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Abstract In this work, the rapid and efficient preparation of isolated galloyl glucoside tautomer free radical inhibitors was investigated using Saxifraga tangutica as a raw material. Four highly polar galloyl glucoside tautomers, 3-O-galloyl-α-d-glucose ⇌ 3-O-galloyl-β-d-glucose (Fr2-1-1), 2-O-galloyl-α-d-glucose ⇌ 2-O-galloyl-β-d-glucose (Fr2-1-2/2-1-3), 1-O-galloyl-β-d-glucose (Fr2-2-1), and 6-O-galloyl-α-d-glucose ⇌ 6-O-galloyl-β-d-glucose (Fr2-3-1/Fr2-3-2), were obtained via two-step medium-pressure liquid chromatography (with solid loading instead of conventional liquid injection) and one-step high-performance chromatography coupled with on-line RPLC-DPPH techniques for targeted isolation. This separation integration technique not only increases sample intake and reduces time cost but also visualizes each step of targeted separation. All four compounds were isolated from the plant for the first time. In vitro antioxidant activity assays by DPPH (1,1‑diphenyl-2-picrylhydrazyl) revealed that Fr2-1-2/Fr2-1-3 (IC50: 5.52 ± 0.32 μM), Fr2-2-1 (IC50: 7.22 ± 0.57 μM), and Fr2-3–1/Fr2-3-2 (IC50: 7.36 ± 0.25 μM) had superior free radical scavenging abilities and that both were superior to that of quercetin (IC50: 18.61 ± 3.55 μM). Oxidative stress assays revealed that Fr2-1-2/Fr2-1-3 significantly inhibited oxidative stress damage in H2O2-induced HepG2 cells, decreased the level of ROS (P

Obesity is acknowledged as a significant risk factor for various metabolic diseases, and the inhibition of human pancreatic lipase (hPL) can impede lipid digestion and absorption, thereby offering potential benefits for obesity treatment. Anthraquinones is a kind of natural and synthetic compounds with wide application. In this study, the inhibitory effects of 31 anthraquinones on hPL were evaluated. The data shows that AQ7, AQ26, and AQ27 demonstrated significant inhibitory activity against hPL, and exhibited selectivity towards other known serine hydrolases. Then the structure-activity relationship between anthraquinones and hPL was further analysed. AQ7 was found to be a mixed inhibition of hPL through inhibition kinetics, while AQ26 and AQ27 were effective non-competitive inhibition of hPL. Molecular docking data revealed that AQ7, AQ26, and AQ27 all could associate with the site of hPL. Developing hPL inhibitors for obesity prevention and treatment could be simplified with this novel and promising lead compound.

Growing concerns about the environmental impact of ionic liquids (ILs) have spurred research into their (eco)toxic effects, but studies on their mode of toxic action (MOA) still remain limited. However, understanding the MOA and identifying structural features responsible for enhanced toxicity is crucial for characterising the hazard and designing safer alternatives. Therefore, 45 ILs, with systematically varied chemical structures, were tested for cytotoxicity and two specific endpoints in reporter gene assays targeting the Nrf2-ARE mediated oxidative stress response (AREc32) and aryl hydrocarbon receptor activation (AhR-CALUX). While none of the ILs activated the reporter genes, cytotoxicity was high and markedly different between cell lines. Seven and 25 ILs proved more cytotoxic than predicted by baseline toxicity model in the AREc32 and the AhR-CALUX assays, respectively. The length of the side chain and headgroup structures of ILs altered the MOA of ILs. Cellular metabolism of the ILs, investigated by LC-MS/MS, showed side-chain oxidation of the long-chain quaternary ammonium compounds in AhR-CALUX cells and, to a lower extent, in AREc32 cells, however, this transformation could not explain the high cytotoxicity. Effect data for 72 ILs for ten endpoints retrieved from the Tox21 database identified the inhibition of aromatase activity and of mitochondrial membrane potential as potential MOAs. However, in vitro fluorimetric assays for these endpoints demonstrated that effects were activated in a non-specific manner, probably through cytotoxicity. Although many of the ILs tested induced cytotoxicity at concentrations lower than baseline toxicity, the specific MOAs responsible could not be identified. Alternatively, we suggest that the descriptors currently used may fail to define the affinity of ILs for cells. Testing of the affinity of ILs for a diverse range of biomolecules is needed to accurately describe their interactions with cells.

Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity. We were able to enhance the in vitro activity and to maintain the specificity of the parent compound. We found the most active candidate to be quite stable in plasma, although it was metabolized by hepatic microsomes. This chemical probe should be useful for in vitro studies and needs to be tested for in vivo pharmacological activity. This could be an important lead toward the development of a first-in-class orally active agonist of the secretin receptor, which could be useful for multiple disease states.

Abstract Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure‐activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potentially improved efficacy and reduced toxicity against tumors. To realize the biosynthesis of the novel aglycone polyethers, the gene clusters and the post‐polyketide synthase tailoring pathways for aglycone polyethers endusamycin and lenoremycin are identified and subjected to combinatorial biosynthesis studies, resulting in the creation of a novel aglycone polyether termed End‐16, which demonstrates significant potential for treating bladder cancer (BLCA). End‐16 demonstrates the ability to suppress the proliferation, migration, invasion, and cellular protrusions formation of BLCA cells, as well as induce cell cycle arrest in the G1 phase in vitro. Notably, End‐16 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti‐BLCA drug cisplatin in vivo, thereby warranting further preclinical studies. This study highlights the significant potential of integrating combinatorial biosynthesis strategies with rational design to create unnatural products with enhanced pharmacological properties.

Most previous studies on the bioactive substances from the edible red macroalga (Bangia fuscopurpurea) have concentrated on the polysaccharides and proteins. We explored the possible effects of two phenolic acids (HBP2—3) and two derivatives (HBP1 and HBP4) originated from Bangia fuscopurpurea and two structural analogues in an in vitro model of Parkinson’s disease. We also performed in silico evaluation of the pharmacological potential of these six compounds. Our present study showed that HBP1—3 had neuroprotective effects. Moreover, HBP3 (10 nM) could protect SH-SY5Y cells from 6-hydroxydopamine (6-OHDA) damage via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) cascade, and the up-regulation of this pathway could inhibited reactive oxygen species (ROS) production. In addition, we speculated the preliminary structure–activity relationships on the neuroprotective effects of HBP1—3. This study demonstrated that neuroprotective effects of HBP1—3 originated from Bangia fuscopurpurea.

