Butenolide Derivatives Research Articles

Novel Butenolide Derivatives as Dual-Chitinase Inhibitors to Arrest the Growth and Development of the Asian Corn Borer.

OfChtI and OfChi-h are considered potential targets for the control of Asian corn borer (Ostrinia furnacalis). In this work, the previously reported OfChtI inhibitor 5f was found to show certain inhibitory activity against OfChi-h (Ki = 5.81 μM). Two series of novel butenolide derivatives based on lead compound 5f were designed with the conjugate skeleton, contributing to the π-binding interaction to chitinase, and then synthesized. Compounds 4a-l and 7a-p displayed excellent inhibitory activities against OfChtI and OfChi-h, respectively, at a concentration of 10 μM. Compound 4h was found to be a good dual-Chitinase inhibitor, with Ki values of 1.82 and 2.00 μM against OfChtI and OfChi-h, respectively. The inhibitory mechanism studies by molecular docking suggested that π-π stacking interactions were crucial to the inhibitory activity of novel butenolide derivatives against two different chitinases. A preliminary bioassay indicated that 4h exhibited certain growth inhibition effects against O. furnacalis. Butenolide-like analogues should be further studied as promising novel dual-chitinase inhibitor candidates for the control of O. furnacalis.

Auto tandem triple cascade organocatalysis: access to bis-lactone and butenolide derivatives.

The synthesis of bis-lactone and butenolide derivatives was described using alkylidene Meldrum's acid as nucleophiles. The process operates in a triple cascade through an auto tandem catalysis promoted by DBU.

Phototriggered Butenolide Formation from a Cyclobutenedione and an Acidic Nucleophile.

A phototriggered conjugation reaction of an aminocyclobutenedione and an acidic nucleophile was discovered. Upon blue light irradiation of the materials, a butenolide derivative with substituents derived from the aminocyclobutenedione and the nucleophile was produced. The reaction proceeded efficiently under organic solvent or organic solvent/aqueous buffer (1/1) conditions. This reaction would be useful for the synthesis of unique butenolide derivatives and derivatization of acidic functional groups contained in aqueous biomolecules.

Preparation and antibacterial activity of coronarin E derivatives

Coronarin E is a main diterpene ever isolated from Hedychium yunnanense. With the aim to enlarge its potential application, four butenolide derivatives (compounds 4a, 4b, 5a and 5b) were obtained from coronarin E via synthetic method, and their antibacterial effects were also evaluated. It is noteworthy that compounds 5a and 5b exhibited stronger antibacterial activities against most of the tested bacterial strains than ampicillin and kanamycin, two first- and second-line antimicrobials in clinical. For example, minimum inhibitory concentration (MIC) of 5a, 5b, ampicillin and kanamycin against Acinetobacter baumanii were 2, 1, 8 and 4 μg/mL, respectively, and MIC of the four compounds mentioned above against Klebsiella pneumonia were 1, 0.5, 16 and 4 μg/mL, respectively. The current studies not only enrich the structural diversity of diterpenes derived from Hedychium genus, but also provide potent candidates for the development of antibacterial medicines.

Design and structure optimization of novel butenolide derivatives as low bee-toxicity candidates

The discovery of new neonicotinoid alternatives with high efficiency against pests and eco-safety toward bees has become an increasingly urgent need in recent years. The relationship between the oil-water partition coefficient (logP) and the bee-toxicity of commercial nicotinic acetylcholine receptor (nAChR) competitive modulators was explored in this work. Compared compounds with a high bee-toxicity, compounds with low bee-toxicity were found to have higher logP values. Therefore, two series of novel butenolide derivatives with different hydrophobic groups were designed and synthesized by including different hydrophobic groups. The insecticidal activity study showed that compounds I-01 (LC50=112.96 μg/mL), II-05 (LC50=124.68 μg/mL), and II-11 (LC50=87.89 μg/mL) were with higher insecticidal activity against Aphis glycines and lower calculated logP values among all synthesized compounds. Molecular dynamics simulations indicated that three butenolide compounds formed some hydrogen bonding or π-π stacking interactions with insect acetylcholine binding protein (AChBP). In addition, the bee-toxicity bioassay also showed that compounds I-01, II-05 and II-11 were with much lower contact bee-toxicity than imidacloprid. The possible mechanism of the bee toxicity of the novel butenolide compounds was explored based on the nAChR function subunit AmeIα8/ratβ2. This study will provide rational guidance on novel butenolide compounds as low-bee-toxicity candidates based on their molecular hydrophobic properties.

