Structural modification of natural axinelline A: Achieving reduced colitis side effects through balanced COX inhibition.

Marine natural products continue to hold great promise as potential candidates for the discovery of anti-inflammatory drug. In our previous investigation, we successfully synthesized axinelline A, a naturally occurring cyclooxygenase-2 (COX-2) inhibitor, as a promising anti-inflammatory lead compound. This study was to discover novel COX inhibitors with balanced inhibition, aiming to mitigate the severe adverse effects through further structural modification of axinelline A. Of the synthetic derivatives, compound 5e showed highest COX-2 inhibitory activity and balanced COX inhibition (IC50 = 1.74 µM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 16.32). The in vitro anti-inflammatory results indicated that 5e effectively suppressed the expression of pro-inflammatory mediators via the NF-κB signaling pathway rather than the MAPK signaling pathway. The in vivo ulcerative colitis assay demonstrated 5e significantly ameliorated the histological damages and showed strong protection against DSS-induced acute colitis. Therefore, our findings suggest that compound 5e exhibits potential as a promising anti-inflammatory agent with attenuated colitis-related adverse effects.

A Chemo-Enzymatic Approach for Preparing Efinaconazole with High Optical Yield.

Herein, we present a novel and ecofriendly biocatalytic approach for synthesizing efinaconazole (7), a clinically used antifungal agent. This method involves utilizing benzaldehyde lyase (BAL) to catalyze the crucial benzoin condensation step in the ketone precursor. Treating 2,4-difluorobenzaldehyde with BAL in the presence of thiamin-diphosphate (ThDP) and Mg2+ resulted in the formation of α-hydroxy ketone which then underwent the preparation of 7. This innovative approach not only provides a greener alternative but also offers significant advantages over the traditional chemical process. Through our efforts and development work, we have established efficient and scalable procedures that enable the production of 7 in a moderate 38% yield.

1,2,4-Oxadiazole as a potential scaffold in agrochemistry: a review.

N,O-containing heterocycles have been incorporated into various approved pesticides and pesticide candidates. The persistent challenge in contemporary crop protection lies in the continuous pursuit of novel N,O-heterocycle-containing compounds with pesticidal properties. Among them, the 1,2,4-oxadiazole scaffold is one of the most extensively explored heterocycles in new pesticide discovery and development. This review focuses on elucidating the molecular design strategy employed along with highlighting the bioactivity of 1,2,4-oxadiazole derivatives since 2012. Throughout this time frame, tioxazafen and flufenoxadiazam have emerged as prominent examples in which 1,2,4-oxadiazole derivatives were utilized as the core active structure within numerous applications. Additionally, the preparation methods for substituted 1,2,4-oxadiazole derivatives are elaborated upon, and their potential value within agrochemistry is discussed.

Synthesis and Anti-Inflammatory Activity of the Natural Cyclooxygenase-2 Inhibitor Axinelline A and Its Analogues.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used medications to treat conditions such as arthritis, pain, and fever. They reduce inflammation by inhibiting cyclooxygenase (COX) enzymes that catalyze the committed step in prostaglandin (PG) biosynthesis. Despite their significant therapeutic benefits, many NSAIDS have undesirable adverse effects. The aim of this study was to discover novel COX inhibitors from natural sources. Here, we describe the synthesis and anti-inflammatory activity of the COX-2 inhibitor axinelline A (A1), which was isolated from Streptomyces axinellae SCSIO02208, and its analogues. Compared to the synthetic analogues, the natural product A1 has stronger COX inhibitory activity. Although A1 is more active against COX-2 than COX-1, its selectivity index is low; therefore, it may be classified as a nonselective COX inhibitor. Its overall activity is comparable to the clinically used drug diclofenac. In silico studies showed that A1 binds to COX-2 in a similar manner to diclofenac. Inhibition of COX enzymes by A1 in LPS-stimulated murine RAW264.7 macrophages resulted in suppression of the NF-κB signaling pathway, leading to reduced expression of pro-inflammatory factors such as iNOS, COX-2, TNF-α, IL-6, and IL-1ß and reduced production of PGE2, NO, and ROS. The potent in vitro anti-inflammatory activity of A1, together with its lack of cytotoxicity, makes it an attractive candidate for a new anti-inflammatory lead.

Identification and Biological Activity of NFAT-133 Congeners from Streptomyces pactum.