B-cell lymphoma 2 protein (Bcl-2) is an important regulator of cell apoptosis. Inhibitors that mirror the structural domain 3 (BH3) of Bcl-2 can activate apoptosis in cancer cells, making them a promising target for anticancer treatment. Hence, the present study aimed to investigate potential BH3-mimetic peptides from two vicilin-derived legume proteins from soybean and cowpea bean. The proteins were isolated and sequentially hydrolyzed with pepsin/pancreatin. Peptides < 3 kDa from vicilin-derived proteins from soybean and cowpea beans experimentally inhibited the growth of cultivated breast and prostate cancer cells. In silico analysis allowed the identification of six potential candidates, all predicted to be able to interact with the BH3 domain. The VIPAAY peptide from the soybean β-conglycinin β subunit showed the highest potential to interact with Bcl-2, comparable to Venetoclax, a well-known anticancer drug. Further experiments are needed to confirm this study’s findings.

Abstract Three‐way catalysts are widely used to control criterion pollutant emissions from the increasing gasoline engines. With the stringent requirements of automotive pollutant emission standards in various countries, Rh has become an irreplaceable component of three‐way catalysts due to its superior NOx elimination, high N2 selectivity, and simultaneous elimination of CO and hydrocarbons. In this review, we systematically review the recent development of Rh‐based three‐way catalysts in terms of potential supports and effective active center construction strategies. We further summarize the key role of Rh metal in the three‐way catalytic mechanism and reaction kinetics. Finally, we conclude the current challenges and future opportunities facing Rh‐based catalysts. It is believed that based on the deep understanding of Rh‐based three‐way catalysts, the design of Rh‐based catalysts with good low‐temperature catalytic performance and low cost is expected to be realized in the future.

Excessive oxidation can lead to inflammation and affect health. Studies have shown that ursolic acid (UA) and gallic acid are widely employed in medicine and cosmetics owing to their obvious antioxidant and anti-inflammatory properties. In this study, a series of 16 novel UA hybrids tethered via 1,2,3-triazole to the modified gallate moieties were synthesized via CuAAC 1,3-cycloaddition reactions. In vitro, all derivatives were proved to be effective in antioxidation and anti-inflammation activities. Interestingly, compound 20 significantly inhibited the expression of pro-inflammatory cytokines including mRNA of inducible nitric oxide synthase (iNOS) (p

ABSTRACTFoot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established serotypes. The prevailing preventive and control strategies are limited to restriction of animal movement and elimination of infected or exposed animals, which can be potentially combined with vaccination. However, FMD vaccination has limitations including delayed protection and lack of cross-protection against different serotypes. Recently, antiviral drug use for FMD outbreaks has increasingly been recognized as a potential tool to augment the existing early response strategies, but limited research has been reported on potential antiviral compounds for FMDV. FMDV 3C protease (3Cpro) cleaves the viral-encoded polyprotein into mature and functional proteins during viral replication. The essential role of viral 3Cpro in viral replication and the high conservation of 3Cpro among different FMDV serotypes make it an excellent target for antiviral drug development. We have previously reported multiple series of inhibitors against picornavirus 3Cpro or 3C-like proteases (3CLpros) encoded by coronaviruses or caliciviruses. In this study, we conducted structure-activity relationship studies for our in-house focused compound library containing 3Cpro or 3CLpro inhibitors against FMDV 3Cpro using enzyme and cell-based assays. Herein, we report the discovery of aldehyde and α-ketoamide inhibitors of FMDV 3Cpro with high potency. These data inform future preclinical studies that are related to the advancement of these compounds further along the drug development pathway.IMPORTANCEFood-and-mouth disease (FMD) virus (FMDV) causes devastating disease in cloven-hoofed animals with a significant economic impact. Emergency response to FMD outbreaks to limit FMD spread is critical, and the use of antivirals may overcome the limitations of existing control measures by providing immediate protection for susceptible animals. FMDV encodes 3C protease (3Cpro), which is essential for virus replication and an attractive target for antiviral drug discovery. Here, we report a structure-activity relationship study on multiple series of protease inhibitors and identified potent inhibitors of FMDV 3Cpro. Our results suggest that these compounds have the potential for further development as FMD antivirals.

Diabetes mellitus has become one of the most serious chronic diseases all over the world, which need to be to prevented, intervened, regulated by innovative means. Food derived small peptides can regulate blood glucose by acting with receptors, enzymes, biological molecules and glucose transporters. They show high tissue affinities, significant specificities, with low side effects, which are promising strategies for diabetes mellitus. This survey summarizes the mechanisms, food protein sources, preparation and activity evaluation procedures, structure-activity relationships and challenges during commercial development of food derived blood glucose regulating peptides. Specifically, it includes the sequence characteristics of DPP-IV inhibitory peptide, α-glucosidase inhibitory peptides and α-amylase inhibitory peptides. Besides, the active sites are also discussed from different perspectives of sequence alignment: bioinformatics technologies such as in silico analysis, molecular structure alignment/docking, and quantitative structure activity relationship analysis. It may provide ideas for future research: a. Exploring the mechanism from the aspect of cell pathways and metabonomic to improve in vivo efficacy. b. Combining cell/animal experiments with clinical trials to evaluate digestive stability, bioavailability and safety. c. Innovative carriers to improve the solubility, stability and permeability of peptides. Supports for promoting the industrial application of diabetes functional foods are expected.

Protein–protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.

