OP in circulation, preventing it from reaching target tissues enriched with AChE. As imidazolium oximes were previously identified as potent BChE reactivators, we prepared eight novel N-substituted imidazolium oximes and tested them as reactivators of both human AChE and BChE inhibited by pesticide derivative paraoxon, and nerve warfare agents (sarin, cyclosarin, tabun VX, and five A-series agents). Oxime 3 (1,3-dibenzyl-2-hydroxy (imino)methylimidazolium bromide) was identified as the most potent reactivator, showing nanomolar affinity with native BChE and reactivation efficacy superior to standard oximes for cyclosarin-, sarin-, and tabun-BChE conjugate that was 1400-fold, 20-fold and 40-fold higher, respectively. In human whole blood, 30 μM cyclosarin was pseudo-catalytically decomposed by supplemented BChE and oxime 3, restoring 65% of total cholinesterase activity within 10 min. Although less potent, we identified two oximes capable of reactivating A-230-BChE conjugate. Furthermore, oxime 3 was not toxic to neural SH-SY5Y and hepatic HepG2 cells in concentrations relevant for biological activity. These findings highlight oxime 3 as well as the N,N'-dibenzyl imidazolium scaffold as the most potent BChE reactivators reported to date, providing a critical foundation for the advancement of bioscavenging-based therapies for OP poisoning.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a potential radiotherapeutic target for cancer treatment. Herein, two series of analogues, benzophenanthridinone derivatives and benzophenanthridine derivatives, were designed an...Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a potential radiotherapeutic target for cancer treatment. Herein, two series of analogues, benzophenanthridinone derivatives and benzophenanthridine derivatives, were designed and synthesized based on the reported TDP1 inhibitor NTD119B showing strong radiosensitization in vitro and in vivo. The structural modification gave seventeen analogues with stronger TDP1 inhibitory activity than NTD119B (IC = 6.9 μM). B11 showed the most potent TDP1 inhibition (IC = 1.2 ± 0.7 μM), 5.8-fold greater than NTD119B. Colony formation assays showed four TDP1 inhibitors A6, A26, B1, B7 showing stronger radiosensitizing activity than NTD119B in HCT116 cells. Further studies demonstrate that A6 targets TDP1 in cells and suppresses NHEJ repair activity, enhancing ionizing radiation-induced DNA damage resulting in a strong radiosensitizing activity both in HCT116 cells and xenografts animal model. The structure-activity relationship for TDP1 inhibition is also analyzed.
Severe drug-resistant childhood epilepsy is caused by KCNT1 gain-of-function genetic variants, resulting in increased K1.1 channel activity. KCNT1-associated epilepsy is thought to affect around 1 in 300,000 births world...Severe drug-resistant childhood epilepsy is caused by KCNT1 gain-of-function genetic variants, resulting in increased K1.1 channel activity. KCNT1-associated epilepsy is thought to affect around 1 in 300,000 births worldwide. Current treatment for KCNT1 epilepsy only provides mild symptomatic relief and uses a cocktail of experimental medications which must be personalised for the individual and are often poorly tolerated. Critically, with many patients, no therapeutic benefit is achieved. We sought to address this by using large-scale virtual screening to accelerate the development of a molecule which binds directly to KCNT1 to supress overactivity. We purchased a total of 71 compounds and using a combination of fluorescent thallium flux assays and patch clamp electrophysiology, identified a series of eight structurally diverse, novel inhibitors of the K1.1 channel with potency in the low micromolar range. These provide potential starting points for further development of drugs to treat KCNT1-associated epilepsy.
