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Alzheimer's disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure-activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC 50  = 1.22 μM), although the potency was increased by 2' substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3β-specific inhibitory activity (2, IC 50  = 0.0021 μM), and the electron-withdrawing group and 2' and 3' substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14-35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R 2 ). Increasing the linker length and introduction of a methoxy group (R 2 ) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3β. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3β, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC 50  = 0.024 μM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y.N., T. Su., N.H., R.N., M.Y., A.I., and F.S. are listed as inventors on a PCT international patent application (WO/2021/106988) that covers compound 7i, a compound studied in this paper. The remaining authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The STING (stimulator of interferon genes) pathway is one of the pathways that regulate innate immunity, and the extracellular hydrolytic enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as its dominant negative regulator. Since activation of the innate immune system is a promising strategy for the treatment of various infectious diseases and cancers, ENPP1 inhibitors have attracted great attention as candidate drugs. We have previously identified small-molecule ENPP1 inhibitors having a [1,2,4]triazolo[1,5-a]pyrimidine scaffold by means of chemical screening using a fluorescence probe, TG-mAMP. In this study, we evaluated the structure-activity relationships of the hit and lead compounds in detail, and succeeded in developing compounds that strongly and selectively inhibit ENPP1 not only in vitro, but also in cellular systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with IC 50 s of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic cancer cells. The lead compounds inhibit the proliferation of human pancreatic cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice., Competing Interests: Declaration of competing interest On behalf of all the authors, the corresponding author declares that there is no known financial interests or personal relationships that that could inappropriately influence (bias) the work reported in the manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Diphyllin is a naturally occurring lignan comprised of an aryl naphthalene lactone scaffold that demonstrates beneficial biological activities in disease models of cancer, obesity, and viral infection. A target of diphyllin and naturally occurring derivatives is the vacuolar ATPase (V-ATPase) complex. Although diphyllin-related natural products are active with in vitro models for viral entry, the potencies and unknown pharmacokinetic properties limit well-designed in vivo evaluations. Previous studies demonstrated that diphyllin derivatives have the utility of blocking the Ebola virus cell entry pathway. However, diphyllin shows limited potency and poor oral bioavailability in mice. An avenue to improve the potency was used in a new library of synthetic derivatives of diphyllin. Diphyllin derivatives exploiting ether linkages at the 4-position with one-to-three carbon spacers to an oxygen or nitrogen atom provided compounds with EC 50 values ranging from 7 to 600 nM potency and selectivity up to >500 against Ebola virus in infection assays. These relative potencies are reflected in the Ebola virus infection of primary macrophages, a cell type involved in early pathogenesis. A target engagement study reveals that reducing the ATPV0a2 protein expression enhanced the potency of diphyllin derivatives to block EBOV entry, consistent with effects on the endosomal V-ATPase function. Despite the substantial enhancement of antiviral potencies, limitations were identified, including rapid clearance predicted by in vitro microsome stability assays. However, compounds with similar or improved half-lives relative to diphyllin demonstrated improved pharmacokinetic profiles in vivo. Importantly, these derivatives displayed suitable plasma levels using oral administration, establishing the feasibility of in vivo antiviral testing., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. The corresponding author is a founder and CSO of Amplified Sciences, Inc and Aromarc Therapeutics, Inc. These companies hold no competing or common interests in the work being submitted for publication. All other authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sphingosine kinase 2 (SphK2) has emerged as a promising target for cancer therapy due to its critical role in tumor growth. However, the lack of potent and selective inhibitors has hindered its clinical application. Herein, we report the design and synthesis of a series of novel SphK2 inhibitors, culminating in the identification of compound 12q as a highly selective and potent inhibitor of SphK2. Molecular dynamics simulations suggest that the incorporation of larger substitution groups facilitates a more effective occupation of the binding site, thereby stabilizing the complex. Compared to the widely used inhibitor ABC294640, compound 12q exhibits superior anti-proliferative activity against various cancer cells, inducing G2 phase arrest and apoptosis in liver cancer cells HepG2. Notably, 12q inhibited migration and colony formation in HepG2 and altered intracellular sphingolipid content. Moreover, intraperitoneal administration of 12q in mice resulted in decreased levels of S1P. 12q provides a valuable tool compound for exploring the therapeutic potential of targeting SphK2 in cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC 50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC 50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC 50 values of 3.48 and 1.38 μM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Broussonetine S (9), its C-1' and C-10' stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10' epimer (10'-epi-9) were nanomolar inhibitors of bovine liver β-galactosidase and β-glucosidase; while their C-1' stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1' hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver β-glucosidase and β-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of β-glucosidase or β-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of β-glucosidase and β-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower β-glucosidase and β-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of β-galactosidase and β-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

