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Fungal diseases could severely harm agricultural productions. To develop new antifungal agents, based on the Global Natural Products Social Molecular Networking, typical bromine isotope peak ratios, and ultraviolet absorptions, cultivation of the soft coral-derived endophytic fungi Aspergillus terreus EGF7-0-1 with NaBr led to the targeted isolation of 14 new brominated aromatic butenolides ( 1 - 14 ) and six known analogues ( 15 - 20 ). Their structures were elucidated by extensive spectroscopic analysis and quantum chemical calculations. Compounds 1 - 14 exhibited wildly antifungal activities (against Colletotrichum gloeosporioides , Pestalotiopsis microspora , Fusarium oxysporum f. sp. cubense , Botrytis cinerea , and Diaporthe phoenicicola ). The bioassay results showed that compounds 1 - 14 exhibited excellent antifungal activities against C. gloeosporioides , with concentration for 50% of maximal effect (EC 50 ) values from 2.72 to 130.41 nM. The mechanistic study suggests that compound 1 may disrupt nutrient signaling pathways by reducing the levels of metabolites, such as carbohydrates, lipids, and amino acids, leading to an increase in low-density granules and a decrease in high-density granules in the cytoplasm, accompanied by numerous vacuoles, thereby inhibiting the growth of C. gloeosporioides . Monobrominated γ-butenolide 1 may be expected to exploit a novel agriculturally antifungal leading drug. Meanwhile, compound M1 has conformed antifugual activities against C. gloeosporioides by papayas in vivo .

Four undescribed polyketides, beshanzones A (1) and B (2) as well as beshanhexanols A (3) and B (4), along with three known ones (5-7) were isolated from the rice fermentation of two endophytic fungi associated with the critically endangered Chinese endemic conifer Abies beshanzuensis. γ-Butyrolactone derivatives 1, 2, and 5 were isolated from Phomopsis sp. BSZ-AZ-2, an interesting strain that drawn our attention this time. The cyclohexanol derivatives 3, 4, 6, and 7 were obtained during a follow-up investigation on Penicillium commune BSZ-P-4-1. The chemical structures including absolute configurations of compounds 1-4 were determined by spectroscopic methods, Mo 2 (OAc) 4 induced electronic circular dichroism (IECD), GIAO NMR calculations and DP4+ probability analyses. In particular, compound 2 contains a novel 5/5 bicyclic ring system, which might be biogenetically derived from the known compound 5 through hydrolysis followed by an Aldol reaction. All isolates were evaluated for their antimicrobial activities against a small panel of bacterial and fungal pathogens. Compounds 6 and 7 showed moderate inhibitory activities against Candida albicans, with MIC values of 16 and 32 μg/mL, respectively., 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 B.V. All rights reserved.)

Ethnopharmacological Relevance: The natural anodyne Ligustilide (Lig), derived from Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort., has been traditionally employed for its analgesic properties in the treatment of dysmenorrhea and migraine, and rheumatoid arthritis pain. Despite the existing reports on the correlation between TRP channels and the analgesic effects of Lig, a comprehensive understanding of their underlying mechanisms of action remains elusive., Aim of the Study: The objective of this study is to elucidate the mechanism of action of Lig on the analgesic target TRPA1 channel., Methods: The therapeutic effect of Lig was evaluated in a rat acute soft tissue injury model. The analgesic target was identified through competitive inhibition of TRP channel agonists at the animal level, followed by Fluo-4/Ca 2+ imaging on live cells overexpressing TRP proteins. The potential target was verified through in-gel imaging, colocalization using a Lig-derived molecular probe, and a drug affinity response target stability assay. The binding site of Lig was identified through protein spectrometry and further analyzed using molecular docking, site-specific mutation, and multidisciplinary approaches., Results: The administration of Lig effectively ameliorated pain and attenuated oxidative stress and inflammatory responses in rats with soft tissue injuries. Moreover, the analgesic effects of Lig were specifically attributed to TRPA1. Mechanistic studies have revealed that Lig directly activates TRPA1 by interacting with the linker domain in the pre-S1 region of TRPA1. Through metabolic transformation, 6,7-epoxyligustilide (EM-Lig) forms a covalent bond with Cys703 of TRPA1 at high concentrations and prolonged exposure time. This irreversible binding prevents endogenous electrophilic products from entering the cysteine active center of ligand-binding pocket of TRPA1, thereby inhibiting Ca 2+ influx through the channel opening and ultimately relieving pain., Conclusions: Lig selectively modulates the TRPA1 channel in a bimodal manner via non-electrophilic/electrophilic metabolic conversion. The epoxidized metabolic intermediate EM-Lig exerts analgesic effects by irreversibly inhibiting the activation of TRPA1 on sensory neurons. These findings not only highlight the analgesic mechanism of Lig but also offer a novel nucleophilic attack site for the development of TRPA1 antagonists in the pre-S1 region., 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 B.V. All rights reserved.)

Herein, we present a highly efficient method for constructing the intricate 5-5-6 fused ring system commonly found in the polycyclic furanobutenolide-derived cembranoid and norcembranoid natural product family with remarkable diastereoselectivity, utilizing an intramolecular Diels-Alder reaction as the cornerstone. Notably, employing a propargyl ether tether as the dienophile yields significant enhancements in the transformation process compared to its propargyl ester counterpart, as demonstrated in our previous total synthesis of havellockate. This advancement holds promising implications for future investigations, offering a streamlined pathway for rapidly assembling the tricyclic core characteristic of this diverse family of natural products.

Two new lactones, γ-butyrolactone and δ-valerolactone were isolated from the methanolic extract of Solanum nigrum . Structure elucidation was carried out by exhaustive 2D NMR analysis. The structures of the lactones depict the outcome of their isolation as a situation that involve the formation of artifacts.