Chemokine receptor 4 (CXCR4) is a clinically significant G protein-coupled receptor implicated in HIV-1 entry, cancer progression, immune regulation, and metastatic dissemination, making it an attractive therapeutic targ...Chemokine receptor 4 (CXCR4) is a clinically significant G protein-coupled receptor implicated in HIV-1 entry, cancer progression, immune regulation, and metastatic dissemination, making it an attractive therapeutic target. This study employed an integrated computational and experimental framework to identify novel small-molecule CXCR4 inhibitors. A curated dataset of 608 compounds from peer-reviewed literature and patents was used to train machine-learning classification models. Decision Tree, Logistic Regression, and AdaBoost models showed balanced performance across key metrics, and external validation on 2146 in-house compounds identified 44 consensus CXCR4 inhibitors. Molecular docking analyses suggested favorable binding modes and key interactions comparable to those predicted for the reference inhibitor IT1t. One hundred-nanosecond molecular dynamics simulations indicated stable CXCR4-ligand complexes, with equilibration occurring within approximately 20 ns and backbone RMSD values maintained between 4 and 8 Å. MM/GBSA free-energy calculations demonstrated favorable energetics, with IS00622 exhibiting the strongest affinity (-70 kcal/mol), followed by IT1t, IS00998, and IS00179. In vitro assays identified IS00127 as a promising lead, showing strong antiproliferative activity against MDA-MB-231 cells and minimal toxicity toward HEK293 cells. ELISA assays confirmed dose-dependent CXCR4 downregulation with negligible effects on CXCR7, indicating high functional selectivity. Overall, this integrative strategy accelerates the discovery of potent, selective CXCR4 inhibitors for translational research.
The overexpression of the transcriptional enhanced associate domain (TEAD), which regulates gene transcription linked to cell growth, drives the proliferation in cases of hepatocellular carcinoma (HCC). In order to disco...The overexpression of the transcriptional enhanced associate domain (TEAD), which regulates gene transcription linked to cell growth, drives the proliferation in cases of hepatocellular carcinoma (HCC). In order to discover novel TEAD inhibitors that are more effective and have better efficacy and pharmacokinetic properties for treating HCC, this study employed a cyclization strategy to generate a novel indole-based scaffold of TEAD inhibitors. A comprehensive and systematic structure-activity relationship (SAR) analysis identified the most promising compound: LC-TD-05, a non-covalent, partial TEAD inhibitor with selective activity against TEAD1, TEAD2 and TEAD4, but reduced potency against TEAD3. LC-TD-05 exhibits good potency against TEAD1/2/4 (TEAD1 IC = 116.6 ± 21.7 nM, TEAD2 IC = 168.7 ± 17.1 nM, TEAD4 IC = 68.3 ± 18.2 nM), demonstrates favorable oral bioavailability (F = 53.7%), and exhibits significant anti-tumor activity in HCC LM3 models in vitro (LM3 cell IC = 248 ± 27.9 nM) and in vivo (TGI = 75%). Overall, this study provides a novel scaffold for TEAD inhibitors, enabling more effective interventions against HCC.
Fungal infections are a significant contributor to global morbidity and mortality, among which Candida albicans infections, a major cause of systemic candidiasis, have a mortality rate of approximately 40%. Developing ef...Fungal infections are a significant contributor to global morbidity and mortality, among which Candida albicans infections, a major cause of systemic candidiasis, have a mortality rate of approximately 40%. Developing effective and safe antifungal drugs with novel chemical scaffolds is urgently needed. In this study, more than 200 fungi from a deep-sea-derived fungal library were screened for anti-C. albicans activity, and a fungus Aspergillus candidus (CHNSCLM-1227) strain with strong activity was discovered. Using anti-C. albicans activity screening combined with LC-MS/MS-based molecular networking, six natural flavones (1-6) were identified, and among them, chlorflavonin (1) showed strong activity with an MIC value of 0.625 μg/mL. Guided by its activity and based on a diversified derivatization strategy, a total of 52 derivatives (7-58) were designed. Notably, a chlorinated flavone derivative, CHNQD-02204 (44) showed remarkable and selective in vitro antifungal activity against C. albicans, along with high safety (MIC = 0.025 μg/mL, SI > 1000). Mechanically, CHNQD-02204 (44) inhibited ergosterol production, thereby damaging the integrity of the fungal cell membrane and hindering the normal growth of C. albicans. It also prevented biofilm formation and morphological changes in cells. Moreover, CHNQD-02204 (44) exhibited excellent therapeutic efficacy in a murine model of systemic candidiasis (2.5 mg/kg, i.v., bid) and demonstrated high safety. These findings warrant further pharmaceutical exploration of the promising potential of CHNQD-02204 (44), a novel antifungal agent, for combating C. albicans infections.