SHP2 is a non-receptor tyrosine phosphatase encoded by PTPN11, which performs the functions of regulating cell proliferation, differentiation, apoptosis, and survival through removing tyrosine phosphorylation and modulating various signaling pathways. The overexpression of SHP2 or its mutations is related to developmental diseases and several cancers. Numerous allosteric inhibitors with striking inhibitory potency against SHP2 allosteric pockets have recently been identified, and several SHP2 tunnel allosteric inhibitors have been applied in clinical trials to treat cancers. However, based on clinical results, the efficacy of single-agent treatments has been proven to be suboptimal. Most clinical trials involving SHP2 inhibitors have adopted drug combination strategies. This review briefly discusses the research progress on SHP2 allosteric inhibitors and pathway-dependent drug combination strategies for SHP2 in cancer therapy. In addition, we summarize the current bifunctional molecules of SHP2 and elaborate on the design and structural optimization strategies of these bifunctional molecules in detail, offering further direction for the research on novel SHP2 inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Uncontrolled diabetes can lead to hyperglycemia, which causes neuropathy, heart attacks, retinopathy, and nervous system damage over time, therefore, controlling hyperglycemia using potential drug target inhibitors is a promising strategy. This work focused on synthesizing new derivatives via the diazo group, using a hybridization strategy involving two approved drugs, paracetamol and several sulfonamides. The newly designed diazo-paracetamols 5-12 were fully characterized and then screened for in vitro α-amylase and α-glucosidase activities and exhibited inhibitory percentages (IP) = 92.5-96.5 % and 91.0-95.7 % compared to Acarbose IP = 96.5 and 95.8 %, respectively at 100 μg/mL. The IC 50 values of the synthesized derivatives were evaluated against α-amylase and α-glucosidase enzymes, and the results demonstrated moderate to potent activity. Among the tested diazo-paracetamols, compound 11 was found to have the highest potency activity against α-amylase with IC 50 value of 0.98 ± 0.015 μM compared to Acarbose IC 50  = 0.43 ± 0.009 μM, followed by compound 10 (IC 50  = 1.55 ± 0.022 μM) and compound 9 (IC 50  = 1.59 ± 0.023 μM). On the other hand, for α-glucosidase, compound 10 with pyrimidine moiety demonstrated the highest inhibitory activity with IC 50  = 1.39 ± 0.021 μM relative to Acarbose IC 50  = 1.24 ± 0.029 μM and the order of the most active derivatives was 10 > 9 (IC 50  = 2.95 ± 0.046 μM) > 11 (IC 50  = 5.13 ± 0.082 μM). SAR analysis confirmed that the presence of 4,5-dimethyl-isoxazole or pyrimidine nucleus attached to the sulfonyl group is important for activity. Finally, the docking simulation was achieved to determine the mode of binding interactions for the most active derivatives in the enzyme's active site., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as an emerging target class in oncology and other diseases. A successful strategy to identify PRMT substrate-competitive inhibitors has been to exploit chemical scaffolds able to mimic the arginine substrate. (S)-Alanine amide moiety is a valuable arginine mimic for the development of potent and selective PRMT4 inhibitors; however, its high hydrophilicity led to derivatives with poor cellular outcomes. Here, we describe the development of PRMT4 inhibitors featuring a central pyrrole core and an alanine amide moiety. Rounds of optimization, aimed to increase lipophilicity and simultaneously preserve the inhibitory activity, produced derivatives that, despite good potency and physicochemical properties, did not achieve on-target effects in cells. On the other hand, masking the amino group with a NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive trigger group, led to prodrugs able to reduce arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155). These results indicate that prodrug strategies can be successfully applied to alanine-amide containing PRMT4 inhibitors and provide an option to enable such compounds to achieve sufficiently high exposures in vivo., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC 50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The inhibitory potential of 17 flavonoids on lactate dehydrogenase A (LDHA), a key enzyme in the downstream process of aerobic glycolysis in cancer cells, is investigated. Fisetin exhibited excellent inhibitory activity (IC 50  = 0.066 µM). Quercetin 3-β-D-glucoside, quercetin 3-galactoside, luteolin, neoeriocitrin, and luteolin 7-O-β-D-glucoside showed good inhibitory activity (IC 50  = 1.397-15.730 µM). Biochanin A, baicalein, quercetin, scutellarein-7-glucuronide, diosmetin, baicalein 7-O-β-D-glucuronide, and apigenin 7-apioglucoside demonstrated moderate inhibitory activity (IC 50  = 33.007-86.643 µM). Eriodictyol, quercetin 7-O-β-D-glucoside, apigenin 7-O-β-D-glucoside, and epicatechin were inactive. The Lineweaver-Burk plot showed that fisetin competitively inhibits NADH binding (K i  = 0.024 µM). K i values for other compounds were calculated using the Cheng-Prusoff equation (K i  = 0.2799-2.1661 µM). The study revealed that the inhibitory effect of flavonoids varies with the number and position of OH groups and bound sugars. Molecular docking analyses indicated that flavonoids exhibited strong interactions with the NADH binding site of LDHA through hydrophobic interactions and hydrogen bonds. Molecular dynamic simulations tested the stability of the fisetin-LDHA complex over 100 ns and showed fisetin's high binding affinity to LDHA, maintaining strong hydrogen bonds. The binding energy of fisetin with LDHA was -33.928 kcal/mol, indicating its effectiveness as an LDHA inhibitor. Consequently, flavonoids identified as strong inhibitors could be potential cancer treatment sources through LDHA inhibition., (© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Trihydroxypiperidines are a therapeutically valuable class of iminosugar. We applied a one-pot amination-cyclisation cascade reaction to synthesise 3,4,5-trihydroxypiperidine stereoisomers in three steps from commercially available pentoses and in excellent overall yields. Using our methodology, the yields of the syntheses of meso-1, meso-2 and 3L are the highest reported to date. The synthetic methodology was readily extended to the three-step synthesis of N-alkyl derivatives by replacing the ammonia nitrogen source with a primary amine. The trihydroxypiperidines and N-alkyl analogues were screened for enzyme inhibitory activity using Fabrazyme (Fabry disease), GCase (Gaucher's disease), Agrobacterium sp. β-glucosidase, and Escherichia coli β-galactosidase. N-Phenylethyl 3,4,5-trihydroxypiperidine (N-phenylethyl-1-(3R,4R,5S)-piperidine-3,4,5-triol) showed good inhibitory activity of Fabrazyme (K i  = 46 μM). This activity was abolished when the N-phenylethyl group was removed or replaced with a non-aromatic alkyl chain., Competing Interests: Declaration of competing interest The authors y declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The high level of tyrosinase leads to the generation of neuromelanin, further causing the abnormality of redox-related protein level and mediating the occurrence and development of Parkinson's disease (PD). However, the existing tyrosinase inhibitors are mostly natural product extracts or polyphenolic derivatives, which hindered them from penetrating the blood-brain barrier (BBB). Herein, we obtained a novel tyrosinase inhibitor, 2-06 (tyrosinase: monophenolase IC 50  = 70.44 ± 22.69 μM, diphenolase IC 50  = 1.89 ± 0.64 μM), through the structure-based screening method. The compound 2-06 presented good in vitro and in vivo safety, and can inhibit the tyrosinase and melanogenesis in B16F10. Moreover, this compound showed neuroprotective effects and Parkinsonism behavior improving function. 2-06 was proved to penetrate the BBB and enter the central nervous system (CNS). The exploration of the binding mode between 2-06 and tyrosinase provided the foundation for the subsequent structural optimization. This is the first research to develop a central-targeting tyrosinase inhibitor, which is crucial for in-depth study on the new strategy for utilizing tyrosinase inhibitors to treat PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inhibition of LSD1 was proposed as promising and attractive therapies for treating osteoporosis. Here, we synthesized a series of novel TCP-(MP)-Caffeic acid analogs as potential LSD1 inhibitors to assess their inhibitory effects on osteoclastogenesis by using TRAP-staining assay and try to explore the preliminary SAR. Among them, TCP-MP-CA (11a) demonstrated osteoclastic bone loss both in vitro and in vivo, showing a significant improvement in the in vivo effects compared to the LSD1 inhibitor GSK-LSD1. Additionally, we elucidated a mechanism that 11a and its precursor that 11e directly bind to LSD1/CoREST complex through FAD to inhibit LSD1 demethylation activity and influence its downstream IκB/NF-κB signaling pathway, and thus regulate osteoclastic bone loss. These findings suggested 11a or 11e as potential novel candidates for treating osteoclastic bone loss, and a concept for further development of TCP-(MP)-Caffeic acid analogs for therapeutic use in osteoporosis clinics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Compounds with sulfhydryl substituents and azole compounds exhibit potent anti-tyrosinase potency. 2-Thiobenzothiazole (2-TBT), a hybrid structure of sulfhydryl and azole, exists in two tautomeric forms, with the thione form being predominant according to several studies. 