Background: The discovery of agricultural fungicide candidates from natural products is one of the key strategies for developing environment friendly agricultural fungicides with high efficiency, high selectivity and unique modes-of-action. Based on previous work, a series of novel α-methylene-γ-butyrolactone (MBL) derivatives containing benzothiophene moiety were designed and synthesized., Results: The majority of the proposed compounds displayed moderate to considerable antifungal efficacy against the tested pathogenic fungi and oomycetes, some exhibiting broad spectrum antifungal activity. Notably, compounds 2 (3-F-Ph) and 7 (4-Cl-Ph) showed excellent antifungal activity against Rhizoctonia with half maximal effective concentration (EC 50 ) values of 0.94 and 0.99 mg L -1 , respectively, comparable to the commercial fungicide tebuconazole (EC 50  = 0.96 mg L -1 ), and also displayed significant inhibitory effects against V alsa mali with EC 50 values of 2.26 and 1.67 mg L -1 , respectively - better than famoxadone and carabrone. The in vivo protective and curative effects against R. solani of compound 2 were 57.2% and 53.7% at 100 mg L -1 , respectively, which were equivalent to tebuconazole (51.6% and 52.4%). Further investigations found that compound 2 altered the ultrastructure of R. solani cell, significantly increased the relative conductivity of the cells, and reduced the activity of complex III in a dose-dependent manner. Molecular docking results showed that compound 2 matched well with the Qo pocket., Conclusion: The results revealed that MBL derivatives containing benzothiophene moiety are promising antifungal candidates and provide a new backbone structure for further optimization of novel fungicides. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Corn ear rot and fumonisin caused by Fusarium verticillioides pose a serious threat to food security. To find more highly active fungicidal and antitoxic candidates with structure diversity based on naturally occurring lead xanthatin, a series of novel spiropiperidinyl-α-methylene-γ-butyrolactones were rationally designed and synthesized. The in vitro bioassay results indicated that compound 7c showed broad-spectrum in vitro activity with EC 50 values falling from 3.51 to 24.10 μg/mL against Rhizoctonia solani and Alternaria solani , which was more active than the positive controls xanthatin and oxathiapiprolin. In addition, compound 7c also showed good antitoxic efficacy against fumonisin with a 48% inhibition rate even at a concentration of 20 μg/mL. Fluorescence quenching and the molecular docking validated both 7c and oxathiapiprolin targeting at FvoshC. RNA sequencing analysis discovered that FUM gene cluster and protein processing in endoplasmic reticulum were downregulated. Our studies have discovered spiropiperidinyl-α-methylene-γ-butyrolactone as a novel FvoshC target-based scaffold for fungicide lead with antitoxin activity.

Within bioplastics, natural poly(3-hydroxybutyrate) (PHB) stands out as fully biocompatible and biodegradable, even in marine environments; however, its high isotacticity and crystallinity limits its mechanical properties and hence its applications. PHB can also be synthesized with different tacticities via a catalytic ring-opening polymerization (ROP) of rac-β-butyrolactone (BBL), paving the way to PHB with better thermomechanical and processability properties. In this work, the catalyst family is extended based on aluminum phenoxy-imine methyl catalyst [AlMeL 2 ], that reveals efficient in the ROP of BBL, to the halogeno analogous complex [AlClL 2 ]. As well, the impact on the ROP mechanism of different initiators is further explored with a particular focus in dimethylaminopyridine (DMAP), a hardly studied initiator for the ROP of BBL. A thorough mechanistic study is performed that evidences the presence of two concomitant DMAP-mediated mechanisms, that lead to either a DMAP or a crotonate end-capping group. Besides, in order to increase the possibilities of PHB post-polymerization functionalization, the introduction of a side-chain functionality is explored, establishing the copolymerization of BBL with β-allyloxymethylene propiolactone (BPL OAll ), resulting in well-defined P(BBL-co-BPL OAll ) copolymers., (© 2024 The Authors. Macromolecular Rapid Communications published by Wiley‐VCH GmbH.)

Five undescribed γ-butyrolactones harzianolides BF (1-5), one precursor harzianolide G (6) along with two known analogues, were isolated and identified from the EtOAc extract of the liquid fermentation of Trichoderma harzianum ZN-4, which was obtained from the sediment of Zhoushan coastal area. Notably, compound 1 featured an unusual carbon skeleton with methylene-bridged furan rings system. Their structures were determined by detailed interpretation of NMR and mass spectroscopic data, and the absolute configurations were unambiguously established based on ECD quantum chemical calculations. In bioassay, 1 and 7 showed inhibitory activity against Pestalotiopsis theae, with MIC values of 25 and 50 μg/mL, respectively., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Alterbutenolide ( 1 ), a new butenolide derivative with a long-chain aliphatic acid substitution, together with seven known phenolic compounds i.e. alternariol ( 2 ), asperigillol B ( 3 ), p -hydroxyphenylacetic acid ( 4 ), p -hydroxyphenylethyl alcohol ( 5 ), methyl p -hydroxyphenyl acetate ( 6 ), 2-(4-hydroxyphenyl)ethyl acetate ( 7 ), and 5,6-dihydro-4-methyl-2 H -pyran-2-one ( 8 ), was isolated from the cultures of a sponge-derived fungus Alternaria alternata I-YLW6-1. The structure of 1 was established on the basis of HR-MS, 1D and 2D NMR, as well as by comparison of the optical rotation data with the literature reported. Compounds 2 and 3 showed significant to moderate inhibitory activities against three harmful microalgae with IC 50 values from 3.0 to 36.2 μg/mL, whereas compound 1 only displayed moderate inhibition against Chattonella marina with IC 50 value of 34.6 μg/mL. Meanwhile, compounds 3 and 4 showed weak toxicity against brine shrimp larvae with LC 50 values >100 μg/mL.