DNA polymerase theta (Polθ)-mediated polymerase theta-mediated end joining (TMEJ) is a critical DNA repair pathway in homologous recombination (HR)-deficient cancers, making Polθ a promising synthetic-lethal target. Here...DNA polymerase theta (Polθ)-mediated polymerase theta-mediated end joining (TMEJ) is a critical DNA repair pathway in homologous recombination (HR)-deficient cancers, making Polθ a promising synthetic-lethal target. Herein, employing multiple structure-based drug design strategies including cyclization and bioisosteric replacement, we present the discovery of compound XL-20, a potent and orally bioavailable (F = 137%) Polθ ATPase inhibitor. XL-20 exhibits low-nanomolar inhibition of Polθ ATPase (IC = 4.3 nM), and demonstrates synergistic antitumor efficacy with PARP inhibition both in HR-deficient MDA-MB-436 cells and in vivo xenograft models. Notably, this selenium-containing compound XL-20 also significantly activates the cGAS-STING pathway and upregulates PD-L1, supporting its combination potential with immunotherapy. The promising dual-action efficacy and high oral bioavailability of XL-20 position it as a promising lead for further development.
Vitamin E and its water-soluble analogue Trolox are potent radical scavengers but require high concentrations to inhibit ferroptosis effectively. The discovery of a Trolox amide derivative 1 showing 95-fold greater poten...Vitamin E and its water-soluble analogue Trolox are potent radical scavengers but require high concentrations to inhibit ferroptosis effectively. The discovery of a Trolox amide derivative 1 showing 95-fold greater potency inspired the systematic synthesis of a focused library. Most amide derivatives demonstrated significantly enhanced potency, with IC values in the sub-micromolar range. Notably, compound 20, which features an indazole moiety, emerged as the most potent inhibitor, exhibiting a 556-fold improvement in activity (IC = 0.036 μM) over Trolox and a favorable safety index. Mechanistically, compound 20 selectively inhibits ferroptosis (not apoptosis or necroptosis) by scavenging ROS and suppressing lipid peroxidation independently of glutathione. Molecular dynamics simulations reveal its preferential membrane localization within the peroxidation-active mid-chain region, exhibiting confined lateral motion and local enrichment, and adopting a preferred orientation of the phenolic hydroxyl toward the hydrophobic core with low structural fluctuation, facilitated by indazole-lipid headgroup hydrogen bonding. In a murine model of corneal alkali burn, topical administration of compound 20 significantly ameliorate corneal neovascularization and edema. These findings highlight Trolox amide derivatives as promising anti-ferroptosis agents with translational prospects for treating ocular surface diseases.
Photopharmacology offers a powerful strategy for the spatiotemporal modulation of protein function with molecular precision. While all the current photoswitchable ligands developed to date act on single targets, we repor...Photopharmacology offers a powerful strategy for the spatiotemporal modulation of protein function with molecular precision. While all the current photoswitchable ligands developed to date act on single targets, we report Azo23, the first bifunctional photoswitchable ligand that exerts opposing efficacy modulation toward two closely related G protein-coupled receptors, cannabinoid receptors CB1 and CB2. Upon ultraviolet irradiation, Azo23 isomerizes from its trans to cis form, resulting in a potent CB1 agonist and CB2 antagonist, with a remarkable activity shift exceeding 50-fold. Molecular dockings reveal distinct receptor interactions underlying this dual behavior. Azo23 thus represents a unique photopharmacological tool for dissecting the complex and often overlapping roles of CB1 and CB2, and emerges as a promising lead compound for light-controlled modulation of cannabinoid signaling.