2-TBT derivatives were synthesized as potential tyrosinase inhibitors as the thione tautomeric form has the same N-CS moiety as phenylthiourea (PTU), which is suitable for chelation with the copper ions present in the tyrosinase active site. Eight of the ten 2-TBT derivatives inhibited the monophenolase and diphenolase activities of mushroom tyrosinase, with IC 50 values of 0.02-0.83 μM. Kinetic studies and molecular dynamics simulations were performed to determine their mode of action and confirm that the 2-TBT derivatives bind to the tyrosinase active site with high stability. Derivatives 3, 4, 8, and 10 strongly inhibited melanogenesis in B16F10 cells in a pattern similar to the results of cellular tyrosinase inhibition, thereby suggesting that their ability to inhibit melanogenesis was due to their tyrosinase inhibitory activity. In a depigmentation experiment using zebrafish embryos, all 2-TBT derivatives showed better potency than kojic acid, even at 400 to 2000 times lower concentration, and 1 and 10 reduced zebrafish larva pigmentation more strongly than PTU even at 20 times lower concentration. Experiments investigating the changes in tyrosinase inhibitory activity of 2-TBT derivatives in the presence and absence of CuSO 4 and their copper chelating ability supported that these derivatives exert their anti-melanogenic effect by chelating the copper ions of tyrosinase. These results suggest that 2-TBT derivatives are promising candidates for the treatment of hyperpigmentation-related disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II (GMII) inhibition is considerably impeded by an undesired co-inhibition of lysosomal α-mannosidase leading to severe side-effects. In this contribution, we describe a fully stereoselective synthesis of (5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of GMII. The synthesis starts from a previously reported aldehyde readily available from l-ribose, and the key features include an intramolecular reductive amination with substrate-controlled stereoselectivity and a late-stage derivatisation of the benzyl group via ipso-substitution. These novel swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type α-mannosidase AMAN-2 (K i  = 23-75 nM) with excellent selectivity (selectivity index = 205-870) over the lysosomal-type Jack bean α-mannosidase. Finally, molecular docking and pK a calculations were performed to provide more insight into the structure of the inhibitor:enzyme complexes, and a pair interaction energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency and selectivity of the inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC 50  = 0.95 µM, hDHODH IC 50  = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe 2+ , GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp 2 -iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and β-glucosidase isoenzymes. The most effective derivative reached over a 10 3 -fold higher inhibitory potency towards human β-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and β-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hyperpigmentation disorders may result from inappropriate melanin deposition and/or excessive melanin synthesis. They are classified mainly as aesthetic problems, but they can significantly affect human health by decreasing self-esteem. There are available only limited treatment options for hyperpigmentation disorder, among others, cosmetic products applied topically. Depigmenting ingredients were found to be ineffective and characterized by various side effects. As a result, many efforts are made to discover novel, potent, and safe melanogenesis inhibitors for possible use in topical cosmetic depigmenting formulations. Cinnamic acid derivatives constitute a widely tested group for that purpose. This article reports research in the group of N-alkyl cinnamamide derivatives (un)substituted in phenyl ring. Among tested series, (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide (compound 21) showed the most promising inhibitory properties in mushroom tyrosinase assay (IC 50  = 36.98 ± 1.07 µM for monophenolase activity, IC 50  = 146.71 ± 16.82 µM for diphenolase activity) and melanin production inhibition in B16F10 mouse melanoma cell line at concentration 6.25 µM resulting probably from decreasing of Tyr, Mitf, Tyrp-1, and Tyrp-2 genes expression. This compound also showed melanin production inhibitory properties in pigmented reconstructed human epidermis when used in 1 % and 2 % solutions in 50 % PEG400. In vitro evaluation of its safety profile showed no cytotoxicity to human keratinocytes HaCaT, human skin fibroblasts BJ, and human primary epidermal melanocytes HEMa, no mutagenicity in the Ames test, no genotoxicity in micronucleus test, no phototoxicity, as well as no skin irritation potential tested in PEG400 solution. This compound was also shown to penetrate across the epidermis to reach the possible site of action. The performed research led to classify (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide as a novel potential depigmenting cosmetic ingredient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer. The chemical synthesis, molecular characterization, and preliminary biological evaluation as 17β-HSD7 inhibitors of novel carbamate derivatives 3 and 4 are described. Like previous 17β-HSD7 inhibitors 1 and 2, compounds 3 and 4 bear a hydrophobic nonyl side chain at the C-17β position of a 4-aza-5α-androstane nucleus, but compound 3 has an oxygen atom replacing the CH 2 in the steroid A-ring C-2 position, while compound 4 has a C17-spiranic E-ring containing a carbamate function. They both inhibited the in vitro transformation of estrone (E1) into E2 by 17β-HSD7, but the introduction of a (17 R)-spirocarbamate is preferable to replacing C-2 methylene with an oxygen atom since compound 4 (IC 50 = 63 nM) is an inhibitor 14 times more powerful than compound 3 (IC 50 = 900 nM). Furthermore, when compared to the reference inhibitor 1 (IC 50 = 111 nM), the use of a C17-spiranic E-ring made it possible to introduce differently the hydrophobic nonyl side chain, without reducing the inhibitory activity., Competing Interests: Declaration of Competing Interests MZ declares no competing interests, while JYS, RM, SXL, and DP are owners of a patent on 17β-HSD type 7 inhibitors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The tyrosinase (TYR) enzyme catalyses sequential reactions in the melanogenesis pathway: l-tyrosine is oxidised to yield L-3,4-dihydroxyphenylalanine (l-dopa), which in turn is converted to dopaquinone. These two reactions are the first two steps of melanin biosynthesis and are rate limiting. The accumulation or overproduction of melanin may cause skin hyperpigmentation and inhibitors of TYR are thus of interest to the cosmeceutical industry. Several TYR inhibitors are used to treat skin hyperpigmentation, however, some are ineffective and possess questionable safety profiles. This emphasises the need to develop novel TYR inhibitors with better safety and efficacy profiles. The small molecule, 3-hydroxycoumarin, has been reported to be a good potency TYR inhibitor (IC 50  = 2.49 µM), and based on this, a series of eight structurally related 3-hydroxyquinolin-2(1H)-one derivatives were synthesised with the aim to discover novel TYR inhibitors. The results showed that four of the derivatives inhibited TYR from the champignon mushroom Agaricus bisporus (abTYR) with IC 50  < 6.11 µM. The most potent inhibitor displayed an IC 50 value of 2.52 μM. Under the same conditions, the reference inhibitors, thiamidol and kojic acid, inhibited abTYR with IC 50 values of 0.130 and 26.4 μM, respectively. Based on the small molecular structures of the active 3-hydroxyquinolin-2(1H)-one inhibitors which are amenable to structure optimisation, it may be concluded that this class of compounds are good leads for the design of TYR inhibitors for cosmeceutical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: To discover novel fungicide candidates, five series of novel norbornene hydrazide, bishydrazide, oxadiazole, carboxamide and acylthiourea derivatives (2a-2t, 3a-3f, 4a-4f, 5a-5f and 7a-7f) were designed, synthesized and assayed for their antifungal activity toward seven representative plant fungal pathogens., Results: In the in vitro antifungal assay, some title norbornene derivatives presented good antifungal activity against Botryosphaeria dothidea, Sclerotinia sclerotiorum and Fusarium graminearum. Especially, compound 2b exhibited the best inhibitory activity toward B. dothidea with the median effective concentration (EC 50 ) of 0.17 mg L -1 , substantially stronger than those of the reference fungicides boscalid and carbendazim. The in vivo antifungal assay on apples revealed that 2b had significant curative and protective effects, both of which were superior to boscalid. In the preliminary antifungal mechanism study, 2b was able to injure the surface morphology of hyphae, destroy the cell membrane integrity and increase the intracellular reactive oxygen species (ROS) level of B. dothidea. In addition, 2b could considerably inhibit the laccase activity with the median inhibitory concentration (IC 50 ) of 1.02 μM, much stronger than that of positive control cysteine (IC 50  = 35.50 μM). The binding affinity and interaction mode of 2b with laccase were also confirmed by molecular docking., Conclusion: This study presented a promising lead compound for the study of novel laccase inhibitors as fungicidal agrochemicals, which demonstrate significant anti-B. dothidea activity and laccase inhibitory activity. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