Background: Strongyloidiasis, a parasitic infection, presents a significant public health challenge in tropical regions due to the limited repertoire of effective treatments. The screening of chemical libraries against the therapeutically relevant third-stage larvae (L3) of the model parasite Strongyloides venezuelensis yielded meager success rates. This situation is reminiscent of Gram-negative bacteria, where drug entry is a limiting factor. Methods: Here, we set out to determine whether similar barriers are in place and establish whether structural and property requirements exist for anti-strongyloides drug discovery. We focused on dyes as their uptake and effects on viability can be independently assessed in the multicellular parasite, thus providing a means to study the possibility of similar entry rules. We tested different dyes in in vitro assays on L3s. Results: We found that staining was necessary to reduce parasite viability, with some dyes achieving anti-strongyloides effects at concentrations similar to those of the reference drug, ivermectin (IV). Some dyes also showed activity against female adults at concentrations well below that of ivermectin. Unfortunately, the most potent dye, Methylene Blue, was unable to prevent the infection in a preliminary in vivo mouse model assay, presumably due to fast dye clearance. Structural analysis showed that positive charges facilitated the access of the compounds to the L3 tissue, thus providing a structural tool for the introduction of activity. For female adults, low globularity is additionally required. As a proof of concept, we added a positive charge to an inactive compound of one of our chemical libraries and re-determined the activity. Conclusions: These findings allow us to establish structural rules for parasite entry that could be of interest for future drug screening or drug development campaigns. These rules might also be applicable to other related parasites.

Kainoid synthases are key enzymes in the biosynthesis of kainoids. Kainoids, as represented by DA and KA, are a class of naturally occurring non-protein amino acids with strong neurotransmitter activity in the mammalian central nervous system. Marine algae kainoid synthases include PnDabC from diatoms, which synthesizes domoic acid (DA), and DsKabC and GfKabC from red algae, which synthesize kainic acid (KA). Elucidation of the catalytic mechanism of kainoid synthases is of great significance for the rational design of better biocatalysts to promote the industrial production of kainoids for use in new drugs. Through modeling, molecular docking, and molecular dynamics simulations, we investigated the conformational dynamics of kainoid synthases. We found that the kainoid synthase complexes showed different stability in the simulation, and the binding and catalytic processes showed significant conformational transformations of kainoid synthase. The residues involved in specific interactions with the substrate contributed to the binding energy throughout the simulation process. Binding energy, the relaxed active pocket, electrostatic potential energy of the active pocket, the number and rotation of aromatic residues interacting with substrates during catalysis, and the number and frequency of hydrogen bonds between the individual functional groups revealed the structure–activity relationships and affected the degree of promiscuity of kainoid synthases. Our research enriches the understanding of the conformational dynamics of kainoid synthases and has potential guiding significance for their rational design.

Highlights Density functional theory calculations indicates that interstitial B atoms can tune the atomic spacing of host metal Os and achieve a reversal hydrogen adsorption-distance relationship. The structure–activity relationship between the spacing of active Os atoms and catalytic activity is established. Prepared OsB2 with increasing dOs-Os of 2.96 Å presents the optimal hydrogen evolution reaction activity (8 mV @ 10 mA cm−2) and robust stability in alkaline media.

Abstract This review examines the role of defective carbon‐based electrodes in sodium‐ion and vanadium flow batteries. Methods for introducing defects into carbon structures are explored and their effectiveness in improving electrode performance is demonstrated. In sodium‐based systems, research focuses primarily on various precursor materials and heteroatom doping to optimise hard carbon electrodes. Defect engineering increases interlayer spacing, porosity, and changes the surface chemistry, which improves sodium intercalation and reversible capacities. Heteroatom functionalisation and surface modification affect solid electrolyte interface formation and coulombic efficiencies. For flow batteries, post‐fabrication electrode enhancement methods produce defects to improve electrode kinetics, although these methods often introduce oxygen functional groups as well, making isolation of defect effects difficult. Continued research efforts are key to developing carbon‐based electrodes that can meet the unique challenges of future battery systems.

Pancreatic cancer is a highly aggressive disease with a poor prognosis. Its tumor microenvironment is characterized by severe nutrient deprivation and hypoxia, leading to the activation of adaptive pathways that allow cancer cells to survive and thrive under these harsh conditions. This makes conventional therapies less effective, highlighting the urgent need for novel treatment strategies. Naphthoquinones have recently emerged as promising anti-austerity agents, demonstrating preferential cytotoxicity against pancreatic cancer cells in nutrient-deprived medium (NDM). To further explore their potential, we investigated the structure–activity relationships and mechanism of action of a library of 28 natural and synthetic naphthoquinones. Our results reveal a significant influence of functional groups at positions C-2, C-3, C-5, and C-6 on anticancer activity. Strong electron-donating substituents at C-3 decreased the activity, while electron-withdrawing groups at C-3 and H-bond acceptors at C-6 (without H-bond donor activity) increased the potency. The naphthoate esters 4 and 5 exhibited the strongest activity against PANC-1 cells, with PC50 values of 0.87 and 0.42 μM, respectively. These compounds significantly altered cancer cell morphology, induced apoptosis, and inhibited colony formation. Further investigation revealed that compound 5 downregulated the expression of Akt and p-Akt(S473) proteins, suggesting that its anti-austerity activity might involve suppression of the Akt signaling pathway. These findings demonstrate the immense potential of naphthoquinones as novel anticancer agents targeting the austerity-adapted pancreatic cancer cells. Further development of these promising compounds holds significant potential for treating this devastating disease.

Aconitine (AC), which is the primary bioactive diterpene alkaloid derived from Aconitum L plants, have attracted considerable interest due to its unique structural feature. Additionally, AC demonstrates a range of biological activities, such as its ability to enhance cardiac function, inhibit tumor growth, reduce inflammation, and provide analgesic effects. However, the structure-activity relationships of AC are remain unclear. A clear understanding of these relationships is indeed critical in developing effective biomedical applications with AC. In line with these challenges, this paper summarized the structural characteristics of AC and relevant functional and bioactive properties and the structure-activity relationships presented in biomedical applications. The primary temporal scope of this review was established as the period spanning from 2010 to 2023. Subsequently, the objective of this review was to provide a comprehensive understanding of the specific action mechanism of AC, while also exploring potential novel applications of AC derivatives in the biomedical field, drawing upon their structural characteristics. In conclusion, this review has provided a comprehensive analysis of the challenges and prospects associated with AC in the elucidation of structure-bioactivity relationships. Furthermore, the importance of exploring modern biotechnology approaches to enhance the potential biomedical applications of AC has been emphasized.