Neurodegenerative diseases (NDs) comprise a complex group of disorders characterized by the progressive loss of neurons in the CNS, resulting in cognitive and motor dysfunctions. Elucidating the molecular mechanisms unde...Neurodegenerative diseases (NDs) comprise a complex group of disorders characterized by the progressive loss of neurons in the CNS, resulting in cognitive and motor dysfunctions. Elucidating the molecular mechanisms underlying these diseases is essential to identify effective therapeutic strategies. The hallmarks of NDs include oxidative stress, mitochondrial dysfunction, neuroinflammation, and protein misfolding. Among the implicated molecular targets, monoamine oxidase B (MAO-B) plays a crucial role since it catalyzes the oxidative deamination of biogenic amines, such as amine neurotransmitters, and therefore plays an important role in the physiopathology of the brain and nervous system generating reactive oxygen species, so contributing to oxidative stress and inflammation. Elevated hMAO-B activity has been observed in Alzheimer's and Parkinson's disease, underscoring its potential as a therapeutic target for neuroprotection. Given the role of MAO-B activity in various molecular pathways related to neuroinflammatory and neurodegenerative processes that underlie the onset and progression of NDs, the development of more active and selective hMAO-B inhibitors could represent a promising avenue leading to safer and more effective therapies for Alzheimer's and Parkinson's disease. In this view, MAO-B inhibitors have long been investigated for their therapeutic potential in NDs. Building upon previous reviews, this updated overview focuses on the most recent advances from 2020 to today in the field of new small molecules hMAO-B inhibitors, highlighting results from preclinical studies. Attention is paid to the various classes of synthetic compounds that have emerged in recent years and, where available, the main structure-activity relationships (SARs) are discussed to provide insights into the molecular features responsible for hMAO-B inhibitory activity and selectivity. The aim is to provide researchers with a current perspective on the evolving landscape of hMAO-B inhibitor-based therapies for NDs.
Decharuangsilp S, Koompapong K, Arwon U
… +11 more, Tuyapala N, Hoarau M, Tanasugarn L, Pengon J, Talawanich Y, Saeyang T, Vanichtanankul J, Yuthavong Y, Kamchonwongpaisan S, Mahittikorn A, Kongkasuriyachai D
Toxoplasma gondii is an obligate intracellular blood and tissue protozoan parasite that infects up to a third of the population worldwide. Several antimalarial drugs, in particular pyrimethamine (PYR), have been used for...Toxoplasma gondii is an obligate intracellular blood and tissue protozoan parasite that infects up to a third of the population worldwide. Several antimalarial drugs, in particular pyrimethamine (PYR), have been used for decades to treat toxoplasmosis. Here, the clinical candidate P218, a potent inhibitor of Plasmodium falciparum dihydrofolate reductase (PfDHFR), and a series of flexible diaminopyrimidine butyrolactone analogues were identified as potent T. gondii dihydrofolate reductase (TgDHFR) inhibitors. The most promising butyrolactone analogue, LA4, displayed an improved TgDHFR inhibition (K 1.71 nM), increased antiparasitic properties in vitro (IC 0.44 nM), and a higher cell selectivity compared to PYR (K 13.0 nM, IC 410 nM) while P218 (K 2.19 nM, IC 370 nM) presented an improved activity with comparable cell selectivity to PYR. The in vivo results against T. gondii RH strain-infected mice showed that P218 reduced parasitic burden in blood whereas LA4 decreased parasite load in peritoneal fluid and blood with an extended mice survival. These findings position butyrolactone LA4 as a new potential for the treatment of acute toxoplasmosis.
Topoisomerase inhibitors are a key focus in the development of antitumor agents. In this work, using matrine as a lead compound, a series of novel derivatives were designed and synthesized as potential dual inhibitors of...Topoisomerase inhibitors are a key focus in the development of antitumor agents. In this work, using matrine as a lead compound, a series of novel derivatives were designed and synthesized as potential dual inhibitors of Topoisomerase I and II (Topo I/II). Among these compounds, A6 and A10 exhibited significant cytotoxicity against MCF-7 cells, with IC values of 0.6 μM and 0.7 μM, respectively, comparable to those of the positive controls (CPT, VP-16). Given their superior cytotoxicity and dual Topo I/II inhibitory activity, these two compounds were selected for further pharmacological evaluation. Mechanistic investigations demonstrated that A6 and A10 effectively suppressed the proliferation, invasion, and migration of MCF-7 cells in vitro by inducing DNA damage and activating the mitochondrial apoptotic pathway. Collectively, these findings underscore the potential of A6 and A10 as novel dual Topo I/II inhibitors for cancer therapy.