Alterbutenolide, a new butenolide derivative from a sponge-derived fungus Alternaria alternata I-YLW6-1

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-2H-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 IC50 values from 3.0 to 36.2 μg/mL, whereas compound 1 only displayed moderate inhibition against Chattonella marina with IC50 value of 34.6 μg/mL. Meanwhile, compounds 3 and 4 showed weak toxicity against brine shrimp larvae with LC50 values >100 μg/mL.

First total synthesis of type II abyssomicins: (±)-abyssomicin 2 and (±)-neoabyssomicin B.

The intramolecular Diels-Alder reaction (IMDA) of a butenolide derivative, as an entry to the type II abyssomicin scaffold, and the total synthesis of (±)-abyssomicin 2 and (±)-neoabyssomicin B are reported for the first time. A facile route to the IMDA precursor, the formation of a type I intermediate and two paths to (±)-neoabyssomicin B are also discussed.

Two New Alkaloids and a New Butenolide Derivative from the Beibu Gulf Sponge-Derived Fungus Penicillium sp. SCSIO 41413.

Marine sponge-derived fungi have been proven to be a prolific source of bioactive natural products. Two new alkaloids, polonimides E (1) and D (2), and a new butenolide derivative, eutypoid F (11), were isolated from the Beibu Gulf sponge-derived fungus, Penicillium sp. SCSIO 41413, together with thirteen known compounds (3-10, 12-16). Their structures were determined by detailed NMR, MS spectroscopic analyses, and electronic circular dichroism (ECD) analyses. Butenolide derivatives 11 and 12 exhibited inhibitory effect against the enzyme PI3K with IC50 values of 1.7 μM and 9.8 μM, respectively. The molecular docking was also performed to understand the inhibitory activity, while 11 and 12 showed obvious protein/ligand-binding effects to the PI3K protein. Moreover, 4 and 15 displayed obvious inhibitory activity against LPS-induced NF-κB activation in RAW264.7 cells at 10 µM.

Butenolide derivatives from Aspergillus terreus selectively inhibit butyrylcholinesterase.

Two undescribed butenolide derivatives, asperteretal J (1) and K (2), together with 13 known ones (3-15) were isolated from an endophytic fungus Aspergillus terreus SGP-1, the fermentation product of which exhibited selective inhibitory activity toward butyrylcholinesterase. The structures of the new compounds were elucidated based on HRMS and NMR data, and the absolute configurations were determined by specific optical rotation comparison. All compounds were evaluated for cholinesterase inhibitory effects with galantamine as a positive control. Compounds 4-8 selectively inhibited butyrylcholinesterase with IC50 values of 18.4-45.8µM in a competitive manner, with Ki values of 12.3-38.2µM. The structure-activity relationship was discussed. Molecular docking and dynamic simulation of the inhibitor-enzyme complex were performed to better understand the interactions.

Sargassumin C, a Novel Butenolide from Sargassum micracanthum

Objective: In our ongoing effort to search for the novel secondary metabolites from the marine algae, chemical investigation of a methanolic extract of Sargassum micracanthum led to the isolation of a novel butenolide (1) and a known compound (2). Methods: The methanolic extract of S. micracanthum was partitioned and subjected to medium pressure column chromatography and preparative-HPLC to yield two compounds (1 and 2). Their structures were established based on comprehensive spectroscopic data (1D NMR, 2D NMR, and HRESIMS). These compounds (1 and 2) were evaluated for the production of the NO in lipopolysaccharide (LPS)-induced RAW264.7 cells and pro-inflammatory cytokines such as IL-6, IL-1 β, TNF- α, and IL-10. Results: A new compound (1) was determined to be a new butenolide derivative, and a known compound (2) were identified as 2-hydroxy-(5 E,9 E)-6,10,14-trimethylpentadeca-5,9-dien-12-one. Compounds 1 and 2 showed inhibitory activities in a dose-dependent manner on LPS-induced NO production in RAW264.7 cells and pro-inflammatory cytokines. Conclusion: A new butenolide, sargassumin C (1), and 2-hydroxy-(5 E,9 E)-6,10,14-trimethylpentadeca-5,9-dien-12-one (2) were isolated from the brown alga, S. micracanthum. Compound 2 was more effective than 1 on NO production and pro-inflammatory cytokines.