In heterogeneous catalysis, operando measurements probe catalysts in their active state and are essential for revealing complex catalyst structure–activity relationships. The development of appropriate operando sample environments for spatially resolved studies has come strongly into focus in recent years, particularly when coupled to the powerful and multimodal characterization tools available at synchrotron light sources. However, most catalysis studies at synchrotron facilities only measure structural information about the catalyst in a spatially resolved manner, whereas gas analysis is restricted to the reactor outlet. Here, a fully automated and integrated catalytic profile reactor setup is shown for the combined measurement of temperature, gas composition and high-energy X-ray diffraction (XRD) profiles, using the oxidative dehydrogenation of C2H6 to C2H4 over MoO3/γ-Al2O3 as a test system. The profile reactor methodology was previously developed for X-ray absorption spectroscopy and is here extended for operando XRD. The profile reactor is a versatile and accessible research tool for combined spatially resolved structure–activity profiling, enabling the use of multiple synchrotron-based characterization methods to promote a knowledge-based optimization of a wide range of catalytic systems in a time- and resource-efficient way.

Porphyromonas gingivalis is crucial for the pathogenesis of periodontitis. This research investigated the effects of the fruit-derived flavonoid phloretin and its analogs on the growth of pure P. gingivalis and the flora of P. gingivalis mixed with the symbiotic oral pathogens Fusobacterium nucleatum and Streptococcus mitis. The results showed that the tested flavonoids had little effect on the biofilm amount of pure P. gingivalis, but significantly reduced the biofilm amount of mixed flora to 83.6~89.1%. Biofilm viability decreased to 86.7~92.8% in both the pure- and mixed-bacterial groups after naringenin and phloretin treatments. SEM showed that phloretin and phlorizin displayed a similar and remarkable destructive effect on P. gingivalis and the mixed biofilms. Transcriptome analysis confirmed that biofilm formation was inhibited by these flavonoids, and phloretin significantly regulated the transcription of quorum sensing. Phlorizin and phloretin reduced AI-2 activity to 45.9% and 55.4%, respectively, independent of the regulation of related gene transcription. This research marks the first finding that these flavonoids possess anti-biofilm properties against P. gingivalis and its intricate bacterial community, and the observed performance variations, driven by structural differences, underscore the existence of intriguing structure–activity relationships.

Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of N-hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg2+ ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC50 values in the low μM range (1.1–7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure–activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents.

Abstract Surface activation can increase the sensitivity of carbon electrodes for electrochemical detection of neurotransmitters, such as dopamine (DA). However, fully understanding the changes in DA behavior after electrode activation remains elusive. Herein, we use scanning electrochemical cell microscopy (SECCM) to investigate DA adsorption and electrochemistry on glassy carbon (GC) after anodization in alkaline media. Through localized microscale anodization to different extents (two distinct times and same potential), followed by spatially‐resolved SECCM, we achieve direct visualization of DA electrochemistry across unmodified and anodized GC regions, with complementary microscopy and spectroscopy unraveling the effects of co‐located carbon surface chemistry and structure. Our findings reveal that short anodization times (60 s) enhance DA adsorption, rapidly reaching nearly complete monolayer coverage. Longer anodization (300 s) induces further changes in electrochemical surface area so that although the DA surface concentration increased based on geometric area, it was smaller based on specific surface area. This work highlights that even small differences in surface properties after activation can significantly impact electrode performance for neurotransmitter sensing, and separating the individual contribution of chemical and topographical factors remains challenging. SECCM provides an excellent platform to assess activation methods in a high throughput format to help accelerate the discovery of optimal modified electrodes.

A series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. In vitro antifungal activity studies demonstrated that most of the compounds inhibited the growth of six human pathogenic fungi. In particular, parts of phenyl-propionamide-containing compounds had excellent, broad-spectrum antifungal activity against Candida albicans SC5314, Cryptococcus neoformans 22-21, Candida glabrata 537 and Candida parapsilosis 22-20 with MIC values in the range of ≤0.125 µg/mL–4.0 µg/mL. In addition, compounds A1, A2, A6, A12 and A15 showed inhibitory activities against fluconazole-resistant Candida albicans and Candida auris. Preliminary structure-activity relationships (SARs) are also summarised. Moreover, GC-MS analysis demonstrated that A1, A3, and A9 interfered with the C. albicans ergosterol biosynthesis pathway by inhibiting Cyp51. Molecular docking studies elucidated the binding modes of A3 and A9 with Cyp51. These compounds with low haemolytic activity and favourable ADME/T properties are promising for the development of novel antifungal agents.

In this study, the in vitro DNA-binding interactions of the food/drug additive, 5-hydroxymethylfurfural (HMF) and its major degradant, 5, 5'[oxy-bis(methylene)]bis-2-furfural (OBMF) were investigated. OBMF was synthesized and characterized using IR, NMR and mass spectrometry. Photometric titrations revealed OBMF induced more extensive perturbations in the 258 nm band of DNA and exhibited binding constants that were 5–12-folds higher than those of HMF. The greatest net changes in viscosity of DNA induced by HMF and OBMF were 10.5 and 8.9%, respectively which confirmed both compounds as minor groove binders. Docking revealed that OBMF and HMF bound to the guanine–cytosine regions of minor groove of DNA with global binding energies of −36.36 and −26.12 kcal/mol, respectively. DFT calculations revealed the higher electrophilicity of OBMF contributed to its increased interaction with the negatively charged DNA backbone. There is a need for stricter control of permissible levels of OBMF in food and drug products.

