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The main protease M pro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M pro inhibitors was the peptidomimetic α-ketoamide 13b , whose cocrystal structure with M pro paved the way for multiple lead-finding studies. We established structure-activity relationships for the 13b series by modifying residues at the P1', P3, and P4 sites. Guided by cocrystal structures, we reduced the P1' substituent size to better fill the pocket and added a fluorine substituent to the pyridone ring, enabling a new hydrogen bond with Gln189 in P3. Among 22 novel analogues, 6d and 12d inhibited M pro with IC 50 s of 110 nM and 40 nM, improving the potency of 13b by up to 9.5-fold. Compound 6d had pronounced antiviral activity with an EC 50 of 1.6 μM and was stable in plasma and microsomes. The study illustrates the potential of structure-based design to systematically improve peptidomimetic α-ketoamides.

Background: Scientists have faced difficulties in synthesizing natural substances with potent biological activity from cost-effective sources. Endophytic fungi metabolites with nanoparticles have been utilized to develop a friendly, suitable procedure to address this problem and ameliorate the average amount of antioxidant, antimicrobial, and anticancer materials. Therefore, this study utilized endophytic fungi as a source of the natural extract with biosynthesized manganese nanoparticles (MnNPs) in the form of nanocomposites., Methods: Thirty endophytic fungi were isolated and were assessed for their antioxidant activity by 1, 1-Diphenyl-2-picrylhydrazyl (DPPH) and antimicrobial activity. The most potent isolate was identified utilizing 18S rRNA and was applied to purify and separate their natural antimicrobial products by Flash column chromatography. In addition, the most potent product was identified based on instrumental analysis through Nuclear magnetic resonance (NMR), Fourier-transform infrared (FTIR), and Gas chromatography-mass spectrometry (GC.MS). The purified product was combined with biosynthsesized manganese nanoparticles (MnNPs) for the production of nanocomposite (MnNCs). Later on, the physicochemical features of MnNPs and its MnNCs were examined and then they were assessed for determination their biological activities., Results: The most potent isolate was identified as Aspergillus terreus with accession number OR243300. The antioxidant and antimicrobial product produced by the strain A. terreus was identified as an amide derivative consisting of 3-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-4-oxopentanoic acid (HDOCOX) with the chemical formula C 13 H 18 O 5 . Furthermore, purified HDOCOX, MnNPs and Mn-HDOCOX-NPs nanocomposite (MnNCs) showed significant antimicrobial effectiveness. The minimum inhibitory concentrations (MICs) determined for MnNCs were 10 µg/mL against C. albicans and E.coli. Furthermore, MnNCs were reduced hepatocellular carcinoma viability., Conclusion: The use of HDOCOX, either alone or in combination with MnNPs, is a potential candidate for inhibiting pathogenic microbes and the development of an anticancer drug pipeline., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of Zagazig University. It was reviewed by the Institutional Review Board under the number ZU-IRB #11249-31/10-2023. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Funtumine is a pregnene-type steroidal alkaloid exhibiting moderate anticancer activity. To discover novel natural product-based anticancer drugs, a series of novel funtumine amide/sulfonamide derivatives were papered and identified using spectroscopic techniques. Additionally, the structures of compounds 2j, 3a, and 4k were further confirmed through X-ray diffraction analysis. Biological activity experiments conducted against three cancer cell lines revealed that several of the synthesized compounds demonstrated inhibition activities comparable to or exceeding those of the commercial anticancer agent, 5-Fluorouracil. Especially compound 4i demonstrated a notably strong growth inhibitory effect on HePG2 (IC 50 =14.89 μM) and HCT116 (IC 50 =15.67 μM) cell lines, while exhibiting minimal cytotoxicity towards human normal BEAS-2B cells. Preliminary structure-activity relationships (SARs) analysis indicated that the conversion of the carbonyl group at the C-20 position of funtumine to a hydroxyl group could yield more potent compounds., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Thuwalamides A-E (1, 3, 5, 6 and 8), previously undescribed polychlorinated amides, along with ten previously reported related compounds (2, 4, 7 and 9-15), were isolated from the organic extract of the marine sponge Lamellodysidea herbacea (Keller), collected off the village of Thuwal in the Red Sea at Saudi Arabia. The structures of the isolated compounds have been determined through extensive analysis of their NMR and MS data, while their absolute stereochemistry was unequivocally established via single crystal X-ray diffraction. Additionally, the absolute stereochemistry of the previously reported compounds 2 and 4, whose configuration was not determined, has also been established using single-crystal X-ray crystallographic analysis. The antibacterial activity of compounds 1-15 was evaluated against Escherichia coli and Staphylococcus aureus. Among them, compound 14 displayed activity against S. aureus comparable to vancomycin that was used as a positive control with a MIC value of 4 μg/mL., 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.)

Seeking new drug candidates among compounds of natural origin is an effective and widely used method of fighting various diseases, especially cancer. Lasalocid acid is one of the naturally occurring polyether ionophore antibiotics, which also exhibits interesting anticancer activity. Therefore, to expand the knowledge about the anticancer properties of lasalocid derivatives, a series of its new amides were synthesized and their antiproliferative activity against cancer cell lines was studied. Amides 7-9 with an aromatic substituent, displayed potent antiproliferative activity (IC 50 : 0.84-5.18 μM) and demonstrated a good selectivity index (SI: 1.4-15.3). Furthermore, almost all of lasalocid amides overcame the drug resistance of the doxorubicin-resistant cancer cell line (LoVo/DX). Because the biological activity of ionophores is strictly connected with their ability to transport the Na + cation through lipid bilayers, the crystal structure of the complex of compound 8 with the Na + cation was resolved. Lasalocid amides exhibit a pseudocyclic structure and are able to coordinate the Na + cation., 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.)

Introduction: People with HIV currently face a tenfold higher risk of developing cardiovascular disease (CVD) than those without HIV. Studies have shown various off-target effects of antiretroviral treatment (ART) on the cardiovascular system, but little is known about the effects of currently used integrase strand transfer inhibitors (INSTIs) on platelets. Platelet activation is associated with increased CVD, thrombus formation, and release of proinflammatory mediators, so exploring platelet effects from currently prescribed ART may contribute to the understanding of CVD etiopathogenesis in people with HIV., Methods: We aimed to identify potential effects of INSTIs on platelet aggregation and activation markers from individuals without HIV after in vitro treatment with clinically relevant drug concentrations. We used bictegravir (BIC) and dolutegravir (DTG) individually or in the therapeutic drug combinations BIC/emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) or DTG/lamivudine (3TC). Additionally, we conducted a pilot study to compare platelet activity profiles from people with HIV on BIC/FTC/TAF and DTG/3TC., Results: Changes to in vitro platelet aggregation responses upon exposure to different INSTIs were observed both upon individual drug application and when using therapeutic combinations. However, these effects were not reflected in flow-cytometric evaluation of platelet degranulation. A pilot study in eight people with HIV and eight without HIV revealed no significant effects but established protocols for future patient studies., Conclusion: There is currently no consistent evidence of an effect of INSTIs on platelet activation. Further study is warranted, focusing on models with more pathophysiological relevance, including extensive studies in people with HIV., (© 2024 The Author(s). HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Favipiravir, a broad-spectrum RNA-dependent RNA polymerase inhibitor widely used during the COVID-19 pandemic, effectively reduces viral load but has been linked to inflammatory changes in tissues such as the liver and kidneys. High-dose and prolonged use of favipiravir for COVID-19 raises concerns about its potential toxic effects on the lungs, particularly in patients with pre-existing pulmonary conditions. This study investigated favipiravir's effects on lung tissue in healthy rats. Experimental groups included a Control (saline) and three favipiravir doses: Low (200 mg/kg/day loading, 100 mg/kg/day maintenance), Medium (400 mg/kg/day loading, 200 mg/kg/day maintenance), and High (600 mg/kg/day loading, 300 mg/kg/day maintenance), all administered via gavage for 10 days. Histopathological analysis showed normal lung structure in the Control group, while favipiravir-treated groups exhibited Bronchus-Associated Lymphoid Tissue (BALT) enlargement, inflammation, fibrosis, and hemorrhage. Immunohistochemical analysis revealed dose-dependent increases in TNF-α, TGF-β, IL-6, IFN-γ, IL1-β, α-SMA, and collagen-1, especially in the High-dose group (p < 0.05). These findings suggest favipiravir may induce lung inflammation and fibrosis, emphasizing the need for careful evaluation of its safety in clinical settings, particularly for COVID-19 treatment. Future research should investigate the underlying mechanisms of these effects with clinical studies to assess their relevance to humans, high-risk pulmonary patients., 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 © 2025 Elsevier Ltd. All rights reserved.)