The design of novel agrochemicals starting from bioactive natural products is one of the most effective ways in the discovery and development of new pesticidal agents. In this paper, a series of novel butenolide-containing methylxanthine derivatives (Ia-Ir) were designed based on natural methylxanthine caffeine and stemofoline, and the derivatized insecticide flupyradifurone of the latter. The structures of the synthesized compounds were confirmed via 1 H-NMR, 13 C NMR, HRMS and X-ray single crystal diffraction analyses. The biological activities of the compounds were evaluated against a variety of agricultural pests including oriental armyworm, bean aphid, diamondback moth, fall armyworm, cotton bollworm, and corn borer; the results indicated that some of them have favorable insecticidal potentials, particularly toward diamondback moth. Among others, Ic and Iq against diamondback moth possessed LC 50 values of 6.187 mg ⋅ L -1 and 3.269 mg ⋅ L -1 , respectively, - 2.5- and 4.8-fold of relative insecticidal activity respectively to that of flupyradifurone (LC 50 =15.743 mg ⋅ L -1 ). Additionally, both the DFT theoretical calculation and molecular docking with acetylcholine binding protein were conducted for the highly bioactive compound (Ic). Ic and Iq derived from the integration of caffeine (natural methylxanthine) and butenolide motifs can serve as novel leading insecticidal compounds for further optimization., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The relative configuration of the epoxide functionality in pinofuranoxin A (1), α-alkylidene-β-hydroxy-γ-methyl-γ-butyrolactone with trans-epoxy side chain isolated by Evidente et al. in 2021, was revised by DFT-based spectral reinvestigations and stereo-controlled synthesis. The present investigation demonstrates the difficulty of the configurational elucidation of the stereogenic centers on the conformationally flexible acyclic side-chains. Sharpless's enantioselective epoxidations and dihydroxylations were quite effective in the reinvestigations of the configurations. As our syntheses made all diastereomers available, these would be quite effective in the next structure-biological activity relationship studies., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Sea cucumber-derived fungi have attracted much attention due to their capacity to produce an incredible variety of secondary metabolites. Genome-wide information on Aspergillus micronesiensis H39 obtained using third-generation sequencing technology (PacBio-SMRT) showed that the strain contains nonribosomal peptide synthetase (NRPS)-like gene clusters, which aroused our interest in mining its secondary metabolites. 11 known compounds ( 1 - 11 ), including two γ -aromatic butenolides ( γ -AB) and five cytochalasans, were isolated from A. micronesiensis H39. The structures of the compounds were determined by NMR and ESIMS, and comparison with those reported in the literature. From the perspective of biogenetic origins, the γ -butyrolactone core of compounds 1 and 2 was assembled by NRPS-like enzyme. All of the obtained compounds showed no inhibitory activity against drug-resistant bacteria and fungi, as well as compounds 1 and 2 had no anti-angiogenic activity against zebrafish.

Food allergy (FA) poses a growing global food safety concern, yet no effective cure exists in clinics. Previously, we discovered a potent antifood allergy compound, butyrolactone I (BTL-I, 1 ), from the deep sea. Unfortunately, it has a very low exposure and poor pharmacokinetic (PK) profile in rats. Therefore, a series of structural optimizations toward the metabolic pathways of BTL-I were conducted to provide 18 derives ( 2 - 19 ). Among them, BTL-MK ( 19 ) showed superior antiallergic activity and favorable pharmacokinetics compared to BTL-I, being twice as potent with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, C max and area under the concentration-time curve (AUC 0-∞ ) were 565 and 204 times higher than those of BTL-I, respectively. These findings suggest that butyrolactone methyl ketone (BTL-BK) could serve as a drug candidate for the treatment of FAs and offer valuable insights into optimizing the druggability of lead compounds.

Ligustilide is the main active component of the volatile oil from Angelica sinensis and Ligusticum chuanxiong in the Umbelliferae family. It is a phthalein compound with anti-inflammatory, analgesic, antioxidant, anti-tumor, anti-atherosclerosis, neuroprotective, and other pharmacological effects. It can improve the permeability of the blood-brain barrier and has important potential in the treatment of neurodegenerative diseases and other nervous system diseases, such as Alzheimer's disease, ischemic stroke, Parkinson's disease, vascular dementia, and depression. Therefore, the mechanism of ligustilide in the treatment of nervous system diseases was summarized to provide a reference for drug development and clinical application.

While pioneering methods have demonstrated that bacterial N-acyl homoserine lactone (AHL) signaling molecules can influence the growth and self-aggregation of suspended microalgae, whether AHLs can affect the initial adhesion to a carrier has remained an open question. Here we revealed that the microalgae exhibited different adhesion potential under AHL mediation, where the performance was affiliated to both AHL types and concentrations. The result can be well explained by the interaction energy theory, where the energy barrier between the carriers and the cells varied due to AHL mediation. Depth analyses revealed that AHL acted through modifying the properties of the surface electron donor of the cells, which were dependent upon three major components, i.e., extracellular protein (PN) secretion, the PN secondary structure, and the PN amino acid composition. These findings expand the known diversity of AHLs mediation on microalgal initial adhesion and metabolisms, which may interface with other major cycles and become helpful to theoretically guide the application of AHLs in microalgal culture and harvesting., 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 © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Two new pairs of enantiomeric butenolides, (+)- and (-)-suberiteslide A, (+)- and (-)-subertieslide B had been obtained from the marine sponge Suberties sp. The structures with absolute configurations of these compounds were unequivocally determined by spectroscopic analyses and ECD (Electronic Circular Dichroism) method. It was the first separation of butenolides from the marine sponges of genus Suberites. Additionally, the anti-inflammatory, antibacterial and cytotoxic activities of these compounds were evaluated. The result indicated that only (-)-subertieslide B showed weak anti-inflammatory activity with the IC 50 value of 40.8 μM., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Bacteria produce natural products (NPs) via biosynthetic gene clusters. Unfortunately, many biosynthetic gene clusters are silent under traditional laboratory conditions. To access novel NPs, a better understanding of their regulation is needed. γ-Butyrolactones, including the A-factor and Streptomyces coelicolor butanolides, SCBs, are a major class of Streptomyces ' hormones. Study of these hormones has been limited due to challenges in accessing them in stereochemically pure forms. Herein, we describe an efficient route to ( R )-paraconyl alcohol, a key intermediate for these molecules, as well as a biocatalytic method to access the exocyclic hydroxyl group that differentiates A-factor-type from SCB-type hormones. Utilizing these methods, a library of hormones have been synthesized and tested in a green fluorescent protein reporter assay for their ability to relieve repression by the repressor ScbR. This allowed the most quantitative structure-activity relationship of γ-butyrolactones and a cognate repressor to date. Bioinformatics analysis strongly suggests that many other repressors of NP biosynthesis likely bind similar molecules. This efficient, diversifiable synthesis will enable further investigation of the regulation of NP biosynthesis.