Avermectins, a fermentation-derived macrocyclic lactones isolated from Streptomyces avermitilis, exhibiting a long history as biopharmaceuticals used in agriculture, medical and veterinary fields. Due to the significant biological activity and low mammalian toxicity, avermectins have been recognized as one of the most market-competitive anthelmintics and insecticides, with research related to these compounds has been awarded the 2015 Nobel Prize in Physiology or Medicine. Avermectin molecules contain multiple reaction sites, such as carbon-carbon double bonds, hydroxyl groups and oleandrose, facilitating the further development of derivatives with improved physicochemical properties, bioavailability, pest spectrum, and efficacy by chemical modification. Presently, thousands of avermectin derivatives have been studied and various species have been commercialized for crop protection and pharmaceutical use. Herein, we review the research progress achieved on structural modification reactions of avermectin and further summarize their structure-activity relationships. This mini-review may provide important insights into the future development of efficient avermectin-based anthelmintics, fungicides, and insecticides.

To discover new lead compounds with anti-tumour activities, in the present study, natural diosgenin was hybridised with the reported benzoic acid mustard pharmacophore. The in vitro cytotoxicity of the resulting newly synthesised hybrids (8–10, 14a–14f, and 15a–15f) was then evaluated in three tumour cells (HepG2, MCF-7, and HeLa) as well as normal GES-1 cells. Among them, 14f possessed the most potential anti-proliferative activity against HepG2 cells, with an IC50 value of 2.26 µM, which was 14.4-fold higher than that of diosgenin (IC50 = 32.63 µM). Furthermore, it showed weak cytotoxicity against GES-1 cells (IC50 > 100 µM), thus exhibiting good antiproliferative selectivity between normal and tumour cells. Moreover, 14f could induce G0/G1 arrest and apoptosis of HepG2 cells. From a mechanistic perspective, 14f regulated cell cycle-related proteins (CDK2, CDK4, CDK6, cyclin D1 and cyclin E1) as well mitochondrial apoptosis pathway-related proteins (Bax, Bcl-2, caspase 9, and caspase 3). These findings suggested that hybrid 14f serves as a promising anti-hepatoma lead compound that deserves further research.

Toxicity and pharmacological activity scales of molecules, in particular toxicants, xenobiotics, drugs, nutraceuticals, etc., are described by multiples indicators, and the most popular is the median lethal dose (LD50). At the molecular level, reversible inhibition or binding constants provide unique information on the potential activity of molecules. The important problem concerning the meaningfulness of IC50 for irreversible ligands/inhibitors is emphasized. Definitions and principles for determination of these quantitative parameters are briefly introduced in this article. Special attention is devoted to the relationships between these indicators. Finally, different approaches making it possible to link pharmacological and toxicological properties of molecules in terms of molecular interactions (or chemical reactions) with their biological targets are briefly examined. Experimental trends for future high-throughput screening of active molecules are pointed out.

Nuciferine aporphine alkaloid mainly exists in Nelumbo nucifera Gaertn and is a beneficial to human health, such as anti-obesity, lowering blood lipid, prevention of diabetes and cancer, closely associated with inflammation. Importantly, nuciferine may contribute to its bioactivities by exerting intense anti-inflammatory activities in multiple models. However, no review has summarized the anti-inflammatory effect of nuciferine. This review critically summarized the information regarding the structure-activity relationships of dietary nuciferine. Moreover, biological activities and clinical application on inflammation-related diseases, such as obesity, diabetes, liver, cardiovascular diseases, and cancer, as well as their potential mechanisms, involving oxidative stress, metabolic signaling, and gut microbiota has been reviewed. The current work provides a better understanding of the anti-inflammation properties of nuciferine against multiple diseases, thereby improving the utilization and application of nuciferine-containing plants across functional food and medicine.

Natural bioactive compounds are valuable resources for drug discovery due to their diverse and unique structures. However, these compounds often lack optimal drug-like properties. Therefore, structural optimization is a crucial step in the drug development process. By employing medicinal chemistry principles, targeted molecular operations can be applied to natural products while considering their size and complexity. Various strategies, including structural fragmentation, elimination of redundant atoms or groups, and exploration of structure-activity relationships, are utilized. Furthermore, improvements in physicochemical properties, chemical and metabolic stability, biophysical properties, and pharmacokinetic properties are sought after. This article provides a concise analysis of the process of modifying a few marketed drugs as illustrative examples.

µ-Conotoxins are small, potent pore-blocker inhibitors of voltage-gated sodium (NaV) channels, which have been identified as pharmacological probes and putative leads for analgesic development. A limiting factor in their therapeutic development has been their promiscuity for different NaV channel subtypes, which can lead to undesirable side-effects. This review will focus on four areas of µ-conotoxin research: (1) mapping the interactions of µ-conotoxins with different NaV channel subtypes, (2) µ-conotoxin structure–activity relationship studies, (3) observed species selectivity of µ-conotoxins and (4) the effects of µ-conotoxin disulfide connectivity on activity. Our aim is to provide a clear overview of the current status of µ-conotoxin research.

Molecular recognition is fundamental in biology, underpinning intricate processes through specific protein–ligand interactions. This understanding is pivotal in drug discovery, yet traditional experimental methods face limitations in exploring the vast chemical space. Computational approaches, notably quantitative structure–activity/property relationship analysis, have gained prominence. Molecular fingerprints encode molecular structures and serve as property profiles, which are essential in drug discovery. While two-dimensional (2D) fingerprints are commonly used, three-dimensional (3D) structural interaction fingerprints offer enhanced structural features specific to target proteins. Machine learning models trained on interaction fingerprints enable precise binding prediction. Recent focus has shifted to structure-based predictive modeling, with machine-learning scoring functions excelling due to feature engineering guided by key interactions. Notably, 3D interaction fingerprints are gaining ground due to their robustness. Various structural interaction fingerprints have been developed and used in drug discovery, each with unique capabilities. This review recapitulates the developed structural interaction fingerprints and provides two case studies to illustrate the power of interaction fingerprint-driven machine learning. The first elucidates structure–activity relationships in β2 adrenoceptor ligands, demonstrating the ability to differentiate agonists and antagonists. The second employs a retrosynthesis-based pre-trained molecular representation to predict protein–ligand dissociation rates, offering insights into binding kinetics. Despite remarkable progress, challenges persist in interpreting complex machine learning models built on 3D fingerprints, emphasizing the need for strategies to make predictions interpretable. Binding site plasticity and induced fit effects pose additional complexities. Interaction fingerprints are promising but require continued research to harness their full potential.