Ursolic acid (3-hydroxy-urs-12-ene-28-oic acid, UA) is a pentacyclic triterpene present in numerous plants, fruits and herbs and exhibits various pharmacological effects. However, UA has limited clinical applicability since it is classified as BCS class IV molecule, characterized by low solubility, low oral bioavailability and low permeability. In the present study, UA was isolated from the biomass marc of Lavandula angustifolia and was structurally modified by an induction of indole ring at the C-3 position and amide group at the C-17 position with the aim to enhance its pharmacological potential. This modification resulted in the synthesis of a series of compounds which were investigated for their anti-inflammatory potential both in-vitro and in animal models in comparison to UA. In RAW 264.7 cells, UA and its derivatives were non-cytotoxic up to 10 µM. The derivative UA-1 exhibited a significantly lower IC 50 (2.2 ± 0.4 µM) for NO inhibition compared to UA (17.5 ± 2.0 µM). Molecular docking showed strong interactions of UA-1 with TNF-α and NF-κB. UA-1 significantly reduced LPS-induced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in RAW 264.7 macrophages with the inhibition levels of 74.2 ± 2.1 % for TNF-α, 55.9 ± 3.7 % for IL-6 and 59.7 ± 4.2 % for IL-1β at 5.0 µM, respectively and reactive oxygen species while upregulating anti-inflammatory cytokine, IL-10. It also downregulated iNOS, COX-2, p-NF-κB p65, and p-IκBα at both mRNA and protein levels. In LPS-induced systemic inflammation mice model, UA-1 significantly lowered NO, TNF-α, IL-6, IL-1β and serum biochemical parameters, reduced tissue damage, and exhibited improved aqueous solubility and moderate lipophilicity. Overall, UA-1 demonstrated superior anti-inflammatory potential, improved solubility, and better therapeutic potential compared to UA., 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.)

To discover new fungicides to protect food safety and quality, thirty-four novel pyrazole-amide-isothiazole compounds were designed, synthesised by using scaffold hopping theory for the first time. The bioactivity of all the target compounds against five plant pathogens (Including Penicillium digitatum, Physalospora piricola, Helminthosporium maydis, Sclerotinia sclerotiorum and Botrytis cinerea) were determined, the results showed that most of the compounds exhibited certain biological activities against B. cinerea in vitro. Compounds 7-XHU-6 had better antifungal activities than fluopyram with the EC 50 values were 1.02, 1.78 mg/L, respectively. Moreover, the SDH inhibiting activities results indicated that 7-XHU-6 possessed outstanding activities with an IC 50 value of 0.47 mg/L which better than fluopyram (IC 50  = 0.88 mg/L). Besides, the in vivo experiments indicated that compound 7-XHU-6 had excellent protection efficiency and therapeutic efficiency. In addition, molecular docking studies demonstrated that compound 7-XHU-6 (-10 kcal/mol) has superior binding energy compared to fluopyram (-8.6 kcal/mol)., 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.)

In this presented study, a series of new carbonitrile-substituted pyrazole-tosyl amide derivatives were designed and synthesized according to previous studies. The antiproliferative effects of the synthesized compounds on MDA-MB-231, MCF-7, HepG2, PC-3, and A549 cancer cell lines were assessed by MTT assay compared with non-cancerous cells. The results demonstrate that compounds 9d, 9e, and 9f had a higher antiproliferative effect (IC 50 <10 μM) against both breast cancer cells. To investigate the ability of these compounds (9d-f) to induce apoptosis against breast cancer cells, BCL-2 levels and Caspase-3 activities of compound-treated breast cancer cell lines were measured by ELISA. The results revealed that these compounds significantly inhibited the levels of anti-apoptotic protein BCL-2 and increased the activity of apoptotic protein Caspase-3 in MDA-MB-231 and MCF-7 cells. Molecular docking studies confirmed that the selected compounds have high binding affinity towards the active site in the crystal structures of BCL-2 and Caspase-3. Moreover, drug-likeness and pre-ADMET evaluation showed that the compounds had suitable drug properties. This study may be a new milestone in terms of the promising importance of carbonitrile-substituted pyrazole-tosyl amide scaffolds as apoptosis-inducing agents for cancer therapy in the future., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The influenza RNA-dependent RNA polymerase harbours an endonuclease subunit characterized by a catalytic site housing two divalent metal ions. By effectively chelating both Mg 2+ and Mn 2+ ions, a small-molecule inhibitor with a metal-binding pharmacophore can halt endonuclease activity. Herein, two 3'-dehydroxypurpurogallin-4-carboxamide series, namely twelve C-4' unsubstituted and twelve C-4' phenyl substituted congeners were designed and prepared to be tested as inhibitors of the metal-dependent viral enzyme. These inhibitors were accessed through the chemoenzymatic reaction of gallic acid with either pyrocatechol or phenylpyrocatechol moderated by laccase, followed by amidation. Experimental IC 50 values were determined using AlphaScreen technology, with the most potent inhibitors exhibiting IC 50 values around 0.35 μM. Using X-ray crystallography, we analyzed structure of the endonuclease in complex with one potent 3'-dehydroxypurpurogallin-carboxamide at 2.0 Å resolution, revealing the coordination of the compound's triad of oxygen atoms with the two metal ions in the influenza A endonuclease active site., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC 50 value of 0.294 μM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC 50 value of 0.519 μM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Thirty-six novel pyrazole-heterocyclic-amide analogues were designed, synthesized, and characterized. The bioassay results showed that most target compounds exhibited good fungicidal activities against Rhizoctonia solani , Gibberella zeae , Pseudoperonospora cubensis , Helminthosporium maydis , and Coniothyrium diplodiella at 20 μg/mL. Compounds 6d , 6f , 6l , and 6j possessed better fungicidal activities than the commercial fungicide prochloraz against H. maydis . Their half maximal effective concentration (EC 50 ) values were 0.47, 0.26, 0.58, and 0.69 μg/mL, respectively, and the EC 50 value of prochloraz was 0.77 μg/mL. Furthermore, the inhibitory activities for the bioactive compounds were determined against sterol 14α-demethylase (CYP51), the results displayed that they had prominent activities, compounds 6d , 6f , 6l , and 6j also showed better inhibitory activities than prochloraz against CYP51, their half maximal inhibitory concentration (IC 50 ) values were 0.543, 0.29, 0.77, 0.66, and 0.86 μg/mL, respectively. The results of molecular dynamics simulations exhibited that compound 6f displayed stronger affinity to CYP51 than prochloraz, and estimated Δ G bind values of -44.9 and -37.2 kcal/mol were found for 6f and prochloraz, respectively.