The present study reports the new thiazole (A-L) derivatives based on benzothiazole fused triazole which were synthesized and assessed against thymidine phosphorylase and α-glucosidase enzymes. Several compounds with the same basic structure but different substituents were found to have high activity against the targeted enzymes, while others with the same basic skeleton but different substituents were found to have medium to low activity among the members of tested series. These analogs showed a varied range of inhibition in both case thymidine phosphorylase and alpha glucosidase, A (IC 50 = 7.20 ± 0.30 µM and IC 50 = 1.30 ± 0.70 µM), B (IC 50 = 8.80 ± 0.10 µM and IC 50 = 2.10 ± 0.30 µM), C (IC 50 = 8.90 ± 0.40 µM and IC 50 = 3.20 ± 0.20 µM) and thiazole containing analogs such as G (IC 50 = 11.10 ± 0.20 µM and IC 50 = 7.80 ± 0.20 µM) and H (IC 50 = 12.30 ± 0.30 µM and IC 50 = 6.30 ± 0.20 µM). When compared with standard drugs 7-Deazaxanthine, 7DX (IC 50 = 10.60 ± 0.50 µM) and acarbose (IC 50 = 4.30 ± 0.30 µM) respectively. These analogs were also subjected to molecular docking studies which indicated the binding interaction of molecules with active sites of the enzyme and strengthen the drug profile of these compounds. ADMET studies also predict the drug-like properties of these compounds, with no violations of drug likeness rules., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tuberculosis is a global serious problem that imposes major health, economic and social challenges worldwide. The search for new antitubercular drugs is extremely important which could be achieved via inhibition of different druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA) enzyme is essential for the survival of M. tuberculosis. In this investigation, a series of coumarin based thiazole derivatives was synthesized relying on a molecular hybridization approach and was assessed against thewild typeMtb H37Rv and its mutant strain (ΔkatG) via inhibiting InhA enzyme. Among the synthesized derivatives, compounds 2b, 3i and 3j were the most potent against wild type M. tuberculosis with MIC values ranging from 6 to 8 μg/ mL and displayed low cytotoxicity towards mouse fibroblasts at concentrations 8-13 times higher than the MIC values. The three hybrids could also inhibit the growth of ΔkatGmutant strain which is resistant to isoniazid (INH). Compounds 2b and 3j were able to inhibit the growth of mycobacteria inside human macrophages, indicating their ability to penetrate human professional phagocytes. The two derivatives significantly suppress mycobacterial biofilm formation by 10-15 %. The promising target compounds were also assessed for their inhibitory effect against InhA and showed potent effectiveness with IC 50 values of 0.737 and 1.494 µM, respectively. Molecular docking studies revealed that the tested compounds occupied the active site of InhA in contact with the NAD + molecule. The 4-phenylcoumarin aromatic system showed binding interactions within the hydrophobic pocket of the active site. Furthermore, H-bond formation and π -π stacking interactions were also recorded for the promising derivatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Asp-tRNA Asn /Glu-tRNA Gln amidotransferase (GatCAB) has been proposed as a novel antibacterial drug target due to its indispensability in prominent human pathogens. While several inhibitors with in vitro activity have been identified, none have been demonstrated to have potent activity against live bacteria. In this work, seven non-hydrolyzable transition state mimics of GatCAB were synthesized and tested as the transamidase inhibitors against GatCAB from the human pathogen Helicobacter pylori. Notably, the methyl sulfone analog of glutamyl-adenosine significantly reduced GatCAB's transamination rate. Additionally, four lipid-conjugates of these mimics displayed antibacterial activity against Bacillus subtilis, likely due to enhanced cell permeability. Inhibitory activity against GatCAB in live bacteria was confirmed using a sensitive gain-of-function dual luciferase reporter in Mycobacterium bovis-BCG. Only the lipid-conjugated methyl sulfone analog exhibited a significant increase in mistranslation rate, highlighting its cell permeability and inhibitory potential. This study provides insights for developing urgently needed novel antibacterial agents amidst emerging antimicrobial drug resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