The diverse structures and profound biological activities of lignan natural products have enticed significant effort in the exploration of new methodologies for their total synthesis. We have prepared γ-butyrolactone oximes from readily available δ-nitro alcohols via Boc 2 O mediated cyclization. The mild conditions are compatible with a wide range of functional groups, and this methodology has been applied to the total synthesis of five lignan natural products.

γ-Butenolide and γ-butyrolactone scaffolds are two types of important core structures in numerous natural products and bioactive targets. However, methods to construct the chiral quaternary arylated γ-butenolide are rarely explored. We herein report an efficient Pd-catalyzed enantioselective γ-arylation of β,γ-unsaturated butenolides with aryl bromides, which shows high γ-selectivity, good functional group tolerance and excellent enantioselectivity. Notably, this protocol also allows for facile construction of tricyclic tetrahydroindolines and tetrahydroisoquinolinones in one step. DFT calculations are consistent with the experimental results, suggesting that the γ-arylation is favoured over the α-arylation. Finally, this method is applied to the rapid synthesis of natural product (R)-(+)-boivinianin A., (© 2022 Wiley-VCH GmbH.)

γ-Aromatic butenolides (γ-AB) are an important type of structures found in many bioactive microbial secondary metabolites (SMs). γ-AB refer to a group of natural products (NPs) containing five-membered (unsaturated) lactones with 3-phenyl and 4-benzyl substituents. Their wide-range biological activities have inspired pharmaceutical chemists to explore its biosynthesis mechanisms and design strategies to construct the γ-AB skeleton. Recently, there are a great deal of interesting research progress on the structures, biological activities and biosynthesis of γ-AB. This review will focus on these aspects and summarize the important achievements of γ-AB from 1975 to 2021., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Objectives: To find a method to distinguish exogenous gamma-hydroxybutyrate (GHB) from endogenous GHB by establishing ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) based on exosome for quantitative detection of GHB in the rat blood., Methods: Adult male SD rats were divided into 1 h, 5 h, 10 h administration group and control group. After 1 h, 5 h and 10 h of single precursor of GHB gamma-butyrolactone (GBL) intraperitoneal injection in administration groups, 5 mL blood was collected from the abdominal aorta. Meanwhile, the control group was given a same dose of normal saline, and 5 mL blood was collected at 1 h. Among the 5 mL blood, 0.5 mL was directly detected by HPLC-MS after pretreatment, and exosomes were extracted from the remaining blood by differential centrifugation and detected., Results: The concentration of GHB in the control group was (87.36±33.48) ng/mL, and the concentration with administration at 1 h, 5 h and 10 h was (110 400.00±1 766.35) ng/mL, (1 479.00±687.01) ng/mL and (133.60±12.17) ng/mL, respectively. The results of exosome detection showed that no peak GHB signal was detected in the control group and the 10 h administration group, and the concentrations of GHB at 1 h and 5 h administration groups were (91.47±33.44) ng/mL and (49.43±7.05) ng/mL, respectively., Conclusions: GHB was detected in blood exosome by UPLC-MS, which indicated that exogenous GHB could be detected in plasma exosomes, while endogenous GHB could not be detected, suggesting that this method may be used as a basis to determine whether there is exogenous drug intake.

Five undescribed butenolides including two pairs of enantiomers, (+)-asperteretal G ( 1a ), (-)-asperteretal G ( 1b ), (+)-asperteretal H ( 2a ), (-)-asperteretal H ( 2b ), asperteretal I ( 3 ), and para -hydroxybenzaldehyde derivative, ( S )-3-(2,3-dihydroxy-3-methylbutyl)-4-hydroxybenzaldehyde ( 14 ), were isolated together with ten previously reported butenolides 4 - 13 , from the coral-derived fungus Aspergillus terreus SCSIO41404. Enantiomers 1a / 1b and 2a / 2b were successfully purified by high performance liquid chromatography (HPLC) using a chiral column, and the enantiomers 1a and 1b were new natural products. Structures of the unreported compounds, including the absolute configurations, were elucidated by NMR and MS data, optical rotation, experimental and calculated electronic circular dichroism, induced circular dichroism, and X-ray crystal data. The isolated butenolides were evaluated for antibacterial, cytotoxic, and enzyme inhibitory activities. Compounds 7 and 12 displayed weak antibacterial activity, against Enterococcus faecalis (IC 50 = 25 μg/mL) and Klebsiella pneumoniae (IC 50 = 50 μg/mL), respectively, whereas 6 showed weak inhibitory effect on acetylcholinesterase. Nevertheless, most of the butenolides showed inhibition against pancreatic lipase (PL) with an inhibition rate of 21.2-73.0% at a concentration of 50 μg/mL.

The biological screening of 44 marine sponge extracts for the research of bioactive molecules, with potential application in the treatment of age-related diseases (cancer and Alzheimer's disease) and skin aging, resulted in the selection of Scopalina hapalia extract for chemical study. As no reports of secondary metabolites of S. hapalia were found in the literature, we undertook this research to further extend current knowledge of Scopalina chemistry. The investigation of this species led to the discovery of four new compounds: two butenolides sinularone J ( 1 ) and sinularone K ( 2 ), one phospholipid 1- O -octadecyl-2-pentanoyl- sn -glycero-3-phosphocholine ( 3 ) and one lysophospholipid 1- O -(3-methoxy-tetradecanoyl)- sn -glycero-3-phosphocholine ( 4 ) alongside with known lysophospholipids ( 5 and 6 ), alkylglycerols ( 7 - 10 ), epidioxysterols ( 11 and 12 ) and diketopiperazines ( 13 and 14 ). The structure elucidation of the new metabolites ( 1 - 4 ) was determined by detailed spectroscopic analysis, including 1D and 2D NMR as well as mass spectrometry. Molecular networking was also explored to complement classical investigation and unravel the chemical classes within this species. GNPS analysis provided further information on potential metabolites with additional bioactive natural compounds predicted.