Abstract 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) represents a promising drug target for metabolic syndrome, including obesity and type 2 diabetes. Our initial screen of a collection of natural products from Danshen led to the identification of tanshinones as the potent and selective 11β-HSD1 inhibitors. To improve the druggability and explore the structure–activity relationships (SARs), more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials. More than 10 derivatives exhibited potent in vitro 11β-HSD1 inhibitory activity and good selectivity over 11β-HSD2 across human and mouse species. Based on the biological results, SARs were further discussed, which was also partially rationalized by a molecular docking model of 1 bound to the 11β-HSD1. Remarkably, compounds 1, 17 and 30 significantly inhibited 11β-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice, which merits further investigations as anti-diabetic agents. This study not only provides a series of novel selective 11β-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes, but also expands the boundaries of the chemical and biological spaces of tanshinones. Graphic Abstract

Developing new catalysts with improved performance is crucial for establishing a sustainable chemical industry and requires atomic-scale knowledge of the relevant catalyst-species interactions. A powerful experimental technique to gather such detailed knowledge is Steady-State Isotopic Transient Kinetic Analysis (SSITKA). By combining SSITKA with (micro)kinetic modeling, the observed catalyst performance can be rationalized to advance the development of structure-activity relationships, and to obtain fundamental insights in complex reaction pathways. In turn, tailored experimental and computational methodologies provide the tools to access this detailed information. This mini review summarizes the developments that have been made in these fields during the last decade.

Three series of podophyllotoxin derivatives with various nitrogen-containing heterocycles were designed and synthesized. The antitumor activity of these podophyllotoxin derivatives was evaluated in vitro against a panel of human tumor cell lines. The results showed that podophyllotoxin-imidazolium salts and podophyllotoxin-1,2,4-triazolium salts a1–a20 exhibited excellent cytotoxic activity. Among them, a6 was the most potent cytotoxic compound with IC50 values of 0.04–0.29 μM. Podophyllotoxin-1,2,3-triazole derivatives b1–b5 displayed medium cytotoxic activity, and podophyllotoxin-amine compounds c1–c3 has good cytotoxic activity with IC50 value of 0.04–0.58 μM. Furthermore, cell cycle and apoptosis experiments of compound a6 were carried out and the results exhibited that a6 could induce G2/M cell cycle arrest and apoptosis in HCT-116 cells.

α-amylase inhibitors (α-AI) are a kind of active substances which show inhibitory activities to human, insect pancreas and saliva. α-AI can reduce blood glucose index in human body and kill insects, thus widely used in medicine and agriculture. This review summarizes the source, structure and action mechanisms of protein and non-protein-based α-AI, focuses on the mechanisms from the view of structure-function relationship. The applications of α-AI in disease prevention, agricultural production and plant protection are also summarized. This review may provide new insights into the comprehensive exploitation and application of α-AI from different sources.

In this work, the privileged scaffold of 4-hydroxy-2quinolinone is investigated through the synthesis of carboxamides and hybrid derivatives, as well as through their bioactivity evaluation, focusing on the ability of the molecules to inhibit the soybean LOX, as an indication of their anti-inflammatory activity. Twenty-one quinolinone carboxamides, seven novel hybrid compounds consisting of the quinolinone moiety and selected cinnamic or benzoic acid derivatives, as well as three reverse amides are synthesized and classified as multi-target agents according to their LOX inhibitory and antioxidant activity. Among all the synthesized analogues, quinolinone–carboxamide compounds 3h and 3s, which are introduced for the first time in the literature, exhibited the best LOX inhibitory activity (IC50 = 10 μM). Furthermore, carboxamide 3g and quinolinone hybrid with acetylated ferulic acid 11e emerged as multi-target agents, revealing combined antioxidant and LOX inhibitory activity (3g: IC50 = 27.5 μM for LOX inhibition, 100% inhibition of lipid peroxidation, 67.7% ability to scavenge hydroxyl radicals and 72.4% in the ABTS radical cation decolorization assay; 11e: IC50 = 52 μM for LOX inhibition and 97% inhibition of lipid peroxidation). The in silico docking results revealed that the synthetic carboxamide analogues 3h and 3s and NDGA (the reference compound) bind at the same alternative binding site in a similar binding mode.

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0.70 (0.52–0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics.

According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds.

Polysaccharides are usually composed of more than ten monosaccharide units, which are connected by linear or branched glycosidic bonds. The immunomodulatory effect of natural polysaccharides is one of the most important bioactive function. In this review, molecular weight, monosaccharide (including galactose, mannose, rhamnogalacturonan-I arabinogalactan and uronic acid), functional groups (namely sulfate, selenium, and acetyl groups), types of glycoside bond connection (including β-1,3-D-glucosyl, α-1,4-D-glucosyl, β-1,4-D-glucosyl, α-1,6-D-glucosyl, β-1,4-D-mannosyl, and β-1,4-D-Xylopyranosyl), conformation and the branching degrees are systematically identified as their contribution to the immunostimulatory activity of polysaccharides. At present, studies on the structure-activity relationships of polysaccharides are limited due to their low purity and high heterogeneity. However, it is an important step in providing useful guidance for dietary supplements with polysaccharides. The chemical structures and the process of immune responses induced are necessary to be discussed. Polysaccharides may bind with the cell surface receptors to modulate immune responses. This review mainly discusses the structure-activity relationship of dietary polysaccharides.