As an oncogenic phosphatase, SHP2 acts as a converging node in the RTK-RAS-MAPK signaling pathway in cancer cells and suppresses antitumor immunity by passing signals downstream of PD-1. Here, we utilized the extra druggable pocket outside the previously identified SHP2 allosteric tunnel site by the (6,5 fused), 6 spirocyclic system. The optimized compound, JAB-3312 , exhibited a SHP2 binding K d of 0.37 nM, SHP2 enzymatic IC 50 of 1.9 nM, KYSE-520 antiproliferative IC 50 of 7.4 nM and p-ERK inhibitory IC 50 of 0.23 nM. For JAB-3312 , an oral dose of 1.0 mg/kg QD was sufficient to achieve 95% TGI in KYSE-520 xenograft model of mouse. JAB-3312 was well-tolerated in animal models, and a close correlation was observed between the plasma concentration of JAB-3312 and the p-ERK inhibition in tumors. Currently, JAB-3312 is undergoing clinical trials as a potential anticancer agent.

Inhibiting O -GlcNAcase and thereby up-regulation of the O -GlcNAc levels of tau was a potential approach for discovering AD treatments. Herein, a series of novel highly potent OGA inhibitors embracing a 4-(arylethynyl)piperidine moiety was achieved by capitalizing on the substrate recognition domain. Extensive structure-activity relationships resulted in compound 81 with significant enzymatic inhibition (IC 50 = 4.93 ± 2.05 nM) and cellular potency (EC 50 = 7.47 ± 3.96 nM in PC12 cells). It markedly increased the protein O -GlcNAcylation levels and reduced the phosphorylation on Ser199, Thr205, and Ser396 of tau in the OA-injured SH-SY5Y cell model, suggesting its potential role for AD treatment. In fact, an in vivo efficacy of ameliorating cognitive impairment was observed following treatment of APP/PS1 mice with compound 81 (100 mg/kg). Additionally, the appropriate plasma PK and beneficial BBB penetration properties were also observed. Compound 81 deserves to be further explored as an anti-AD agent.