Anesthetics play a crucial role during surgery by effectively alleviating intraoperative pain and other discomforts. Compared to other anesthesia methods, intravenous anesthesia is simple to administer, acts rapidly, and...Anesthetics play a crucial role during surgery by effectively alleviating intraoperative pain and other discomforts. Compared to other anesthesia methods, intravenous anesthesia is simple to administer, acts rapidly, and has a high safety profile, with minimal impact on the patient's postoperative daily life and relatively low side effects. Etomidate, as an intravenous anesthetic, offers advantages such as rapid onset and stable anesthesia induction; however, its side effect of inhibiting adrenal cortical hormone synthesis limits its clinical application, often accompanied by paradoxical excitation phenomena. In recent years, researchers have focused on optimizing compound structures to develop lead compounds that provide excellent anesthetic effects while minimizing adrenal cortical suppression and other side effects. This article summarizes these structural optimization achievements, offering insights and references for future related research.
Therapeutics for acute mountain sickness (AMS) remain limited, with no new drugs introduced since acetazolamide over half a century ago. Recently, H0802, whose target protein was unknown, was an FGF21 and GDF15 mRNA Expr...Therapeutics for acute mountain sickness (AMS) remain limited, with no new drugs introduced since acetazolamide over half a century ago. Recently, H0802, whose target protein was unknown, was an FGF21 and GDF15 mRNA Expression regulator with promising anti-hypoxic effects. Given that FGF21 and GDF15 have been identified as key factors in hypoxia-related metabolic reprogramming, this study proposes a drug-discovery approach based on the RNA-regulation phenotypes of FGF21 and GDF15 to explore the structure-activity relationship of H0802. We designed and synthesized 28 new compounds and tested them on primary liver cells using mRNA expression of FGF21 and GDF15 as indicators. YXX0237 and YXX0248 emerged as the most promising candidates. They significantly increased FGF21 and GDF15 levels both in vitro and in vivo, thereby enhancing mice's hypoxia tolerance in closed hypoxia experiments. Preliminary safety tests showed that YXX0237 and YXX0248 have favorable safety profiles, with low cytotoxicity within the effective dose range, and their LD values in mice exceed 500 mg/kg. Pharmacokinetic studies revealed that YXX0237 has higher bioavailability than YXX0248, enters the bloodstream quickly, and maintains stable exposure. Overall, this research offers a new strategy for developing small molecules that enhance hypoxia tolerance by inducing the expression of FGF21 and GDF15. Structure-activity relationship analysis provides a foundation for further structural optimization of H0802 derivatives. YXX0237 could be a potential candidate for treating hypoxia-related diseases.
A series of novel naphtho[2,3-b]furan-4,9-dione derivatives were designed and synthesized as dual inhibitors targeting 17β-HSD10 and CDK5/p25. Through in vitro enzymatic inhibition assays, blood-brain barrier permeabilit...A series of novel naphtho[2,3-b]furan-4,9-dione derivatives were designed and synthesized as dual inhibitors targeting 17β-HSD10 and CDK5/p25. Through in vitro enzymatic inhibition assays, blood-brain barrier permeability prediction, and molecular docking analysis, derivative 5l was identified as a lead candidate and selected for further in vivo evaluation. Pharmacodynamic assessment in APP/PS1 transgenic mice demonstrated that 5l significantly improved cognitive performance in the Morris water maze test. Mechanistic studies revealed that 5l not only effectively ameliorated mitochondrial function, but also attenuated aberrant Tau phosphorylation, reduced Aβ deposition, inhibited neuroinflammation, and enhanced neurotrophic support. Western blot results indicated that the neuroprotective effects of 5l were not mediated by modulating the expression levels of 17β-HSD10 and CDK5, but rather through inhibiting their enzymatic activities. Collectively, these findings demonstrate that this class of dual inhibitors counteracts key pathological features of Alzheimer's disease through multi-target and multi-pathway synergy, providing a solid experimental foundation for the development of novel therapeutic agents for AD.