The soil bacterium Streptomyces pactum ATCC 27456 produces a number of polyketide natural products. Among them is NFAT-133, an inhibitor of the nuclear factor of activated T cells (NFAT) that suppresses interleukin-2 (IL-2) expression and T cell proliferation. Biosynthetic gene inactivation in the ATCC 27456 strain revealed the ability of this strain to produce other polyketide compounds including analogues of NFAT-133. Consequently, seven new derivatives of NFAT-133, TM-129-TM-135, together with a known compound, panowamycin A, were isolated from the culture broth of S. pactum ATCC 27456 ΔptmTDQ. Their chemical structures were elucidated on the basis of their HRESIMS, 1D and 2D NMR spectroscopy, and ECD calculation and spectral data. NFAT-133, TM-132, TM-135, and panowamycin A showed no antibacterial activity or cytotoxicity, but weakly reduced the production of LPS-induced nitric oxide in RAW264.7 cells in a dose-dependent manner. A revised chemical structure of panowamycin A and proposed modes of formation of the new NFAT-133 analogues are also presented.

Anti-inflammatory effects of an optimized PPAR-γ agonist via NF-κB pathway inhibition.

In our previous study, a PPAR-γ agonist (+)-(R,E)-6a1 was elaborated as an anti-inflammatory lead. However, in silico analysis showed that (+)-(R,E)-6a1 lacks key hydrogen bonding with Tyr473 of PPAR-γ LBD (ligand binding domain). To facilitate additional hydrogen bonding with Tyr473, a more polar head group was introduced to the structure of (+)-(R,E)-6a1, and we also attempted to synthesize enzymatically stable derivatives. Of the synthetic derivatives, compound (+)-(R,E)-5f showed highest PPAR-γ transcriptional activity and reasonable metabolic stability. Compound (+)-(R,E)-5f suppressed the expression of pro-inflammatory mediators such as inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α). Reduction of nitric oxide (NO), and ROS was also observed. Compound (+)-(R,E)-5f was found to suppress the NF-κB pathway by inhibiting phosphorylation of IKK (IκB kinase), and this may lead to subsequent inhibition of IκBα (inhibitor of NF-κBα) phosphorylation and inhibition of NF-κB activation. These results indicate that (+)-(R,E)-5f exerts anti-inflammatory activity via NF-κB pathway inhibition, and may serve as a potential anti-inflammatory lead.

Viriditoxin Stabilizes Microtubule Polymers in SK-OV-3 Cells and Exhibits Antimitotic and Antimetastatic Potential.

Microtubules play a crucial role in mitosis and are attractive targets for cancer therapy. Recently, we isolated viriditoxin, a cytotoxic and antibacterial compound, from a marine fungus Paecilomyces variotii. Viriditoxin has been reported to inhibit the polymerization of bacterial FtsZ, a tubulin-like GTPase that plays an essential role in bacterial cell division. Given the close structural homology between FtsZ and tubulin, we investigated the potential antimitotic effects of viriditoxin on human cancer cells. Viriditoxin, like paclitaxel, enhanced tubulin polymerization and stabilized microtubule polymers, thereby perturbing mitosis in the SK-OV-3 cell line. However, the morphology of the stabilized microtubules was different from that induced by paclitaxel, indicating subtle differences in the mode of action of these compounds. Microtubule dynamics are also essential in cell movement, and viriditoxin repressed migration and colony formation ability of SK-OV-3 cells. Based on these results, we propose that viriditoxin interrupts microtubule dynamics, thus leading to antimitotic and antimetastatic activities.

Colletoindole A from the Mangrove Plant Endophytic Fungus Colletotrichum tropicale SCSIO 41022.

A new indole derivative colletoindole A (1), along with two new indole derivatives (2 and 3) and one known compound acropyrone (4) were isolated from cultures of Colletotrichum tropicale SCSIO 41022 derived from a mangrove plant Kandelia candel. The structures of 1-4 were determined by analysis of NMR and MS data. The cytotoxicity of 1, 2 and 4, and the COX-2 inhibitory activity of 1 and 2 were evaluated.

An Algal Metabolite-Based PPAR-γ Agonist Displayed Anti-Inflammatory Effect via Inhibition of the NF-κB Pathway.

In our previous study, a synthetic compound, (+)-(R,E)-6a1, that incorporated the key structures of anti-inflammatory algal metabolites and the endogenous peroxisome proliferator-activated receptor γ (PPAR-γ) ligand 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), exerted significant PPAR-γ transcriptional activity. Because PPAR-γ expressed in macrophages has been postulated as a negative regulator of inflammation, this study was designed to investigate the anti-inflammatory effect of the PPAR-γ agonist, (+)-(R,E)-6a1. Compound (+)-(R,E)-6a1 displayed in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-stimulated murine RAW264.7 macrophages. Compound (+)-(R,E)-6a1 suppressed the expression of proinflammatory factors, such as nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), possibly by the inhibition of the nuclear factor-κB (NF-κB) pathway. In macrophages, (+)-(R,E)-6a1 suppressed LPS-induced phosphorylation of NF-κB, inhibitor of NF-κB α (IκBα), and IκB kinase (IKK). These results indicated that PPAR-γ agonist, (+)-(R,E)-6a1, exerts anti-inflammatory activity via inhibition of the NF-κB pathway.