The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat ( 2 ) and the URAT1 inhibitor probenecid ( 3 ), followed by structure-activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC 50 = 35 nM; URAT1 IC 50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.

Respiratory syncytial virus (RSV) is an RNA virus infecting the upper and lower respiratory tract and is recognized as a major respiratory health threat, particularly to older adults, immunocompromised individuals, and young children. Around 64 million children and adults are infected every year worldwide. Despite two vaccines and a new generation monoclonal antibody recently approved, no effective antiviral treatment is available. In this manuscript, we present the medicinal chemistry efforts resulting in the identification of compound 28 (JNJ-8003), a novel RSV non-nucleoside inhibitor displaying subnanomolar activity in vitro as well as prominent efficacy in mice and a neonatal lamb models.

Human neuraminidases play critical roles in many physiological and pathological processes. Humans have four isoenzymes of NEU, making selective inhibitors important tools to investigate the function of individual isoenzymes. A typical scaffold for NEU inhibitors is 2-deoxy-2,3-didehydro- N -acetylneuraminic acid (DANA) where C9 modifications can be critical for potency and selectivity against human NEU. To design improved DANA analogues, we generated a library of compounds with either a short alkyl chain or a biphenyl substituent linked to the C9 position through one of six amide bioisosteres. Bioisostere linkers included triazole, urea, thiourea, carbamate, thiocarbamate, and sulfonamide groups. Within this library, we identified a C9 biphenyl carbamate derivative ( 963 ) that showed high selectivity and potency for NEU3 ( K i = 0.12 ± 0.01 μM). In contrast, NEU1 and NEU4 isoenzymes preferred amide and triazole linkers, respectively. Finally, analogues with urea, sulfonamide, and amide linkers showed enhanced inhibitory activity for a bacterial NEU, NanI from Clostridium perfringens .

Inositol hexakisphosphate kinases (IP6Ks) have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to the pyrophosphate, 5-diphosphoinositol-1,2,3,4,6-pentakisphosphate (5-IP7). Most of the currently known potent IP6K inhibitors contain a critical carboxylic acid which limits blood-brain barrier (BBB) penetration. In this work, the synthesis and testing of a variety of carboxylic acid isosteres resulted in several new compounds with improved BBB penetration. The most promising compound has an IP6K1 IC 50 of 16 nM with an improved brain/plasma ratio and a favorable pharmacokinetic profile. This series of brain penetrant compounds may be used to investigate the role of IP6Ks in CNS disorders.

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.

Resistant weeds severely threaten crop yields as they compete with crops for resources required for survival. Trifludimoxazin, a protoporphyrinogen IX oxidase (PPO) inhibitor, can effectively control resistant weeds. However, its crop safety record is unsatisfactory. Consequently, a scaffold-hopping strategy is employed in this study to develop a series of new triazinone derivatives featuring an amide structure. Most compounds depicted excellent herbicidal activity across a broad spectrum at 37.5-150 g ai/ha, among which ( R )- I-5 was equivalent to flumioxazin. ( R )- I-5 demonstrated significant crop tolerance to rice and wheat, even at 150 g ai/ha. ( R )- I-5 exhibited superior pharmacokinetic features compared to flumioxazin and trifludimoxazin. This was depicted by the absorption, distribution, metabolism, excretion, and toxicity predictions. Notably, proteomics-based analysis was applied for the first time to investigate variations among plant proteins before and after herbicide application, shedding light on the conservative and divergent roles of PPO.