As part of our ongoing scaffold-hopping work on an antikinetoplastid 3-nitroimidazo[1,2-a]pyridine scaffold, we explored 3-nitroimidazo[1,2-b]pyridazine as a potential new antikinetoplastid series. Using conditions previously described by our lab, we obtained 6-chloro-3-nitro-2-[(phenylsulfonyl)methyl]imidazo[1,2-b]pyridazine with 54% yield. In vitro activity of this compound was evaluated against both the promastigote form of Leishmania donovani, the axenic amastigote form of Leishmania infantum and the trypomastigote blood stream form of Trypanosomabrucei brucei, and its influence on cell viability was assessed on the HepG2 cell line. However, despite good activity against the trypomastigote blood stream form of T. b. brucei (EC50 = 0.38 µM), it showed poor solubility in both HepG2 (CC50 > 7.8 µM) and L. infantum axenic amastigotes (EC50 > 1.6 µM) culture media, associated with a loss of activity against the promastigote form of L. infantum (EC50 > 15.6 µM).

Rhizoma Bolbostemmatis, the dry tuber of Bolbostemma paniculatum, has being used for the treatment of acute mastitis and tumors in traditional Chinese medicine. In this study, tubeimoside (TBM) I, II, and III from this drug were investigated for the adjuvant activities, structure-activity relationships (SAR), and mechanisms of action. Three TBMs significantly boosted the antigen-specific humoral and cellular immune responses and elicited both Th1/Th2 and Tc1/Tc2 responses towards ovalbumin (OVA) in mice. TBM I also remarkably facilitated mRNA and protein expression of various chemokines and cytokines in the local muscle tissues. Flow cytometry revealed that TBM I promoted the recruitment and antigen uptake of immune cells in the injected muscles, and augmented the migration and antigen transport of immune cells to the draining lymph nodes. Gene expression microarray analysis manifested that TBM I modulated immune, chemotaxis, and inflammation-related genes. The integrated analysis of network pharmacology, transcriptomics, and molecular docking predicted that TBM I exerted adjuvant activity by interaction with SYK and LYN. Further investigation verified that SYK-STAT3 signaling axis was involved in the TBM I-induced inflammatory response in the C2C12 cells. Our results for the first time demonstrated that TBMs might be promising vaccine adjuvant candidates and exert the adjuvant activity through mediating the local immune microenvironment. SAR information contributes to developing the semisynthetic saponin derivatives with adjuvant activities.

Introduction: Fusidic acid (FA) has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects.Purpose: Therefore, it is necessary to explore the structure–activity relationships of FA derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum.Methods and result: First, a pharmacophore model was established on the nineteen FA derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the FA derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven FA derivatives have been designed according to the reported structure–activity relationships and the pharmacophore characteristics. The designed FA derivatives were mapped on the pharmacophore model, and the Qfit values of all FA derivatives were over 50 and FA-8 possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of S. aureus. Furthermore, the designed FA derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative FA-7 with a chlorine group as the substituent group at C-25 of FA displayed the best antibacterial property with an MIC of 3.125 µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0.Conclusion: Hence, a computer-aided drug design model was developed for FA, which can be further used to optimize FA derivatives as highly potent antibacterial agents.

BackgroundTannins have demonstrated antibacterial and antibiofilm activity, but there are still unknown aspects on how the chemical properties of tannins affect their biological properties. We are interested in understanding how to modulate the antibiofilm activity of tannins and in delineating the relationship between chemical determinants and antibiofilm activity.Materials and methodsThe effect of five different naturally acquired tannins and their chemical derivatives on biofilm formation and planktonic growth of Salmonella Typhimurium, Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus was determined in the Calgary biofilm device.ResultsMost of the unmodified tannins exhibited specific antibiofilm activity against the assayed bacteria. The chemical modifications were found to alter the antibiofilm activity level and spectrum of the tannins. A positive charge introduced by derivatization with higher amounts of ammonium groups shifted the anti-biofilm spectrum toward Gram-negative bacteria, and derivatization with lower amounts of ammonium groups and acidifying derivatization shifted the spectrum toward Gram-positive bacteria. Furthermore, the quantity of phenolic OH-groups per molecule was found to have a weak impact on the anti-biofilm activity of the tannins.ConclusionWe were able to modulate the antibiofilm activity of several tannins by specific chemical modifications, providing a first approach for fine tuning of their activity and antibacterial spectrum.

Two novel amides, named clauphenamides A and B, and twelve other known compounds were isolated from the twigs and leaves of Clausena lansium Lour. Skeels (Rutaceae). Their structures were elucidated on the basis of extensive spectroscopic analysis and comparison with data reported in the literature. Clauphenamide A (1) featured in the unit of N-2-(4,8-dimethoxyfuro [2,3-b]quinolin-7-yl)vinyl, and clauphenamide B (2) was a unprecedented N-phenethyl cinnamide dimer. Other known compounds belong to pyrrolidone amides (3 and 4), furacoumarins (7–10), simple coumarins (11–14), lignan (5) and sesquiterpene (6). Compounds 5, 6, 10 and 12 were separated from the genus (Clausena) for the first time, while 13 was isolated in the species (C. lansium) for the first time. The antifungal activities of the isolated compounds were assayed. As a result, at the concentration of 100 μg/ml, compared with the control (chlorothalonil, inhibition rate of 83.67%), compounds 1 and 2 were found to exhibit moderate antifungal activity against B. dothidea with inhibition rates of 68.39% and 52.05%, respectively. Compounds 11–14 also exhibited moderate activity against B. dothidea and F. oxysporum, with inhibition rates greater than 40%. In addition, compared with the control (chlorothalonil, inhibition rate of 69.02%), compounds 11–14 showed strong antifungal activity to P. oryzae, with inhibition rates greater than 55%. Among them, compound 14 has the strongest antifungal activity against P. oryzae, and the inhibition rate (65.44%) is close to that of the control chlorothalonil. Additionally, the structure-activity relationships of the separated compounds are also discussed preliminarily in this paper.