The development of novel and safe insecticides remains an important need for a growing world population to protect crops and animal and human health. New chemotypes modulating the insect nicotinic acetylcholine receptors have been recently brought to the agricultural market, yet with limited understanding of their molecular interactions at their target receptor. Herein, we disclose the first crystal structures of these insecticides, namely, sulfoxaflor, flupyradifurone, triflumezopyrim, flupyrimin, and the experimental compound, dicloromezotiaz, in a double-mutated acetylcholine-binding protein which mimics the insect-ion-channel orthosteric site. Enabled by these findings, we discovered novel pharmacophores with a related mode of action, and we describe herein their design, synthesis, and biological evaluation.

Marine myxobacteria present a virtually unexploited reservoir for the discovery of natural products with diverse biological functions and novel chemical scaffolds. We report here the isolation and structure elucidation of eight new deoxyenhygrolides ( 1 - 8 ) from the marine myxobacterium Plesiocystis pacifica DSM 14875 T . The herein described deoxyenhygrolides C-J ( 1 - 8 ) feature a butenolide core with an ethyl residue at C-3 of the γ-lactone in contrast to the previously described derivatives, deoxyenhygrolides A and B, which feature an isobutyl residue at this position. The butenolide core is 2,4-substituted with a benzyl ( 1 , 2 and 7 ), benzoyl ( 3 and 4 ) or benzyl alcohol ( 5, 6 and 8 ) moiety in the 2-position and a benzylidene ( 1 - 6 ) or benzylic hemiketal ( 7 and 8 ) in the 4-position. The description of these new deoxyenhygrolide derivatives, alongside genomic in silico investigation regarding putative biosynthetic genes, provides some new puzzle pieces on how this natural product class might be formed by marine myxobacteria.

Dehydrogenative transformations of alkyl chains to alkenes through methylene carbon-hydrogen (C–H) activation remain a substantial challenge. We report two classes of pyridine-pyridone ligands that enable divergent dehydrogenation reactions through palladium-catalyzed β-methylene C–H activation of carboxylic acids, leading to the direct syntheses of α,β-unsaturated carboxylic acids or γ-alkylidene butenolides. The directed nature of this pair of reactions allows chemoselective dehydrogenation of carboxylic acids in the presence of other enolizable functionalities such as ketones, providing chemoselectivity that is not possible by means of existing carbonyl desaturation protocols. Product inhibition is overcome through ligand-promoted preferential activation of C(sp 3 )–H bonds rather than C(sp 2 )–H bonds or a sequence of dehydrogenation and vinyl C–H alkynylation. The dehydrogenation reaction is compatible with molecular oxygen as the terminal oxidant.

Inflammation is associated with the development of several diseases comprising cancer and cardiovascular disease. Agents that suppress cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, besides chemokines have been suggested to minimise inflammation. Here, a variety of novel heterocyclic and non-heterocyclic compounds were prepared from novel three furanone derivatives. The structures of all synthesised compounds were confirmed by elemental and spectral analysis including mass, IR, and 1 H-NMR spectroscopy. Anti-inflammatory activities of these synthesised compounds were examined in vitro against COX enzymes, 15-LOX, and tumour necrosis factor-α (TNF-α), using inhibition screening assays. The majority of these derivatives showed significant to high activities, with three pyridazinone derivatives ( 5b, 8b, and 8c ) being the most promising anti-inflammatory agents with dual COX-2/15-LOX inhibition activities along with high TNF-α inhibition activity.

A straightforward synthesis of (+)-trans-(4S,5R)- and (+)-cis-(4R,5R)-whisky lactones starting from d-(+)-mannitol has been reported here in fewer number of efficient steps compared to existing literature processes involving d-mannitol as the chiral pool starting material. Chiron approach directly translated chirality of d-mannitol to one of the two chiral centers in these target molecules. Toward this end, stereoisomerically pure trans- and cis-iodomethyl-γ-lactones were formed in the penultimate step. These two acted as versatile advanced common intermediates as they were also converted to the (+)-trans-(4S,5R)- and (+)-cis-(4R,5R)-cognac lactones, respectively. To the best of our knowledge, till date no synthesis of cognac lactones starting from d-mannitol has been reported. All these lactones are identified as the key aroma components of aged alcoholic beverages., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Diabetes mellitus ranks as a major risk cause for disability and death around the world due to its complications, especially diabetic cardiomyopathy (DCM). Glucolipotoxicity is one of the critical causal factors of DCM. Recent finding confirms the beneficial roles of Z-ligustilide in diabetes mellitus. Nevertheless, its efficacy in DCM remains elusive. Here, Z-ligustilide elevated high glucose/high palmitic acid (HG/P)-inhibited cell viability and attenuated HG/P-induced cell apoptosis, caspase-3 activity, pro-apoptotic Bax and anti-apoptotic Bcl-2 protein expression. Furthermore, Z-ligustilide alleviated HG/P-evoked oxidative damage by decreasing HG/P-induced elevation in ROS, lactate dehydrogenase (LDH) and malondialdehyde (MDA) leakage, but increasing antioxidant enzyme-superoxide dismutase (SOD) and glutathione (GSH) levels suppressed by HG/P. Concomitantly, Z-ligustilide attenuated HG/P-induced cardiomyocyte fibrosis by increasing MMP-14 expression and diminishing HG/P-enhanced fibrotic protein expression, including collagen I, collagen II and TGF-β. Mechanistically, Z-ligustilide offset the adverse effects of HG/P on the activation of the AMPK/GSK-3β/Nrf2 pathway. Importantly, blocking the AMPK signaling overturned the protective efficacy of Z-ligustilide against HG/P-induced cardiomyocyte oxidative damage, inflammation and fibrosis. Together, these findings highlight that Z-ligustilide may alleviate glucolipotoxicity-induced cardiomyocyte dysfunction by regulating cell oxidative injury, inflammation and fibrosis via the AMPK/GSK-3β/Nrf2 pathway. Consequently, Z-ligustilide may represent a promising therapeutic agent against DCM by restoring cardiomyocyte dysfunction., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Industrially relevant intermediates such as malonic acid, malonates and 3-oxopropionates can be easily accessed by ozonolysis of α-angelica lactone, derived from the platform chemical levulinic acid. The roles of the solvent and of the quenching conditions are of key importance for the outcome of the reaction.