Though succinate dehydrogenase inhibitors (SDHIs) are quite successful in the modern agrochemical industry, the Fungicide Resistance Action Committee has classified the resistance risk as "medium to high". Structural analysis reveals that these antifungal chemotypes are highly conserved with amides as a consistent feature. This chemical factor may be a potential factor for the ever-increasing resistance risk. Introducing new antifungal structures or models may be a potent method to tackle this and find new bioactive compounds. In this Perspective, the recent progress in SDHIs without amide functionality from either synthetic endeavors or natural sources is showcased, focusing on their biological activities and a brief introduction of their mechanism. Synthetic advances in complex natural products are discussed, aiming to inspire new pharmaceutical discoveries and efficient synthesis methods. The challenges and strategies for the development of SDHIs are also discussed. This may offer insights for developing new SDHIs or chemical entities to combat the increasing resistance to commercial agrochemicals.

Echinacea purpurea is a perennial medicinal herb with important immunomodulatory and anti-inflammatory properties, especially purported for the alleviation of cold and flu symptoms. Different classes of secondary metabolites of the plant, such as alkylamides, caffeic acid derivatives, polysaccharides, flavonoids, and glycoproteins, are believed to be biologically and pharmacologically active. Although previous research suggests that the alkylamides present in Echinacea may be responsible for reducing the symptoms associated with the common cold or flu through their immunomodulatory activity, the roles of specific alkylamides and their targets (i.e., immune and/or antiviral) have not been well-elucidated or established. This study tested the antiviral and cytokine regulatory activity of various specific alkylamides that are present predominantly in Echinacea root extracts and found that one specific alkylamide, Dodeca-2 E ,4 E -Dienoic acid isobutylamide, had potent antiviral activity against rhinovirus (the causative agent of most common colds) and influenza virus, as well as potent inhibition of IL-8 cytokine production. IL-8 is responsible for many of the symptoms associated with the common cold and is upregulated in other common respiratory infections. The broad activity and low cytotoxicity of this specific alkylamide support its potential use for treating rhinovirus and influenza virus infections.

Particulate matter with diameter ≤2.5 μm particles (PM2.5) can trigger pulmonary inflammation and lung injury. However, there is still no specific and effective treatment. Lansiumamide B (LB) is a natural cis-enamide compound isolated from wampee seeds, and has potential anti-inflammatory effect. Herein, two series of pyrazole enamide analogues were designed and synthesized based on the scaffold hopping strategy. The inhibition rates of inflammatory cytokines on compound 11a were superior to other compounds and exhibited good dose-dependent manner and safety. Mechanism studies shown that 11a activated the Keap1/Nrf2/HO-1 signaling pathway and promoted Nrf2 entering into nucleus. Further, 11a alleviated pulmonary inflammation, collagen formation and mucus secretion in PM2.5 induced lung injury mice. Besides, 11a administration inhibited M1 macrophage polarization and neutrophil infiltration. Overall, 11a is an effective anti-inflammatory agent which might be a potent candidate to treat lung injury., 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.)

The emergence of multi-drug resistance (MDR) presents a significant impediment to the efficacy of cancer treatment. Aberrant expression of ABC (ATP-binding cassette) transporters is acknowledged as one of the underlying factors contributing to MDR. P-glycoprotein (P-gp, MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2), and MDR-associated protein 1 (MRP1, ABCC1) are members of the ABC transporter, and their over-expression usually occurs in drug-resistant tumor cells. In this work, the structure-activity relationships of the biaryl amide skeleton were systematically investigated via structural optimization step by step, which led to the identification of an exceptionally potent resistance reversal agent, D2. Compound D2 effectively reversed MDR to paclitaxel and cisplatin in A2780/T, A2780/CDDP and A549/T cell lines. It could directly bind to P-gp and downregulate the expression of both P-gp and MRP1. The treatment with D2 increased the intracellular accumulation of Rh123 and inhibited P-gp-mediated drug efflux of Rh123 in A2780/T cells. Therefore, compound D2 exhibits promising potential in overcoming multidrug resistance (MDR) induced by P-gp 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.)

Transketolase (TKL; EC 2.2.1.1) has been identified as a potential new herbicide target. In order to discover highly herbicidal active compounds targeting TKL and improve their structural diversity for lead compounds, a series of pyrazole-carboxamides 7a - 7v were designed and synthesized through structural optimization for pyrazole-containing phenoxy amide compound 4u . Among the synthesized compounds, compound 7r possessed excellent herbicidal efficacy against Digitaria sanguinalis ( Ds ) and Amaranthus retroflexus ( Ar ) by the small cup method (the inhibition about 95%, 100 mg/L) and the foliar spray method (the inhibition over 90%, 150 g ai/ha) in a greenhouse, which were superior to that of the positive control nicosulfuron. More significantly, compound 7r displayed good crop selectivity toward both maize and wheat even at 375 g of ai/ha. The studies on mode of action (MOA) of high herbicidal active compounds, including the enzyme inhibition activity, fluorescent quenching experiments, and molecular docking analysis between Setaria viridis ( Sv )TKL and ligand, suggested that compound 7r acts as a typical TKL inhibitor, and the benzothiazole ring is an important motif for Sv TKL inhibition activity. Above all, compound 7r could be a potential candidate for the development of herbicides with new MOA for weed control in maize and wheat field.

Every year, dengue virus affects hundreds of millions of individuals worldwide. To date, there is no specific medication to treat dengue virus infections. Nucleobases, the base of a nucleoside without ribose, are understudied as potential treatments for viral infections. Antiviral nucleobases are converted in infected cells to their corresponding nucleoside triphosphate active form. Importantly, the conversion of nucleobases to their active nucleotide form and their antiviral effect can be enhanced when combined with de novo nucleotide biosynthesis inhibitors. In this work, we evaluated seven purine and pyrimidine nucleobases alone or combined with six purine or pyrimidine de novo nucleotide biosynthesis inhibitors, including novel prodrugs. Our study revealed that while a strong potentiation of purine nucleobases by purine de novo nucleotide biosynthesis inhibitors was observed, the pyrimidine nucleobases were not potentiated by pyrimidine de novo nucleotide biosynthesis inhibitors, possibly highlighting a significant difference between the modulation of purine versus pyrimidine de novo pathways and their impact on nucleobase potentiation. Most significant antiviral effects and potentiation were observed for Favipiravir, T-1105, and ribavirin nucleobases combined with purine nucleotide de novo synthesis inhibitors. These results are significant because drug combinations may solve the limited efficacy observed for some antiviral nucleobase drugs such as Favipiravir.

Purpose: To investigate the effect of Rho-associated protein kinase (ROCK) inhibitor Y27632 on bioenergetic capacity and resilience of corneal endothelial cells (CECs) under metabolic stress., Methods: Bovine CECs (BCECs) were treated with Y27632 and subjected to bioenergetic profiling using the Seahorse XFp Analyzer. The effects on adenosine triphosphate (ATP) production through oxidative phosphorylation and glycolysis were measured. BCECs were also challenged with monensin to induce metabolic stress. Cell viability, apoptosis, intracellular sodium levels, and hexokinase localization were assessed using calcein AM assay, flow cytometry, fluorescence imaging, and immunostaining, respectively., Results: Y27632 increased maximal ATP production rates via both oxidative phosphorylation and glycolysis, thereby expanding the overall bioenergetic capacity in BCECs. Under monensin-induced metabolic stress, ROCK inhibitor pretreatment significantly enhanced glycolytic ATP production and reduced apoptosis compared with untreated cells. Y27632 also facilitated sodium export by increasing Na/K-ATPase activity, as evidenced by lower intracellular sodium levels. Additionally, Y27632 promoted the translocation of hexokinase 2 to mitochondria under stress conditions, thereby enhancing glycolytic capacity. The effect of Y27632 on cell viability and sodium export was abrogated when cells were forced to rely on oxidative phosphorylation in galactose media, indicating that the protective effects of Y27632 are dependent on glycolytic ATP production under monensin stress., Conclusions: ROCK inhibitor Y27632 enhances the bioenergetic capacity of BCECs, allowing the cells to better withstand metabolic stress by rapidly generating ATP to meet increased energy demands, maintaining ion homeostasis and reducing apoptosis.