Disulfide bond protein A (DsbA) is an oxidoreductase enzyme that catalyzes the formation of disulfide bonds in Gram-negative bacteria. In Escherichia coli, DsbA (EcDsbA) is essential for bacterial virulence, thus inhibitors have the potential to act as antivirulence agents. A fragment-based screen was conducted against EcDsbA and herein we describe the development of a series of compounds based on a phenylthiophene hit identified from the screen. A novel thiol reactive and "clickable" ethynylfluoromethylketone was designed for reaction with azide-functionalized fragments to enable rapid and versatile attachment to a range of fragments. The resulting fluoromethylketone conjugates showed selectivity for reaction with the active site thiol of EcDsbA, however unexpectedly, turnover of the covalent adduct was observed. A mechanism for this turnover was investigated and proposed which may have wider ramifications for covalent reactions with dithiol-disulfide oxidoreducatases., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Tumour-derived sialoglycans, bearing the charged nonulosonic sugar sialic acid at their termini, play a critical role in tumour cell adhesion and invasion, as well as evading cell death and immune surveillance. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans, are highly upregulated in cancer, with tumour hypersialylation strongly correlated with tumour growth, metastasis and drug resistance. As a result, desialylation of the tumour cell surface using either targeted delivery of a pan-ST inhibitor (or sialidase) or systemic delivery of a non-toxic selective ST inhibitors are being pursued as potential new anti-metastatic strategies against multiple cancers including pancreatic, ovarian, breast, melanoma and lung cancer. Herein, we have employed molecular modelling to give insights into the selectivity observed in a series of selective ST inhibitors that incorporate a uridyl ring in place of the cytidine of the natural donor (CMP-Neu5Ac) and replace the charged phosphodiester linker of classical ST inhibitors with a neutral α-hydroxy-1,2,3-triazole linker. The inhibitory activities of the nascent compounds were determined against recombinant human ST enzymes (ST3GAL1, ST6GAL1, ST8SIA2) showing promising activity and selectivity towards specific ST sub-types. Our ST inhibitors are non-toxic and show improved synthetic accessibility and drug-likeness compared to earlier nucleoside-based ST inhibitors., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Targeting the protein arginine methyltransferase 1 (PRMT1) has emerged as a promising therapeutic strategy in cancer treatment. The phase 1 clinical trial for GSK3368715, the first PRMT1 inhibitor to enter the clinic, was terminated early due to a lack of clinical efficacy, extensive treatment-emergent effects, and dose-limiting toxicities. The incidence of the latter two events may be associated with inhibition-driven pharmacology as a high and sustained concentration of inhibitor is required for therapeutic effect. The degradation of PRMT1 using a proteolysis targeting chimera (PROTAC) may be superior to inhibition as proceeds via event-driven pharmacology where a PROTAC acts catalytically at a low dose. PROTACs containing the same pharmacophore as GSK3368715, combined with a motif that recruits the VHL or CRBN E3-ligase, were synthesised. Suitable cell permeability and target engagement were shown for selected candidates by the detection of downstream effects of PRMT1 inhibition and by a NanoBRET assay for E3-ligase binding, however the candidates did not induce PRMT1 degradation. This paper is the first reported investigation of PRMT1 for targeted protein degradation and provides hypotheses and insights to assist the design of PROTACs for PRMT1 and other novel target proteins., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Telomere replication is essential for continued proliferation of human cells, such as stem cells and cancer cells. Telomerase lengthens the telomeric G-strand, while C-strand replication is accomplished by CST-polymerase α-primase (CST-PP). Replication of both strands is inhibited by formation of G-quadruplex (GQ) structures in the G-rich single-stranded DNA. TMPyP4 and pyridostatin (PDS), which stabilize GQ structures in both DNA and RNA, inhibit telomerase in vitro, and in human cells they cause telomere shortening that has been attributed to telomerase inhibition. Here, we show that TMPyP4 and PDS also inhibit C-strand synthesis by stabilizing DNA secondary structures and thereby preventing CST-PP from binding to telomeric DNA. We also show that these small molecules inhibit CST-PP binding to a DNA sequence containing no consecutive guanine residues, which is unlikely to form GQs. Thus, while these "telomerase inhibitors" indeed inhibit telomerase, they are also robust inhibitors of telomeric C-strand synthesis. Furthermore, given their binding to GQ RNA and their limited specificity for GQ structures, they may disrupt many other protein-nucleic acid interactions in human cells., (© 2024 Johnson et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Succinate dehydrogenase (SDH) has been considered an ideal target for discovering fungicides. To develop novel SDH inhibitors, in this work, 31 novel benzothiazol-2-ylthiophenylpyrazole-4-carboxamides were designed and synthesized using active fragment exchange and a link approach as promising SDH inhibitors. The findings from the tests on antifungal activity indicated that most of the synthesized compounds displayed remarkable inhibition against the fungi tested. Compound Ig N -(2-(((5-chlorobenzo[ d ]thiazol-2-yl)thio)methyl)phenyl)-3-(difluoromethyl)-1-methyl-1 H -yrazole-4-carboxamide, with EC 50 values against four kinds of fungi tested below 10 μg/mL and against Cercospora arachidicola even below 2 μg/mL, showed superior antifungal activity than that of commercial fungicide thifluzamide, and specifically compounds Ig and Im were found to show preventative potency of 90.6% and 81.3% against Rhizoctonia solani Kühn , respectively, similar to the positive fungicide thifluzamide. The molecular simulation studies suggested that hydrophobic interactions were the main driving forces between ligands and SDH. Encouragingly, we found that compound Ig can effectively promote the wheat seedlings and the growth of Arabidopsis thaliana . Our further studies indicated that compound Ig could stimulate nitrate reductase activity in planta and increase the biomass of plants.

SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity ( K D = 0.29 μM), enzymatic activity (IC 50 = 1.2 μM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC 50 = 7-24 μM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability ( F = 14%) and half-life time ( t 1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.