Anti-Inflammatory, Antiallergic and COVID-19 Main Protease (Mpro) Inhibitory Activities of Butenolides from a Marine-Derived Fungus Aspergillus costaricaensis.

Amid the current COVID‐19 pandemic, the emergence of several variants in a relatively high mutation rate (twice per month) strengthened the importance of finding out a chemical entity that can be potential for developing an effective medicine. In this study, we explored ethyl acetate (EtOAc) extract of a marine‐derived fungus Aspergillus cosatricaensis afforded three butenolide derivatives, butyrolactones I, VI and V (1–3), two naphtho‐γ‐pyrones, TMC‐256 A1 (4) and rubrofusarin B (5) and methyl p‐hydroxyphenyl acetate (6). Structure identification was unambiguously determined based on exhaustive spectral analyses including 1D/2D NMR and mass spectrometry. The isolated compounds (1–6) were assessed for their in vitro anti‐inflammatory, antiallergic, elastase inhibitory activities and in silico SARS‐CoV‐2 main protease (Mpro). Results exhibited that only butenolides (1 and 2) revealed potent activities similar to or more than reference drugs unlike butyrolactone V (3) suggesting them as plausible chemical entities for developing lead molecules.

Et3N catalyzed direct α-addition cascade isomerization of deconjugated butenolides with α-ketoesters for the synthesis of α,γ-disubstituted butenolide derivatives

The α,γ-disubstituted butenolides are widespread occurrences in numerous pharmacologically active molecules. In this paper, a highly efficient method for the synthesis of α,γ-disubstituted butenolide derivatives via a direct α-addition cascade isomerization of deconjugated butenolides with α-ketoesters using Et3N as catalyst, has been successfully developed. A series of α,γ-disubstituted butenolides have been obtained in up to 97% yield with excellent regioselectivities (up to >19/1 rr). To the best of our knowledge, there is no precedent for the application of deconjugated butenolides in the direct α-addition cascade isomerization to prepare α,γ-disubstituted butenolides to date.

Photoredox catalyzed difluoro(phenylthio)methylation of 2,3-allenoic acids with {difluoro(phenylthio)methyl}triphenylphosphonium triflate

The photoredox catalyzed difluoro(phenylthio)methylation of 2,3-allenoic acids with {difluoro(phenylthio)methyl}triphenylphosphonium triflate was investigated. A series of 4-aryl-2,3-allenoic acids underwent tandem radical difluoro(phenylthio)methylation/intramolecular cyclization to afford previously unknown 4-difluoro(phenylthio)methylated butenolides, which could be converted to the corresponding difluoro(phenylthio)methylated furan-2(3H)-one and difluoro(phenylsulfonyl)methylated butenolide derivatives.

A new Butenolide Derivative from the Brown Alga Sargassum micracanthum

A new butenolide derivative (1), along with three known compounds (2-4) were isolated from the MeOH extract of brown alga Sargassum micracanthum. The structures of 1 to 4 were determined by the analyses of 1D and 2D NMR and mass spectroscopic data. The known compounds (2-4) were identified as (5 E,10 Z)-6,10,14-trimethylpentadeca-5,10-dien-2,12-dione (2), (5 E,9 E)-6,10,14-trimethylpentadeca-5,9-dien-2,12-dione (3), and (-)-loliolide (4) by comparing with their published spectroscopic data. The antioxidant activities of compounds 1 to 4 were evaluated based on using 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities. Compounds 1 to 4 were inactive at the concentration of 200 μM.