New derivatives 6a-m with benzimidazole-indole-amide scaffold were developed, synthesized, and assessed for potential inhibitory effects on α-glucosidase and acetylcholinesterase (AChE). These compounds were synthesized by various amine derivatives. With the exception of two compounds, the α-glucosidase inhibitory activities of the title derivatives were more than that of the positive control acarbose. Moreover, the anti-AChE activity of these compounds, with the exception of one compound, was better than that of tacrine (standard inhibitor). The most potent compound against α-glucosidase was 3-methylphenyl derivative 6i and the most potent compound against AChE was 3,4-dimethoxyphenethyl derivative 6m. All the synthesized compounds were placed in the active sites of α-glucosidase and AChE by in silico docking method and the obtained binding energies were approximately in agreement with the in vitro observed data. Interaction modes of the most potent compounds 6i and 6m demonstrated that these compounds interacted with important residues of their target enzymes. Molecular dynamics simulation was conducted specifically on compound 6i in complex with α-glucosidase to obtain deeper insights into the behavior of this molecule. Furthermore, in silico pharmacokinetic and toxicity studies on the most potent compound predicted that these compounds have good profiles in terms of oral absorption and toxicity., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Lipid mediator, palmitoylethanolamide (PEA) has recently attracted attention as a potential therapeutic option for various inflammatory autoimmune diseases. It has been reported that PEA exerts an inhibitory effect on inflammation triggered by PRRs, particularly Toll-like receptors expressed on myeloid antigen-presenting cells. However, the precise role of PEA in T cell development and function has not yet been elucidated. Here, we found that PEA suppressed the differentiation of Type 1 T helper (Th1) cells and Th17 cells, which are known to cause autoimmune diseases, as well as Th2 cells, which are associated with allergic diseases. This suppression occurs by inhibiting the expression of the master transcription factors crucial for their differentiation in vitro. Notably, PEA had no impact on the process of differentiating regulatory T cells, which play a crucial role in preventing the onset of autoimmune diseases. To further confirm the effect of PEA in vivo, we administered PEA to a Toxoplasma gondii infection model and an ovalbumin-induced allergic rhinitis model. Mice infected with T. gondii, in which Th1 responses are important for pathogen eradication, exhibited enhanced susceptibility. Mice with allergic rhinitis, where Th2 responses contribute to an exacerbation of symptoms, showed alleviated symptoms. Collectively, these findings suggest that PEA has potential applications as a new therapeutic agent for inflammatory autoimmune and allergic diseases based on excessive T cell activity., Competing Interests: Declaration of competing interest The authors have no competing financial interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Corneal endothelial cells (CECs) dysfunction frequently results in a hazy, edematous cornea due to corneal endothelial decompensation and is a major cause of corneal blindness. Drug interventions provide a less invasive alternative to corneal transplantation surgery. However, endothelial-to-mesenchymal transition (EndMT) limits CECs function. Rho-kinase (ROCK) inhibitors, shown in numerous studies to be an adjunctive therapy for CECs dysfunction, cannot completely reverse pathological EndMT caused by inflammatory environmental damage. Verteporfin (VP) is an inhibitor of Yes-associated protein (YAP) and has significant inhibitory effects on cell fibrosis and mesenchymal transition. Here, we explored VP's utility in mitigating EndMT during ROCK inhibitors treatment of corneal endothelial dysfunction. We surgically constructed a rat model of CECs injury and studied VP and ROCK inhibitors' effects on EndMT, cell proliferation, and corneal edema using RNA-Seq sequencing, immunofluorescence, optical coherence tomography, and qPCR. The results indicated that YAP expression in human fetal CECs was higher than in adults and decreased with age in rats. Moreover, YAP expression in human CECs was negatively correlated with functional genes, such as AQP1 and ATP1A1. VP effectively reversed EndMT and accelerated corneal hydration regression. However, it inhibited CECs proliferation. We also confirmed that the optimal ratio of VP combined with Y-27632 (ROCK inhibitor) was 1:1, promoting CECs proliferation and reversing EndMT by down-regulating transcription factors downstream of TGF-β signaling, thereby increasing CECs functional and intercellular adhesion proteins. These combined effects promote corneal endothelial damage repair, providing a new treatment strategy., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Background: The development of fungicides with low cross resistance, high efficacy and low resistance plays a central role in protecting crops, reducing yield losses, improving quality and maintaining global food security. Based on this important role, after a systematic optimization strategy, novel heterocyclic amide derivatives bearing diphenylmethyl fragment were screened, synthesized and verified with the spectrographic and x-ray diffraction analysis., Results: In this study, the aforementioned optimization obtained compound B19 that was measured for antifungal activity against Rhizoctonia solani (median effective concentration, EC 50  = 1.11 μg mL -1 ). Meanwhile, the anti-R. solani protective effect (79.34%) of compound B19 was evaluated in vivo at 100 μg mL -1 , which is comparable to that of the control agent fluxapyroxad (80.67%). Thence, morphological observations revealed that compound B19 induced mycelium disruption and shrinking, mitochondrial number reduction and apoptosis acceleration, consistent with the results of the mitochondrial membrane potential and cell membrane permeability. Further investigations found that the potential target enzyme of compound B19 was SDH, which exerted fluorescence quenching dynamic curves similar to that of the commercialized SDHI fluxapyroxad. Additionally, research by molecular docking and MD simulations demonstrated that compound B19 had a similar binding mode acting on the surrounding residues in the SDH active pocket to that offluxapyroxad., Conclusion: The above results demonstrated that heterocyclic amide derivatives containing a diphenylmethyl moiety are promising scaffolds for targeting SDH of fungi and provide valuable antifungal leads with the potential to develop new SDH inhibitors. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Objective: Given their neural crest origin, gingival mesenchymal stem cells (GMSCs) possess high neurogenic potential, which makes them suitable for cell replacement therapy against neurodegenerative diseases. This study investigated whether GMSCs can be transdifferentiated into neurons in vitro using a protocol involving small molecules VCRFY (VPA, CHIR99021, Repsox, Forskolin, and Y-27632). The regulatory mechanisms of key signaling pathways were also investigated., Methods: Neuronal induction of GMSCs was conducted using a small molecules-based protocol over 7 days, which included the evaluation of cell morphology, proliferation, expressions of neurogenic markers, and intracellular calcium oscillation. The activation of canonical the Wnt signaling pathway was assessed by examining the protein content and subcellular localization of β-catenin., Results: Small molecules-treated GMSCs displayed neuronal morphology and increased expression of neurogenic markers, including class III beta-tubulin (TUJ1), neuron-specific enolase (NSE), microtube-associated protein 2 (MAP2), and neurofilament medium (NFM), verified through RT-qPCR, western blotting, and immunocytochemistry. Based on the results of Fluo-4 AM calcium flux assay, small molecules-treated GMSCs exhibited enhanced electrophysiological activity. GMSC proliferation halted after 2 days of treatment. Among the small molecules, CHIR99021 exhibited the highest neuronal induction efficiency. Furthermore, activation of the Wnt/β-catenin signaling pathway augmented neuronal differentiation., Conclusions: Small molecule-based cellular reprogramming can efficiently generate neurons from GMSCs, with Wnt/β-catenin signaling to play a critical role in neuronal induction., 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 Ltd.)