Acquired immune deficiency syndrome (AIDS) mainly caused by human immunodeficiency virus (HIV) type 1 (HIV-1) is a deadliest infectious disease, in which the immune system becomes ineffective and opportunistic infections accompany the disease. Reverse transcriptase (RT) is the target for the majority of anti-HIV-1 agents, and HIV RT inhibitors can be categorized into nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). In view of the structural diversity, unique mode of action, high efficacy and low toxicity of NNRTIs in comparison to NRTIs, NNRTIs represent one of the most significant antiretroviral drugs against HIV infections. The purpose of the present review article is to discuss the recent developments (2018-present) in NNRTIs, and the structure–activity relationships (SARs) are also discussed to facilitate further rational design of more effective candidates.

The extractive contents of three softwood species largely used in the wood industry, namely Abies alba (Silver fir), Picea abies (spruce) and Pseudotsuga menziesii (Douglas fir), have been determined quantitatively for knots and at different points chosen along their branches, before analysis using high-performance liquid chromatography coupled with Mass Spectrometry (HPLC-MS). The results indicated that branchwood samples located in close proximity to the stem present high contents of extractives similar to those recorded for the knots. HPLC analysis showed quite similar chemical compositions, indicating that first cm of the branches could be considered as an additional source of knotwood. The antibacterial, antifungal and antioxidant activities of knot’s extractives have been investigated with the dual objective of better understanding the role of high levels of secondary metabolites present in the knot and evaluating their potential for biorefinery applications. The antioxidant activity study showed that crude extracts of Douglas fir knotwood presented higher radical scavenging activity levels than the extracts of Silver fir and spruce, which presented more or less the same activities. Silver fir and spruce knotwood extracts presented higher antibacterial activity levels than the Douglas fir knotwood extracts did, while Douglas fir knotwood extracts presented more fungal growth inhibition than the spruce and fir knotwood extracts did. The structure–activity relationships indicate that radical scavenging and antifungal activities are associated with a higher relative quantity of flavonoids in the crude extracts, while higher relative quantities of lignans are associated with antibacterial activity.

The macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides’ opioid activity, antinociceptive tolerance, and the ability to prevent relapse to extinguished drug-CPP. Six analogs were synthesized using a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, efficacy in the [35S]GTPγS assay, metabolic stability in mouse liver microsomes, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance, and conditioned place preference (CPP) were also assessed in vivo, and the ameliorating effect of analogs on the reinstatement of extinguished cocaine-place preference was assessed. Substitutions of other D-amino acids for D-Trp did not affect (or in one case increased) KOR affinity, while two of the three substitutions of an L-amino acid for Trp decreased KOR affinity. In contrast, all but one substitution increased mu opioid receptor (MOR) affinity in vitro. The metabolic stabilities of the analogs were similar to those of their respective parent peptides, with analogs containing a D-amino acid being much more rapidly metabolized than those containing an L-amino acid in this position. In vivo, CJ-15,208 analogs demonstrated antinociception, although potencies varied over an 80-fold range and the mediating opioid receptors differed by substitution. KOR antagonism was lost for all but the D-benzothienylalanine analog, and the 2′-naphthylalanine analog instead demonstrated significant delta opioid receptor (DOR) antagonism. Introduction of DOR antagonism coincided with reduced acute opioid antinociceptive tolerance and prevented stress-induced reinstatement of extinguished cocaine-CPP.

Mushroom bioactive peptides (MBPs) are bioactive peptides extracted directly or indirectly from edible mushrooms. MBPs are known to have antioxidant, anti-aging, antibacterial, anti-inflammatory and anti-hypertensive properties, and facilitate memory and cognitive improvement, antitumour and anti-diabetes activities, and cholesterol reduction. MBPs exert antioxidant and anti-inflammatory effects by regulating the MAPK, Keap1-Nrf2-ARE, NF-κB and TNF pathways. In addition, MBPs exert antibacterial, anti-tumour and anti-inflammatory effects by stimulating the proliferation of macrophages. The bioactivities of MBPs are closely related to their molecular weights, charge, amino acid compositions and amino acid sequences. Compared with animal-derived peptides, MBPs are ideal raw materials for healthy and functional products with the advantages of their abundance of resources, safety, low price, and easy-to-achieve large-scale production of valuable nutrients for health maintenance and disease prevention. In this review, the preparation, bioactivities, mechanisms and structure–activity relationships of MBPs were described. The main challenges and prospects of their application in functional products were also discussed. This review aimed to provide a comprehensive perspective of MBPs.

Piericidins are a family of α-pyridone antibiotics with fascinating biological activity produced by actinomycetes, derived from land soil, insect or marine samples. There are 39 natural piericidins reported before 2016, and most of them are obtained from soil actinomycetes. However, marine-derived Streptomyces isolates have been showed great importance to produce piericidins with new structures in recent 5 years. This review covers the 40 natural piericidins reported after 2016, together with their obvious cytotoxic activities against cancer cell lines. Their structure–activity relationships are also discussed briefly. The anti-tumor potential, especially as lead compounds for anti-renal cell carcinoma agents, is of great concern recently. This review helps to provide comprehensive chemical information and new insights into the antitumor potential of piericidins.

Resistance to antibacterial agents is a growing global public health problem that reduces the efficacy of available antibacterial agents, leading to increased patient mortality and morbidity. Unfortunately, only 16 antibacterial drugs have been approved by the FDA in the last 10 years, so it is necessary to develop new agents with novel chemical structures and/or mechanisms of action. In response to this, our group takes up the challenge of designing a new family of pyrimidoisoquinolinquinones displaying antimicrobial activities against multidrug-resistant Gram-positive bacteria. Accordingly, the objective of this study was to establish the necessary structural requirements to obtain compounds with high antibacterial activity, along with the parameters controlling antibacterial activity. To achieve this goal, we designed a family of compounds using different strategies for drug design. Forty structural candidates were synthesized and characterized, and antibacterial assays were carried out against high-priority bacterial pathogens. A variety of structural properties were modified, such as hydrophobicity and chain length of functional groups attached to specific carbon positions of the quinone core. All the synthesized compounds inhibited Gram-positive pathogens in concentrations ranging from 0.5 to 64 µg/mL. Two derivatives exhibited minimum inhibitory concentrations of 64 µg/mL against Klebsiella pneumoniae, while compound 28 demonstrated higher potency against MRSA than vancomycin.