Access to α,α-difluoro(arylthio)methyl oxetanes from α,α-difluoro(arylthio)methyl ketones and trimethylsulfoxonium halides: scope, mechanism and applications.

A general and practical method for the synthesis of α,α-difluoro(arylthio)methyl oxetanes that occurs by the reaction of α,α-difluoro(arylthio)methyl ketones with trimethylsulfoxonium halides is reported. This reaction proceeds via the sequential Corey-Chaykovsky epoxidation and regioselective ring-expansion pathways and features mild conditions, operational simplicity, gram-scalability, a broad substrate scope and high yields. α,α-Difluoro(arylthio)methyl oxiranes have been shown to be the reaction intermediates. The obtained α,α-difluoro(arylthio)methyl oxetanes were further converted into useful sulfone, butenolide, and tetrahydrofuran derivatives.

Structures and absolute configurations of butenolide derivatives from the isopod-associated fungus Pidoplitchkoviella terricola

In this research, twenty aromatic and branched aliphatic polyketides, including seven previously undescribed butenolide derivatives, piterriones A-G and one known analogue, along with twelve known altenusin derivatives, were isolated from the isopod-associated fungus Pidoplitchkoviella terricola. Their structures were elucidated by analysis of NMR (1D and 2D) and mass spectrometry data, and their absolute configurations were determined by Mosher's method, microscale derivatization, and comparison of their specific rotations and ECD spectra. Dihydroaltenuene B exhibited mushroom tyrosinase inhibitory activity with an IC50 value of 38.33±1.59μM, which was comparable to that of the positive control, kojic acid (IC50=39.72±1.34μM). A molecular-docking study disclosed the hydrogen bonding interactions between the 3-OH and 4'-OH of dihydroaltenuene B and the His244, Met280 and Gly281 residues of tyrosinase.

Indole diketopiperazine alkaloids and aromatic polyketides from the Antarctic fungus Penicillium sp. SCSIO 05705

A new indole diketopiperazine alkaloid, named penilline D (1), together with five known indole alkaloid analogues (2–5, 11), two meroterpenoids (6 and 12), and four butenolide derivatives (7–10), were isolated from the Antarctic fungus Penicillium sp. SCSIO 05705. Extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation were used to elucidate the structure of penilline D (1), including its absolute configuration. All isolated compounds (1–12) were evaluated for their cytotoxic, antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among them, compound 5 exhibited moderate in vitro cytotoxic activity against the 143B cell line with IC50 value of 12.64 ± 0.78 μM. Compound 6 showed strong inhibitory activity against AChE with IC50 value of 0.36 nM (IC50 18.7 nM for Tacrine), while compounds 6 and 11 showed weak PL enzyme inhibitory activity. Furthermore, an in silico molecular docking study was also performed between 6 and AChE.

Synthetic Analogue of Butenolide as an Antifouling Agent.

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.

Synthesis, antibacterial activity and mechanism of new butenolides derivatives containing an amide moiety

A series of novel butenolide derivatives containing an amide were designed and synthesized with flupyradifurone as the lead compound. The biological activities test found that this series of compounds did not exhibit insecticidal activity, but had good antibacterial activities. Among all target compounds, compound 19 showed good antibacterial activity in vitro against Xanthomonas oryzae pv. oryzae (Xoo), with an EC50 value of 35.8 mg/L, which was superior to that of bismerthiazol (73.5 mg/L). Under greenhouse conditions, the curative and protective activities of compound 19 against bacterial leaf blight were 40.9% and 48.9% at 100 mg/L, respectively, which were superior to those of bismerthiazol (31.2% and 31.4%). In addition, compound 19 can not only cause changes in the cell surface morphology of Xoo, but also increase the activity of rice defense enzymes. The mechanism of action studies showed that the protective activity of compound 19 against rice bacterial leaf blight is closely related to the improvement of defense-related enzyme activities and the upregulation of proteins involved in oxidative phosphorylation.

Anti-Inflammatory, Antiallergic, and COVID-19 Main Protease (Mpro) Inhibitory Activities of Butenolides from a Marine-Derived Fungus Aspergillus terreus.

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 (Mpro) 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.