Background: A defence mechanism of the body includes inflammation. It is a process through which the immune system identifies, rejects, and starts to repair foreign and damaging stimuli. In the world, chronic inflammatory disorders are the leading cause of death., Materials and Methods: To obtain optimized pharmacophore, previously reported febuxostat- based anti-inflammatory amide derivatives series were subjected to pharmacophore hypothesis, ligand-based virtual screening, and 3D-QSAR studies in the present work using Schrodinger suite 2022-4. QuikProp module of Schrodinger was used for ADMET prediction, and HTVS, SP, and XP protocols of GLIDE modules were used for molecular docking on target protein (PDB ID:3LN1)., Result: Utilising 29 compounds, a five-point model of common pharmacophore hypotheses was created, having pIC 50 ranging between 5.34 and 4.871. The top pharmacophore hypothesis AHHRR&#95; 1 model consists of one hydrogen bond acceptor, two hydrophobic groups and two ring substitution features. The hypothesis model AHHRR&#95;1 underwent ligand-based virtual screening using the molecules from Asinex. Additionally, a 3D-QSAR study based on individual atoms was performed to assess their contributions to model development. The top QSAR model was chosen based on the values of R 2 (0.9531) and Q 2 (0.9424). Finally, four potential hits were obtained by molecular docking based on virtual screening., Conclusion: The virtual screen compounds have shown similar docking interaction with amino acid residues as shown by standard diclofenac sodium drugs. Therefore, the findings in the present study can be explored in the development of potent anti-inflammatory agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The Piperaceae family is distributed widely in tropical and subtropical areas. It encompasses around 5 genera and over 3000 species. They are distinguished by the substantial chemical diversity and potential medicinal applications. Amide alkaloids, as the main secondary metabolites in the Piperaceae family, exhibit various biological activities, and the discovery of [2 + 2] and [4 + 2] amide alkaloid dimers has led to a surge in phytochemical research on Piperaceae plants. Although the identification of these dimers has been gradually increasing in recent years, there remains a lack of comprehensive and systematic evaluations of these compounds. This review aims to summarize the latest advancements in the research on natural amide alkaloid dimers, focusing on their structural diversity, biological activities and biosynthetic pathways, and the enzymatic advances of [2 + 2] and [4 + 2] cyclase enzymes. Until October 2024, research has documented 99 amide alkaloid dimers, including 37 dimers possessing [2 + 2] cyclobutanes skeletons and 62 [4 + 2] cyclohexene skeletons derived from the Piperaceae family. These compounds demonstrate a range of in vitro biological activities including anti-inflammatory, anticancer, acetylcholinesterase inhibitory, anti-platelet aggregation, hepatoprotective, antimalarial, antitubercular, anti-diabetic and notable interactions with CYP3A4 and CYP2D6 enzymes. A systematic review of these [2 + 2] and [4 + 2] amide alkaloid dimers in Piperaceae family can provide a critical scientific foundation and theoretical support for the discovery and development of novel pharmaceutical agents., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this article., (Copyright © 2024. Published by Elsevier B.V.)

Palmitoylethanolamide (PEA) is emerging as a promising therapeutic agent for neuropathic and other pain-related conditions. This naturally occurring fatty acid has drawn interest because of its ability to regulate pain and inflammation. Initially identified in food sources, PEA has been the subject of extensive research to elucidate its properties, efficacy, and clinical applications. PEA primarily exerts its effects through interaction with its primary receptor PPAR α, this interaction influences pain signalling pathways and neuroinflammatory processes by modulating the synthesis of pro-inflammatory cytokines, mast cell degranulation, microglial activation, and decrease of oxidative stress. PEA's interaction with endocannabinoid receptors decreases the inflammatory cytokine and chemokine production and thereby a descending pain sensation. The pharmacological and pharmacokinetic characteristics of PEA are examined in this paper, along with its potential for efficiency when used in in combination additional therapies in a variety of neurodegenerative disease models, including multiple sclerosis, Parkinson's disease, and Alzheimer's. Experimental evidence shows that PEA not only reduces pain and inflammation but also lowers the need for higher dosages of other drugs hence minimizing the risk of drug toxicity. The bioavailability of PEA has been enhanced by recent technological developments, which emphasize continuous research efforts to maximize PEA's therapeutic potential in pain treatment and associated medical sectors., Competing Interests: Declarations. Conflict of interest: Authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The emergence of RNA viruses driven by global population growth and international trade highlights the urgent need for effective antiviral agents that can inhibit viral replication. Nucleoside analogs, which mimic natural nucleotides, have shown promise in targeting RNA-dependent RNA polymerases (RdRps). Starting from protected 5-iodouridine, we report the synthesis of hitherto unknown C5 -substituted-(1,3-diyne)-uridines nucleosides and their phosphoramidate prodrugs. The modifications at C5 include 4-(trifluoromethyl)benzene ( a ), 4-pentyl-benzene ( b ), 3,5-dimethoxy-benzene ( c ), 4-(trifluoromethoxy)benzene ( d ), 3-aniline ( e ), 4-pyridine ( f ), 3-thiophene ( g ), C 6 H 13 ( h ), 2-pyrimidine ( i ), cyclopropyl ( j ), and phenyl ( k ) groups. These compounds were synthesized using Sonogashira palladium-catalyzed reactions and nickel-copper-catalyzed C-H activation between various alkynes, yielding between 25% and 67%. The antiviral activities of obtained compounds were measured through HTS against RNA viruses including influenza H1N1 and H3N2, human respiratory syncytial virus (RSV), SARS-CoV-2, Zika, hepatitis C virus (HCV), Hepatitis E virus (HEV), as well as against coronavirus (HCoV-229E). Unfortunately, none of them showed promising antiviral activity, with less than 85% inhibition observed in the cell viability screening of infected cells.