Increasing evidence has demonstrated that oxidative phosphorylation (OXPHOS) is closely associated with the progression of pancreatic cancer (PC). Given its central role in mitochondrial transcription, the human mitochondrial RNA polymerase (POLRMT) is a promising target for developing PC treatments. Herein, structure-activity relationship exploration led to the identification of compound S7 , which was the first reported POLRMT inhibitor possessing single-digit nanomolar potency of inhibiting PC cells proliferation. Mechanistic studies showed that compound S7 exerted antiproliferative effects without affecting the cell cycle, apoptosis, mitochondrial membrane potential (MMP), or intracellular reactive oxygen species (ROS) levels specifically in MIA PaCa-2 cells. Notably, compound S7 inhibited tumor growth in MIA PaCa-2 xenograft tumor model with a tumor growth inhibition (TGI) rate of 64.52% demonstrating significant improvement compared to the positive control (44.80%). In conclusion, this work enriched SARs of POLRMT inhibitors, and compound S7 deserved further investigations of drug-likeness as a candidate for PC treatment.

Based on the structure of caerulomycin A, 90 novel bipyridine derivatives were designed and synthesized. Among these, compound B19 exerted strong antitumor effects in vivo and in vitro. Importantly, NOP2/Sun RNA methyltransferase 3 (NSUN3) protein was identified as the target specific binding to B19 , which inhibits oxidative phosphorylation of mitochondrial energy metabolism and enhances glycolytic activity by binding to NSUN3. Knockdown of NSUN3 inhibited both proliferation and migration of colorectal cancer (CRC) cells by activating AMPK-related signaling and inhibiting downstream STAT3 signaling to exert antiproliferative and pro-apoptotic effects. Our findings support the use of NSUN3 inhibitors as promising therapeutic strategies against CRC.

LSD1 has become an appealing target for the development of new pharmacologic agents to treat cardiovascular diseases, including heart failure. Herein, we reported the design, synthesis, and structure-activity relationship of a series of TCP-based derivatives targeting LSD1. Docking studies were employed to successfully elucidate the SAR. Particularly, compound 7d , characterized by low toxicity, demonstrated a high affinity for LSD1 at molecular and cellular levels. It also displayed favorable pharmacokinetic properties for oral dosing (e.g., F = 77.61%), effectively alleviating Ang II-induced NRCFs activation in vitro and reducing pathological myocardial remodeling in TAC-induced cardiac remodeling and heart failure in vivo . Additionally, mechanism studies revealed that suppression of myocardial dysfunction by compound 7d is related to LSD1 inhibition-induced TGFβ signaling pathway repressing. In summary, the current report presents compound 7d as a potent LSD1 inhibitor with the potential for further development as a therapeutic agent for pressure overload-related heart failure.

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound 12x exhibited significant in vitro activities against Valsa mali , Gaeumannomyces graminis , and Botrytis cinerea , with EC 50 values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of Fluxapyroxad (EC 50 = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound 12x showed promising antifungal activities against Sclerotinia sclerotiorum (EC 50 = 0.82 mg/L) and Rhizoctonia solani (EC 50 = 1.86 mg/L), albeit lower than Fluxapyroxad (EC 50 = 0.23 and 0.62 mg/L). Further in vivo experiments demonstrated compound 12x to possess effective protective antifungal activities against V. mali and S. sclerotiorum at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, Fluxapyroxad showed inhibition rates of 29.2 and 96.4% against V. mali and S. sclerotiorum , respectively. Molecular docking analysis revealed that compound 12x interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound 12x exhibited greater binding energy and SDH enzyme inhibitory activity than Fluxapyroxad (Δ G cal = -46.8 kcal/mol, IC 50 = 1.22 mg/L, compared to Δ G cal = -41.1 kcal/mol, IC 50 = 8.32 mg/L). Collectively, our results suggest that compound 12x could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has a high status in the development of new inhibitors. To develop novel and highly effective PPO inhibitors, active substructure linking and bioisosterism replacement strategies were used to design and synthesize novel tetrahydrophthalimide derivatives containing oxadiazole/thiadiazole moieties, and their inhibitory effects on Nicotiana tobacco PPO ( Nt PPO) and herbicidal activity were evaluated. Among them, compounds B11 ( K i = 9.05 nM) and B20 ( K i = 10.23 nM) showed significantly better inhibitory activity against Nt PPO than that against flumiclorac-pentyl ( K i = 46.02 nM). Meanwhile, compounds A20 and B20 were 100% effective against three weeds ( Abutilon theophrasti , Amaranthus retroflexus , and Portulaca oleracea ) at 37.5 g a.i./ha. It was worth observing that compound B11 was more than 90% effective against three weeds ( Abutilon theophrasti , Amaranthus retroflexus , and Portulaca oleracea ) at 18.75 and 9.375 g a.i./ha. It was also safer to rice, maize, and wheat than flumiclorac-pentyl at 150 g a.i./ha. In addition, the molecular docking results showed that compound B11 could stably bind to Nt PPO and it had a stronger hydrogen bond with Arg98 (2.9 Å) than that of flumiclorac-pentyl (3.2 Å). This research suggests that compound B11 could be used as a new PPO inhibitor, and it could help control weeds in agricultural production.

Weed resistance is a critical issue in crop production. Among the known herbicides, 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are crucial for addressing weed resistance. HPPD inhibitors constitute a pivotal aspect of contemporary crop protection strategies. The advantages of these herbicides are their broad weed spectrum, flexible application, and excellent compatibility with other herbicides. They also exhibit satisfactory crop selectivity and low toxicity and are environmentally friendly. An increasing number of new HPPD inhibitors have been designed by combining computer-aided drug design with conventional design approaches. Herein, the molecular design and structural features of innovative HPPD inhibitors are reviewed to guide the development of new HPPD inhibitors possessing an enhanced biological efficacy.