Cell-cell communication is critical for bacterial survival in natural habitats, in which miscellaneous regulatory networks are encompassed. However, elucidating the interaction networks of a microbial community has been hindered by the population complexity. This study reveals that γ-butyrolactone (GBL) molecules from Streptomyces species, the major antibiotic producers, can directly bind to the acyl-homoserine lactone (AHL) receptor of Chromobacterium violaceum and influence violacein production controlled by the quorum sensing (QS) system. Subsequently, the widespread responses of more Gram-negative bacterial AHL receptors to Gram-positive Streptomyces signaling molecules are unveiled. Based on the cross-talk between GBL and AHL signaling systems, combinatorial regulatory circuits (CRC) are designed and proved to be workable in Escherichia coli (E. coli). It is significant that the QS systems of Gram-positive and Gram-negative bacteria can be bridged via native Streptomyces signaling molecules. These findings pave a new path for unlocking the comprehensive cell-cell communications in microbial communities and facilitate the exploitation of innovative regulatory elements for synthetic biology., (© 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Herein we report a cascade cocatalysis strategy for the facile construction of chiral γ,γ-disubstituted butenolides. The synthetic manifold employs simple alkynoic acids instead of the preformed silyloxy furans or 5-substituted furan-2(3 H )-ones. In situ formed 5-substituted furan-2(3 H )-ones by AgNO 3 or Ph 3 PAuCl/AgOTf catalyzed cyclization of alkynoic acids can smoothly engage in the subsequent chiral diphenylprolinol TMS-ether catalyzed Michael and Michael-aldol reactions. The cascade process serves as a general approach to chiral quaternary γ,γ-disubstituted butenolides.

Butenolide derivatives have the potential to be effective and environmentally friendly antifouling agents. In the present study, a butenolide derivative was structurally modified into Boc-butenolide to increase its melting point and remove its foul smell. The structurally modified Boc-butenolide demonstrated similar antifouling capabilities to butenolide in larval settlement bioassays but with significantly lower toxicity at high concentrations. Release-rate measurements demonstrated that the antifouling compound Boc-butenolide could be released from polycaprolactone-polyurethane (PCL-PU)-based coatings to inhibit the attachment of foulers. The coating matrix was easily degraded in the marine environment. The performance of the Boc-butenolide antifouling coatings was further examined through a marine field test. The coverage of biofouler on the Boc-butenolide coatings was low after 2 months, indicating the antifouling potential of Boc-butenolide.

Biobased poly(γ-methyl-α-methylene-γ-butyrolactone) (PMMBL), an acrylic polymer bearing a cyclic lactone ring, has attracted increasing interest because it not only is biorenewable but also exhibits superior properties to petroleum-based linear analog poly(methyl methacrylate) (PMMA). However, such property enhancement has been limited to resistance to heat and solvent, and mechanically both types of polymers are equally brittle. Here we report the expeditious synthesis of well-defined PMMBL-based ABA tri-block copolymers (tri-BCPs)-enabled by dual-initiating and living frustrated Lewis pairs (FLPs)-which are thermoplastic elastomers showing much superior mechanical properties, especially at high working temperatures (80-130 °C), to those of PMMA-based tri-BCPs. The FLPs consist of a bulky organoaluminum Lewis acid and a series of newly designed bis(imino)phosphine superbases bridged by an alkyl linker, which promote living polymerization of MMBL. Uniquely, such bisphosphine superbases initiate the chain growth from both P-sites concurrently, enabling the accelerated synthesis of tri-BCPs in a one-pot, two-step procedure. The results from mechanistic studies, including the single crystal structure of the dually initiated active species, detailed polymerizations, and kinetic studies confirm the livingness of the polymerization and support the proposed polymerization mechanism featuring the dual initiation and subsequent chain growth from both P-sites of the superbase di-initiator., (© 2021. The Author(s).)

Design and synthesis of a new class of γ-butenolides, viz. β-aryl-γ-propenylidene-γ-butenolides, have been reported from β-aryl- Z -enoate propargylic alcohols in the presence of acid. Isolation of β-aryl-γ-propenylidene-γ-butenolides and their O 18 -isomer confirmed the intermediacy of the allenyl-lactonium ion as well as the cyclic-hemiacetal during the proposed mechanism. By utilizing the β-aryl-γ-methylenecyclohexenylidene-γ-butenolides as starting materials, a highly stereoselective and efficient approach has been developed for the syntheses of frameworks of rubrolide natural products. This strategy was further extended for the total synthesis of rubrolide E.

A new butenolide derivative ( 1 ) featuring octyl substitution at γ-position, together with four known analogues ( 2-5 ) were isolated from marine-derived Streptomyces koyangensis SCSIO 5802. The structure of 1 was elucidated by HR-MS and NMR spectroscopic data analyses. The absolute configuration of the stereo centre in lactone ring of 1 was determined by comparison of CD spectrum with those of known compounds. Compound 1 exhibited mild antiviral activity against herpes simplex virus with EC 50 value of 25.4 µM.

α,β-Butenolides with ≥96% enantiomeric excess are synthesized from β,γ-butenolides via a novel Cu(I)-ligand cooperative catalysis. The reaction is enabled by a chiral biphenyl-2-ylphosphine ligand featuring a remote tertiary amino group. Density functional theory studies support the cooperation between the metal center and the ligand basic amino group during the initial soft deprotonation and the key asymmetric γ-protonation. Remarkably, other coinage metals, that is, Ag and Au, can readily assume the same role as Cu in this asymmetric isomerization chemistry.