Pterygium is an ocular disease in which the conjunctival tissue invades the cornea. When the pterygium tissue reaches the pupillary region, the visual function of the patient is affected. Currently, surgical removal is the only effective treatment. However, the recurrence rate of pterygium after surgery can be high. Pterygium is also a health disparity issue since it is more prevalent in the Hispanic and Latino American population. In this study, we determined if the Rho kinase inhibitor can be used to prevent pterygium recurrence since its anti-fibrosis effects have been reported in other cell and tissue types. We cultured primary pterygium cells from pterygium tissues from Hispanic and Latino American, African American, Caucasian, and Asian donors, and used those cells for viability assays, scratch assays, migration assays, and immunostaining of F-actin, fibronectin, collagen I and α smooth muscle actin. We found that the Rho kinase inhibitor Y27632 decreased cell viability, wound healing, cell migration, as well as the expression of extracellular matrix and myofibroblast markers in cultured pterygium cells. We believe that Rho kinase inhibitors are a potential post-surgical treatment to prevent pterygium recurrence., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Butyric acid (BA) can potentially enhance the function of the intestinal barrier. However, the mechanisms by which BA protects the intestinal mucosal barrier remain to be elucidated. Given that the Ras homolog gene family, member A (RhoA)/Rho-associated kinase 2 (ROCK2)/Myosin light chain kinase (MLCK) signaling pathway is crucial for maintaining the permeability of the intestinal epithelium, we further investigated whether BA exerts a protective effect on epithelial barrier function by inhibiting this pathway in LPS-induced Caco2 cells. First, we aimed to identify the optimal treatment time and concentration for BA and Lipopolysaccharide (LPS) through a CCK-8 assay. We subsequently measured Trans-epithelial electrical resistance (TEER), FITC-Dextran 4 kDa (FD-4) flux, and the mRNA expression of ZO-1, Occludin, RhoA, ROCK2, and MLCK, along their protein expression levels, and average fluorescence intensity following immunofluorescence staining. We then applied the ROCK2 inhibitor Y-27632 and reevaluated the TEER, FD-4 flux, and mRNA, and protein expression of ZO-1, Occludin, RhoA, ROCK2, and MLCK, as well as their distribution in Caco2 cells. The optimal treatment conditions were determined to be 0.2 mmol/L BA and 5 μg/mL LPS for 24 hours. Compared with LPS treatment alone, BA significantly mitigated the reduction in the TEER, decreased FD-4 flux permeability, increased the mRNA expression of ZO-1 and Occludin, and normalized the distribution of ZO-1 and Occludin in Caco2 cells. Furthermore, BA inhibited the expression of RhoA, ROCK2, and MLCK, and normalized their localization within Caco2 cells. Following treatment with Y-27632, the epithelial barrier function, along with the mRNA and protein expression and distribution of ZO-1 and Occludin were further normalized upon inhibition of the pathway. These findings contribute to a deeper understanding of the potential mechanisms through which BA attenuates LPS-induced impairment of the intestinal epithelial barrier., Competing Interests: 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 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

TWIK-related acid-sensitive potassium channel 1 (TASK-1) is expressed ubiquitously across various tissues and plays a significant role in neural activity and anesthetic modulation, making it a crucial target for pharmaceutical research. The high conservation of binding site residues within the TASK family, particularly between TASK-1 and TASK-3, necessitates the development of selective inhibitors for TASK-1. In this study, we utilized a combination of structure-based drug design (SBDD) and ligand-based drug design (LBDD) approaches. Initially, several bisamide-centered molecules were designed using the program MolAICal, which is recognized for its ability to generate selective inhibitors containing bisamide segments, and conducted preliminary screening via molecular docking. Subsequently, 3D-QSAR models were developed for 56 bisamide derivatives targeting TASK-1 and TASK-3, with the models exhibiting robust predictive capabilities (TASK-1: Q 2 = 0.61, R 2 pred = 0.84; TASK-3: Q 2 = 0.60, R 2 pred = 0.71). Using these models, the candidate molecules were subjected to activity prediction and subsequent filtering. Ultimately, molecular dynamics simulations, coupled with free energy calculations, pinpointed two bisamide-core molecules with favorable ADMET properties as potential selective inhibitors for TASK-1. Furthermore, molecular dynamics simulations revealed the critical role of the key residue Leu122 in conferring selectivity to bisamide compounds for TASK-1 channel proteins.

Heat Shock Protein 90 (Hsp90) is responsible for the proper folding and maturation of ~400 client protein substrates, many of which are directly associated with the ten hallmarks of cancer. Hsp90 is a great target for cancer therapy including melanoma, since Hsp90 inhibition can disrupt multiple oncogenic pathways simultaneously. In this study, we report the synthesis and anti-proliferative activity manifested by a series of Hsp90 C-terminal inhibitors against mutant BRAF and wild-type BRAF melanoma cells. Furthermore, we explored structure-activity relationships (SAR) for the amide moiety of 6 (B1), a novel Hsp90C-terminal inhibitor via introduction of amide bioisosteres. Compound 6 displayed an IC 50 of 1.01 μM, 0.782 μM, 0.607 μM and 1.413 μM against SKMel173, SKMel103, SKMel19 and A375 cells, respectively., (© 2024 Wiley-VCH GmbH.)

Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC 50 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype., 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 Masson SAS.. All rights reserved.)

Menopause leads to a decline in estrogen levels, resulting in significant metabolic alterations that increase the risk of developing metabolic syndrome-a cluster of conditions including central obesity, insulin resistance, dyslipidemia, and hypertension. Traditional interventions such as hormone replacement therapy carry potential adverse effects, and lifestyle modifications alone may not suffice for all women. This review explores the potential role of palmitoylethanolamide (PEA), an endogenous fatty acid amide, in managing metabolic syndrome during the postmenopausal period. PEA primarily acts by activating peroxisome proliferator-activated receptor-alpha (PPAR-α), influencing lipid metabolism, energy homeostasis, and inflammation. Evidence indicates that PEA may promote the browning of white adipocytes, enhancing energy expenditure and reducing adiposity. It also improves lipid profiles by boosting fatty acid oxidation and decreasing lipid synthesis, potentially lowering low-density lipoprotein cholesterol and triglyceride levels while increasing high-density lipoprotein cholesterol. Additionally, the anti-inflammatory properties of PEA enhance insulin sensitivity by reducing pro-inflammatory cytokines that interfere with insulin signaling. PEA may aid in weight management by influencing appetite regulation and improving leptin sensitivity. Furthermore, its neuroprotective effects may address the mood disturbances and cognitive decline associated with menopause. Given these multifaceted biological activities and a favorable safety profile, PEA may represent a promising non-pharmacological supplement for managing metabolic syndrome in postmenopausal women. However, further large-scale clinical studies are necessary to establish its efficacy, optimal dosing, and long-term safety. If validated, PEA could become an integral part of strategies to improve metabolic and neuropsychological health outcomes in this population.

2-(Methylthio)- N -(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide 1 was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC 50 = 0.6 μM; EC 90 = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC 50 = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure-activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of 1 led to the discovery of a new potent inhibitor N -(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide 26 , which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC 90 of 0.45 μM with considerably improved MLM stability ( t 1/2 = 74 min) as compared to 1 . Mechanism of action studies show that 26 inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The in vivo efficacy studies of compound 26 on CHIKV infection in mice are reported.

Histone deacetylase inhibitors (HDACi) are established anticancer drugs, especially in hematological cancers. This study aimed to design, synthesize, and evaluate a set of HDACi featuring a pentyloxyamide connecting unit linker region and substituted phenylthiazole cap groups. A structural optimization program yielded HDACi with nanomolar inhibitory activity against histone deacetylase class I/IIb enzymes. The novel inhibitors ( 4d and 4m ) showed superior antileukemic activity compared to several approved HDACi. Furthermore, 4d and 4m displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for 4d with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, 4d demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, 4d effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of 4d and 4m to the catalytic domain 2 of HDAC6 from Danio rerio were determined by X-ray crystallography.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2), a critical regulator of proliferation pathways and immune checkpoint signaling in various cancers, is an attractive target for cancer therapy. Here, we report the discovery of a novel series of substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors. Among them, compound C6 showed excellent inhibitory activity against SHP2 and antiproliferative effect on MV-4-11 cell line with IC 50 values of 0.13 and 3.5 nM, respectively. Importantly, orally administered C6 displayed robust in vivo antitumor efficacy in the MV-4-11 xenograft mouse model (TGI = 69.5 %, 30 mg/kg). Subsequent H&E and Ki67 staining showed that C6 significantly suppressed the proliferation of tumor cells. Notably, flow cytometry, ELISA and immunofluorescence experiments showed that C6 remarkably decreased the population of CD206 + /Ly6C + M2-like tumor-associated macrophages (TAMs), the expression level of interleukin-10 (IL-10), and the number of F4/80 + /CD206 + M2-like TAMs, suggesting that C6 could effectively alleviate the activation and infiltration of M2-like TAMs. Taken together, these results illustrate that C6 is a promising SHP2 inhibitor worthy of further development., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