Quorum sensing interference (QSI), the disruption and manipulation of quorum sensing (QS) in the dynamic control of bacteria populations could be widely applied in synthetic biology to realize dynamic metabolic control and develop potential clinical therapies. Conventionally, limited QSI molecules (QSIMs) were developed based on molecular structures or for specific QS receptors, which are in short supply for various interferences and manipulations of QS systems. In this study, we developed QSIdb (http://qsidb.lbci.net/), a specialized repository of 633 reported QSIMs and 73 073 expanded QSIMs including both QS agonists and antagonists. We have collected all reported QSIMs in literatures focused on the modifications of N-acyl homoserine lactones, natural QSIMs and synthetic QS analogues. Moreover, we developed a pipeline with SMILES-based similarity assessment algorithms and docking-based validations to mine potential QSIMs from existing 138 805 608 compounds in the PubChem database. In addition, we proposed a new measure, pocketedit, for assessing the similarities of active protein pockets or QSIMs crosstalk, and obtained 273 possible potential broad-spectrum QSIMs. We provided user-friendly browsing and searching facilities for easy data retrieval and comparison. QSIdb could assist the scientific community in understanding QS-related therapeutics, manipulating QS-based genetic circuits in metabolic engineering, developing potential broad-spectrum QSIMs and expanding new ligands for other receptors., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In recent years, biofuels have been receiving significant attention because of their potential for decreasing carbon emissions and providing a long-term renewable solution to unsustainable fossil fuels. Currently, lactones are some of the alternatives being produced. Many lactones occur in a range of natural substances and have many advantages over bioethanol. In this study, the oxidation of alpha-angelica lactone initiated by ground-state atomic oxygen, O( 3 P), was studied at 298, 550, and 700 K using synchrotron radiation coupled with multiplexed photoionization mass spectrometry at the Lawrence Berkeley National Lab (LBNL). Photoionization spectra and kinetic time traces were measured to identify the primary products. Ketene, acetaldehyde, methyl vinyl ketone, methylglyoxal, dimethyl glyoxal, and 5-methyl-2,4-furandione were characterized as major reaction products, with ketene being the most abundant at all three temperatures. Possible reaction pathways for the formation of the observed primary products were computed using the CBS-QB3 composite method.

Recent studies suggest that quorum-sensing molecules may play a role in gut microbiota-host crosstalk. However, whether microbiota produces quorum-sensing molecules and whether those molecules can trans-kingdom transport to the host are still unknown. Here, we develop a UPLC-MS/MS-based assay to screen the 27 N-acyl homoserine lactones (AHLs) in the gut microbiota and host. Various AHL molecules are exclusively detected in the cecal contents, sera and livers from conventionally-raised mice but cannot be detected in germ-free mice. Pathogen-produced C4-HSL is detected in the cecal contents and sera of Citrobacter rodentium (C. rodentium)-infected mice, but not found in uninfected controls. Moreover, C. rodentium infection significantly increases the level of multiple AHL molecules in sera. Our findings demonstrate that both commensal and pathogenic bacteria, can produce AHLs that can be detected in host bodies, suggesting that quorum-sensing molecules could be a group of signaling molecules in trans-kingdom microbiota-host crosstalk.

In December 2020, the U.K. authorities reported to the World Health Organization (WHO) that a new COVID-19 variant, considered to be a variant under investigation from December 2020 (VUI-202012/01), was identified through viral genomic sequencing. Although several other mutants were previously reported, VUI-202012/01 proved to be about 70% more transmissible. Hence, the usefulness and effectiveness of the newly U.S. Food and Drug Administration (FDA)-approved COVID-19 vaccines against these new variants are doubtfully questioned. As a result of these unexpected mutants from COVID-19 and due to lack of time, much research interest is directed toward assessing secondary metabolites as potential candidates for developing lead pharmaceuticals. In this study, a marine-derived fungus Aspergillus terreus was investigated, affording two butenolide derivatives, butyrolactones I ( 1 ) and III ( 2 ), a meroterpenoid, terretonin ( 3 ), and 4-hydroxy-3-(3-methylbut-2-enyl)benzaldehyde ( 4 ). Chemical structures were unambiguously determined based on mass spectrometry and extensive 1D/2D NMR analyses experiments. Compounds ( 1 - 4 ) were assessed for their in vitro anti-inflammatory, antiallergic, and in silico COVID-19 main protease (M pro ) and elastase inhibitory activities. Among the tested compounds, only 1 revealed significant activities comparable to or even more potent than respective standard drugs, which makes butyrolactone I ( 1 ) a potential lead entity for developing a new remedy to treat and/or control the currently devastating and deadly effects of COVID-19 pandemic and elastase-related inflammatory complications.

The NMR-based configurational analysis of complex marine natural products is still not a routine task. Different NMR parameters are used for the assignment of the relative configuration: NOE/ROE, homo- and heteronuclear J couplings as well as anisotropic parameters. The combined distance geometry (DG) and distance bounds driven dynamics (DDD) method allows a model-free approach for the determination of the relative configuration that is invariant to the choice of an initial starting structure and does not rely on comparisons with (DFT) calculated structures. Here, we will discuss the configurational analysis of five complex marine natural products or synthetic derivatives thereof: the cis -palau'amine derivatives 1a and 1b , tetrabromostyloguanidine ( 1c ), plakilactone H ( 2 ), and manzamine A ( 3 ). The certainty of configurational assignments is evaluated in view of the accuracy of the NOE/ROE data available. These case studies will show the prospective breadth of application of the DG/DDD method.

The anticancer activity of terretonin N ( 1 ) and butyrolactone I ( 2 ), obtained from the thermophilic fungus Aspergillus terreus TM8, was intensively studied against prostate adenocarcinoma (PC-3) and ovary adenocarcinoma (SKOV3) human cell lines. According to this study, both compounds showed potent cytotoxicity towards ovarian adenocarcinoma cells (SKOV3) with IC 50 1.2 and 0.6 μg/mL, respectively. With respect to metastatic prostate cells (PC-3), the two compounds 1 and 2 showed a significantly promising cytotoxicity effect with IC 50 of 7.4 and 4.5 μg/mL, respectively. The tested fungal metabolites showed higher rates of early and late apoptosis with little or no necrotic apoptotic pathway in all treated prostate adenocarcinoma (PC-3) and ovary adenocarcinoma (SKOV3) human cell lines, respectively. The results reported in this study confirmed the promising biological properties of terretonin N (1) and butyrolactone I (2) as anticancer agents via the induction of cellular apoptosis. However, further studies are needed to elucidate the molecular mechanism by which cellular apoptosis is induced in cancer cells.

γ -Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ -butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ -butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ -butyrolactone classified based on the bond formation in γ -butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ -butyrolactone scaffolds is described.