To facilitate the development of novel agricultural succinate dehydrogenase inhibitor (SDHI) fungicides, we synthesized three series of derivatives by introducing phenyl pyrazole fragments into the structure of pyrazol-4-yl amides. The results of the bioactivity assay showed that most of the target compounds possessed varying degrees of inhibitory activity against the tested fungi. At a concentration of 100 mg/L, the compound B8 exhibited effective protective activity against S. sclerotiorum in vivo. Molecular docking analysis and succinate dehydrogenase (SDH) inhibition assay indicated that B8 was not a potential SDHI. The preliminary antifungal mechanism of studies showed that B8 induced a large amount of reactive oxygen species (ROS) and severe lipid peroxidation damage in S. sclerotiorum mycelium, resulting in mycelial rupture and disruption of the integrity of the cell membrane and leakage of soluble proteins, soluble sugars and nucleic acids. Further transcriptome analysis showed that compound B8 blocked various metabolic pathways by downregulating the differentially expressed genes (DEGs) catalase, disrupting hydrogen peroxide hydrolysis, accelerating membrane oxidative damage, and upregulating neutral ceramidase, accelerating sphingolipid metabolism to disrupt cell membrane structure and cell proliferation and differentiation, potentially accelerating cell death. The above results indicated that the potential target of these dis-pyrazole carboxamide derivatives may be the cell membrane of pathogenic fungi., 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.)

Background and Aims: The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF 1 ) agonist, cortagine., Methods: Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl-ethanolamide, AEA), oleoyl-ethanolamide (OEA) and palmitoyl-ethanolamide (PEA)], and 2-AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine., Key Results: URB597 inhibited cortagine-induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2-AG did not change. URB597 did not modify cortagine-induced defecation/diarrhea versus vehicle., Conclusions and Inferences: URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF 1 signaling supporting a potential strategy of FAAH inhibitors to alleviate stress-related visceral hypersensitivity., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Metabolic dysfunction-associated fatty liver disease (MAFLD) and diabesity (diabetes related to obesity) are interrelated since glucose and lipid alterations play a vital role in the development of both disorders. Due to their multi-variant metabolic features, more than one drug or natural product may be required to achieve proper therapeutic effects. This study aimed to evaluate the effectiveness of a formulation containing co-micronized palmitoylethanolamide and rutin (PEA-Rut) associated with hydroxytyrosol (HT), namely NORM3, against hepatic damage and metabolic alterations in high-fat diet (HFD)-induced diabesity in mice. NORM3 decreased the body weight and fat mass of obese mice. The formulation improved HFD-altered insulin sensitivity and hepatic glucose production and metabolism, as shown by glucose, insulin, pyruvate tolerance tests, Western blot, and real-time PCR. In the liver, NORM3 limited macro- and micro-vacuolar steatosis, as revealed by morphological analysis, and reduced the associated hepatic inflammation. NORM3 counteracted lipid dysfunctions of HFD animals, activating AMPK, a key cellular energy sensor, and normalizing the expression of carnitine palmitoyl-transferase (CPT)1, a rate-limiting enzyme of fatty acid β-oxidation, and other genes involved in lipid homeostasis. Relevantly, the hepatic antioxidant activity of NORM3 was proved (reduced ROS and increased detoxifying factors and enzymes). Finally, in vitro synergistic protective effects of the components (PEA-Rut and HT) on H 2 O 2 -induced oxidative challenge in HepG2 were determined (ROS production, inflammation, and antioxidant defense). Our results show the beneficial effect of NORM3 and its potential as an innovative phytotherapeutic combination in limiting hepatic damage progression and counteracting glucose and lipid dysmetabolism associated with diabesity., (© 2024 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

Introduction: Strenuous eccentric exercise (EE) induces microstructural muscle damage, which decreases muscle performance. Palmitoylethanolamide (PEA) exerts analgesic and anti-inflammatory effects in clinical pain conditions and preclinical models of experimentally induced inflammation. This might hold clues for improved recovery from EE. Therefore, the current study evaluates the effect of PEA supplementation on functional and molecular responses to a single EE bout., Methods: Eleven healthy male participants were included in a double-blind crossover study in which they received PEA (350 mg Levagen+) or placebo (maltodextrin) supplements, in a randomized order. In each experimental condition, participants performed an acute bout of EE (24 × 10 eccentric contractions of the knee extensors on an isokinetic dynamometer). At baseline, 24 (D1), 48 (D2), 72 (D3), and 120 h (D5) following EE, maximal voluntary contraction and jump height were measured. Blood samples were collected at baseline and on D1-D5, and muscle biopsies were collected at baseline and on D2. Perceived muscle soreness, sleep quality, and food intake were recorded daily., Results: Muscle strength and jump height decreased following EE (up to ~40% and ~17%, respectively; Ptime < 0.05) in both conditions. This drop was accompanied by an increase in plasma creatine kinase and perceived muscle soreness ( Ptime < 0.05). Furthermore, EE, but not PEA, increased the expression of the myogenic marker Pax7 and of the catabolic markers p-FoxO1-3a, p62, and LC3BII/I ( Ptime < 0.05)., Conclusions: PEA supplementation does not improve muscle soreness, muscle strength, and jump performance following a single EE bout. In addition, PEA supplementation had no effect on local or systemic markers of muscle damage, catabolism, or regeneration., (Copyright © 2024 by the American College of Sports Medicine.)

Objectives: This study aimed to investigate the effects of Y-27632 on the long-term maintainence of mouse submandibular epithelial cells (SG-Epis) in vitro and to elucidate the underlying mechanisms., Methods: The role of the Rho-associated kinase (ROCK) inhibitor Y-27632 in maintaining SG-Epis and its underlying mechanisms were evaluated by examining the in vitro expansion of mouse SG-Epis. Changes in key cellular characteristics, such as proliferation, long-term expansion, and mRNA and protein expression, were assessed in the presence or absence of Y-27632., Results: Treatment with Y-27632 significantly enhanced the proliferative potential of SG-Epis, preserving Krt8 and Krt14 expression over 17 passages. In the absence of Y-27632, SG-Epis lost their epithelial morphology. However, Y-27632 treatment maintained the epithelial morphology and downregulated mRNA levels of Tgf-β1, Ctgf, and Rock2. Treatment with TGF-β1 indicated that TGF-β/CTGF/p38 signaling is responsible for the maintenance of SG-Epis, while RNA interference studies revealed that ROCK2/c-Jun N-terminal kinase (JNK) signaling is also crucial for SG-Epis proliferation and maintenance., Conclusions: The TGF-β1/CTGF/p38 and ROCK2/JNK signaling pathways are responsible for SG-Epis proliferation, and Y-27632 treatment effectively inactivates these pathways, enabling long-term in vitro maintenance of SG-Epis. The culture method utilizing Y-27632 provides an effective approach for the in vitro expansion of SG-Epis., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to research, authorship, and publication of this article., (Copyright © 2024 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Breast cancer stands as the cancer with the highest incidence and mortality rates among women globally, in which triple-negative breast cancer has been ranked as the most difficult one. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), has been exhibited notable inhibitory effect on both hormone-dependent breast cancer cells and triple-negative breast cancer cells, but showing very low in vivo effeacy. In order to obtain more effective antitumor derivatives than BZA, we have employed a structurally diverse design and synthesis of 57 novel 2-phenylindole amides for detecting their cytotoxities against triple-negative mammary cancer cell line, CMT-7364. Among them, 21 compounds demonstrated significant inhibitory activity against CMT-7364 cells (IC 50  < 20 μM). Notably, compound 49 stood out, displaying both similar tumor cell inhibition (20 % reduce in IC 50 value) and higher selectivity (4.6 times higher in SI value), compared to Bazedoxifene. Additionally, compound 49 exhibited desirable antitumor effects in a CMT-7364 cell-derived mouse in vivo model, achieving the best inhibition rate of 43.1 % and establishing strong molecular bonding with GP130. Our findings are also supported by comprehensive SAR and 3D-QSAR analyses. Furthermore, the best potent compound 49 was determined to block the cell cycle of canine breast cancer cells in the G0G1 phase in a time-dependent manner, by inducing apoptosis and autophagy. In conclusion, this work presents a valuable lead compound as a potential GP130 inhibitor against triple-negative breast cancer cell lines, laying the foundation for further antitumor drug 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.)