The synthesis of phytol-derived γ-butyrolactones as well as their evaluation for deterrent activity towards peach-potato aphid Myzus persicae and antiproliferative activity against four selected cancer cell lines are reported. Products were obtained in good yields (19-96%) and their structures were fully characterized by spectroscopic data (NMR, HRMS). Four synthesized δ-halo-γ-lactones (4-7) are new and have not been previously described in the literature. In the choice test phytol (1) appeared deterrent to M. persicae, whereas modifications of its structure did not cause the avoidance of the treated leaves by the aphids. In contrast, aphids were attracted to the leaves treated with the new trans-δ-chloro-γ-lactone (6). Electrical Penetration Graph (EPG) technique applied to explore the aphid probing and feeding activity revealed that neither phytol nor lactone 6 affected aphid probing and the consumption of phloem sap, which means that both phytol and the lactone 6 might have acted as postingestive modifiers of aphid behavior. The results of in vitro antitumor assays showed that obtained phytol derivatives exhibit cytotoxic activity against studied cancer cell lines (leukemia, lung and colon carcinoma and its doxorubicin resistant subline). Halolactones 4-6 were identified as the compounds, which arrest cell cycle of leukemia cells mainly in G2/M and S phases.

Influenza A virus is a highly variable and contagious respiratory pathogen that can cause annual epidemics and it poses an enormous threat to public health. Therefore, there is an urgent need for a new generation of antiviral drugs to combat the emergence of drug-resistant strains of the influenza virus. A novel series of butene lactone derivatives were screened and the compound 3D was selected, as it exhibited in vitro potential antiviral activity against A/Weiss/43 H1N1 virus with low toxicity. In addition, 3D dose-dependently inhibited the viral replication, expression of viral mRNA and viral proteins. 3D exerted a suppressive effect on A/Virginia/ATCC2/2009 H1N1 and A/California/2/2014 H3N2 in vitro. The time-of-addition analysis indicated that 3D suppressed H1N1 in the early stage of its life cycle. A/Weiss/43 H1N1-induced apoptosis in A549 cells was reduced by 3D via the mitochondrial apoptosis pathway. 3D could decrease the production of H1N1-induced pro-inflammatory cytokines that are induced by H1N1 in vitro and in vivo. The administration of 3D reduced lung lesions and virus load in vivo. These results suggest that 3D, which is a butene lactone derivative, is a promising agent for the treatment of influenza A virus infection.

The marine fungus, Aspergillus flavipes (MTCC 5220), was isolated from the pneumatophore of a mangrove plant Acanthus ilicifolius found in Goa, India. The crude extract of A. flavipes was found to show anti-inflammatory activity. It blocked interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production in lipopolysaccharide (LPS)-activated THP-1 cells with IC 50 of 2.69±0.5 μM and 6.64±0.4 μM, respectively. The chemical investigation led to the isolation of optically inactive 4β-[(1E)-propen-1-yl]cyclopentane-1β,2β-diol (1) along with a new optically active diastereoisomeric compound, 4β-[(1E)-propen-1-yl]cyclopentane-1β,2α-diol (2). In addition, the fungus also produced known compounds (+)-terrein (3), butyrolactone I (4) and butyrolactone II (5) in high yields. Among these, (+)-terrein (3) exhibited IL-6 and TNF-α inhibition activity with IC 50 of 8.5±0.68 μM and 15.76±0.18 μM, respectively, while butyrolactone I (4) exhibited IC 50 of 12.03±0.85 μM (IL-6) and 43.29±0.76 μM (TNF-α) inhibition activity with low toxicity to host cells in LPS stimulated THP-1 cells. This is the first report of the isolation and characterization of 4β-[(1E)-propen-1-yl]cyclopentane-1β,2α-diol (2). The structures of all the isolated compounds were elucidated on the basis of extensive detailed NMR spectroscopic data. Anti-inflammatory activity of the fungi A. flavipes is presented here for the first time, which was due to (+)-terrein and butyrolactone I, as the major constituents and they can be further explored in the therapeutic area., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Inflammatory bowel disease (IBD) is a chronic idiopathic disorder causing inflammation in the gastro-intestinal tract, which is lack of effective drug targets and medications. To identify novel therapeutic agents against consistent targets, we exploited a systems pharmacology-driven framework that incorporates drug-target networks of natural product and IBD disease genes. Our in silico approach found that Ligustilide (LIG), one of the major active components of Angelica acutiloba and Cnidium Officinale, potently attenuated IBD. The following in vivo and in vitro results demonstrated that LIG prevented experimental mice colitis induced by dextran sulfate sodium (DSS) via suppressing inflammatory cell infiltration, the activity of MPO and iNOS, and the expression and production of IL-1β, IL-6, and TNF-α. Subsequently, the network analysis helped to validate that LIG alleviated colitis by inhibiting NF-κB and MAPK/AP-1 pathway through activating PPARγ, which were further confirmed in RAW 264.7 cells and bone marrow-derived macrophages in vitro. In summary, this study reveals that LIG activated PPARγ to inhibit the activation of NF-κB and AP-1 signaling thus eventually alleviated DSS-induced colitis, which has promising activities and may serve as a candidate for the treatment of IBD.Graphical abstract This study suggested novel computational and experimental pharmacology approaches to identify potential IBD therapeutic agents by exploiting polypharmacology of natural products. We demonstrated that LIG could attenuate inflammation in IBD by inhibiting NF-κB and AP-1 pathways via PPARγ activation to reduce the expression of pro-inflammatory cytokines in macrophages. These findings offer comprehensive pre-clinical evidence that LIG may serve as a promising candidate for IBD therapy in the future. Graphical headlights: 1. Systems pharmacology uncovered Ligustilide attenuates experimental colitis in mice. 2. Network-based analysis predicted the mechanism of Ligustilide against IBD, which was validated by inhibiting PPARγ-mediated inflammation pathways. 3. Ligustilide activated PPARγ to inhibit NF-κB and AP-1 activation thus eventually alleviated DSS-induced colitis.4. Ligustilide has promising activities and may serve as a candidate for the treatment of IBD.