Tyrosinase is an enzyme involved in melanin production. To identify inhibitors of this enzyme in natural products, extracts and fractions of hemp seed husk were screened for tyrosinase inhibition. Phenylpropionamides 1-9, which were isolated from the ethyl acetate fraction, had inhibitory effects; compounds 3 and 4 had the greatest inhibitory effects. Cannabisin A (3) was a non-competitive and cannabisin B (4) was a competitive inhibitor. The binding sites and interactions of each inhibitor on tyrosinase were calculated by computational chemistry. Potential inhibitor 3 decreased the melanin content and tyrosinase activity in B16F10 melanoma cells. Therefore, cannabisin A (3) has potential as a tyrosinase inhibitor., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jang Hoon Kim reports administrative support was provided by Rural Development Administration., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inflammatory bowel disease (IBD) is a clinically heterogeneous disease demanding more therapeutic targets and intervention strategies. Vanin-1, an oxidative stress-regulating protein, has emerged as a promising target for alleviating inflammation and oxidative stress. In this study, a series of thiazole carboxamide derivatives as vanin-1 inhibitors were designed and synthesized. The preferred compound, X17 , demonstrated potent inhibition against vanin-1 at the protein, HT-29 cell, and tissue levels, whose binding mode with the target was confirmed via the cocrystal structure. X17 achieved a high bioavailability of 81% in rats, accompanied by concentration-dependent inhibition of serum vanin-1. In a DSS-induced mouse colitis model, X17 exhibited potent anti-inflammatory and antioxidant activities, repressing the inflammatory factor expressions and myeloperoxidase activity, elevating the colonic glutathione reserve, and restoring the intestinal barrier. Collectively, these findings depict the discovery of a potent vanin-1 inhibitor, providing an opportunity for further drug candidate development for treating IBD.

Glucocorticoid-induced osteoporosis (GIOP) is the leading cause of iatrogenic osteoporosis due to the widespread clinical use of glucocorticoids (GC) as immunosuppressants. Previous research identified the proline-rich tyrosine kinase 2, Pyk2, as a critical mediator of GC-induced bone loss, and that blocking Pyk2 could protect the skeleton from adverse GC actions. However, systemic administration of current Pyk2 inhibitors causes harmful side effects, such as skin lesions. To address this, we developed bone-targeted (BT) Pyk2 inhibitors by conjugating them with bisphosphonates (BP), ensuring adherence to the bone matrix and reducing impact on noncalcified tissues. We synthesized BT-Amide by linking a derivative of TAE-226, a Pyk2 inhibitor, with alendronic acid. Oral administration (gavage) of BT-Amide prevented GC-induced bone loss in mice without causing skin lesions, or elevation of any organ toxicity markers. These findings introduce BT-Amide as the first orally effective bone-targeted Pyk2 inhibitor for preventing GC-induced bone loss while minimizing off-target effects.

In an effort to explore new-type high-efficiency antifungal agents, 25 novel L -carvone-based 1,3,4-thiadiazole-amide derivatives were designed, synthesized, and structurally characterized by IR, 1 H NMR, 13 C NMR, and high-resolution mass spectrometry (HRMS) analyses. The antifungal activity of the target compounds was preliminarily assayed at a concentration of 50 μg/mL, and boscalid, a commercialized fungicide identified as a succinate dehydrogenase inhibitor (SDHI), was employed as the positive control. It was found that all of the target compounds showed moderate to potent antifungal activity against the tested fungi compared to boscalid. Surprisingly, compound 4b exhibited broad-spectrum and significant inhibition activity against the growth of eight phytopathogenic strains with inhibitory rates of 67-89%. Further, the results of the EC 50 value test suggested that the EC 50 values of compound 4b against Physalospora piricola and Colletotrichum orbiculare were 16.33 and 18.06 μg/mL, respectively, and both of them were better than those of boscalid (16.64 and >50). Therefore, compound 4b deserves further study as a lead compound for novel fungicides. In addition, the inhibitory activity of compound 4b against succinate dehydrogenase (SDH) was evaluated as well to prove that compound 4b (IC 50 = 3.38 μM) displayed higher SDH-inhibition activity than boscalid (IC 50 = 7.02 μM). The binding mode of compound 4b and SDH was simulated by molecular docking and found to be similar to that of boscalid. The structure-activity relationships (SARs) of the target compounds were analyzed by establishing a 3D-QSAR model. Besides, a 4b -loaded complex 4b/CSTA on a reported L -carvone-based nanochitosan carrier CSTA containing the 1,3,4-thiadiazole-amide group was constructed, and its sustained release performance was investigated in the EtOH-H 2 O system (1:9, v/v). The complex 4b/CSTA exhibited preferred sustained release performance, indicating its potential for developing environmentally friendly nanofungicides.

Favipiravir (FVP) and remdesivir (RDV) have demonstrable antiviral activity against SARS-CoV-2. Here, the efficacy of FVP, RDV, and FVP with RDV (FVP + RDV) in combination was assessed in Syrian golden hamsters challenged with SARS-CoV- 2 (B.1.1.7) following intraperitoneal administration. At day 4 post infection, viral RNA and viral antigen expression were significantly lower in lungs for all three treatment groups compared to the sham treatment. Similarly, viral titres in the lungs were lower in all treatment groups compared to the sham treatment. The FVP + RDV combination was the only treatment group where viral RNA in nasal turbinate and lung, virus titres in lung, and viral antigen expression (lung) were all lower than those for the sham treatment group. Moreover, lower viral titre values were observed in the FVP + RDV group compared to other treatment groups, albeit only significantly lower in comparison to those in the RDV-only-treated group. Further assessment of the potential utility of FVP in combination with RDV may be warranted. Future studies should also consider whether the combination of these two drugs may reduce the speed at which drug resistance mutations are selected.

Succinate dehydrogenase inhibitors (SDHIs) have become one of the most important classes of agrochemical fungicides. According to the data from FRAC, the resistance risk for SDHIs had reached up to medium and even to high. In general, the chemical structure of SDHIs mainly contained three fragments: an acid core, a hydrophobic tail, and an amide linker, corresponding to three modification directions for each fragment. Among them, amide linker modification (ALM) has become a research hotspot for the design of novel SDHIs fungicides in recent years. We presented here a detailed review on the ALM strategy in the past decade, and some of them had entered the market. According to their chemical structures, ALM strategy were classified into four parts: (1) linked aliphatic chain between amide bond and hydrophobic tail, (2) introducing substituents to replacing hydrogen atom in the amide bond, (3) reverse extending the amide linker, and (4) changed with other bioisosteres. Moreover, the structure-activity relationship and the interaction mechanism of ALM-SDHI with SDH were discussed. This review aims to provide a global perspective on research and development of novel SDHIs, as well as suggestions for food safety management.