Chaetochromones A - C, Three New Polyketides from Mangrove Plant Derived Endophytic Fungus Phomopsis sp. SCSIO 41006.

Three new polyketides, chaetochromones A - C (1 - 3), together with a chromone (4), were isolated from the ethyl acetate extract of mangrove-derived fungus Phomopsis sp. SCSIO 41006. Their structures were elucidated by means of spectroscopic techniques (UV, IR, MS, 1D- and 2D-NMR). The absolute configurations of the new compounds were established by CD data.

Aspergchromones A and B, two new polyketides from the marine sponge-associated fungus Aspergillus sp. SCSIO XWS03F03.

Two new polyketides, aspergchromones A (1) and B (2), together with five known compounds, secalonic acid D (3), noreugenin (4), (3S)-5-hydroxymellein (5), (4S)-6-hydroxyisosclerone (6), and (-)-regiolone (7), were isolated from the ethyl acetate extract of marine sponge-derived fungus Aspergillus sp. SCSIO XWS03F03. Their structures were elucidated by means of spectroscopic techniques (1D and 2D NMR, MS, UV, and IR). The absolute configurations of the new compounds were established by ECD calculations. Compound 3 showed moderate antimicrobial activity.

Cytotoxic cytochalasins from marine-derived fungus Arthrinium arundinis.

Four new cytochalasins, arthriniumnins A-D (1-4), a new natural product, ketocytochalasin (5), as well as five known cytochalasin analogues (6-10) were isolated and identified from the fungus Arthrinium arundinis ZSDS1-F3 from the sponge Phakellia fusca. Their structures were elucidated by NMR spectroscopic and mass spectrometric analyses, as well as single crystal X-ray diffraction. Compounds 6 and 9 showed cytotoxicity against K562, A549, Huh-7, H1975, MCF-7, U937, BGC823, HL60, Hela, and MOLT-4 cell lines, with IC50 values ranging from 1.13 to 47.4 µM.

N-(3-aminopropyl)subergorgamide, a new alkaloid from the gorgonian Paraplexaura sp.

A new alkaloid named N-(3-aminopropyl)subergorgamide (1), along with nine known nitrogen-containing compounds (2-10), was isolated from the organic extract of gorgonian Paraplexaura sp. collected from Zhanjiang in Naozhou Island, South China Sea. Their structures were established by detailed MS and NMR spectroscopic analyses, as well as by comparison with literature data.

Synthesis and anti-inflammatory activity of novel firocoxib analogues with balanced COX inhibition.

The adverse effects caused by nonselective and selective cyclooxygenase-2 (COX-2) inhibitors remain a challenge for current anti-inflammatory medications. A balanced inhibition of COX-1/-2 represents a promising strategy for the development of novel COX-2 inhibitors. In this study, we present the design and synthesis of a novel series of firocoxib analogues incorporating an amide bond to facilitate essential hydrogen bonding with amino residues in COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX-1 and COX-2 enzymes. Among them, compound 9d demonstrated potent and balanced inhibition. Inhibition of COX enzymes by 9d in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages resulted in the suppression of the NF-κB signaling pathway to reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, nitric oxide (NO), and reactive oxygen species (ROS). The remarkable in vitro anti-inflammatory activity exhibited by 9d positions it as a promising candidate for further development as a novel lead compound for inflammation treatment.

Structural modification based on the diclofenac scaffold: Achieving reduced colitis side effects through COX-2/NLRP3 selective inhibition.

COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles 4a-4w, triazoles 6a-6m, and cyclic imides 7a and 7b, were synthesized. The synthesized analogues were evaluated for their inhibitory activity against COX-2 enzyme. Among them, compound 6k exhibited potent selective COX-2 inhibition (IC50 = 1.53 µM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 17.19). Treatment with compound 6k effectively suppressed the NF-κB/NLRP3 signaling pathway, resulting in reduced expression of pro-inflammatory factors. The in vivo ulcerative colitis assay demonstrated that compound 6k significantly ameliorated histological damages and showed strong protection against DSS-induced acute colitis. The collected results indicated that compound 6k displays anti-inflammatory activity through COX-2/NLRP3 inhibition. Therefore, compound 6k represents a promising candidate for further development as a new lead compound with reduced colitis side effects.

Genomic Analysis of Kitasatospora setae to Explore Its Biosynthetic Potential Regarding Secondary Metabolites.

Actinomycetes have long been recognized as important sources of clinical antibiotics. However, the exploration of rare actinomycetes, despite their potential for producing bioactive molecules, has remained relatively limited compared to the extensively studied Streptomyces genus. The extensive investigation of Streptomyces species and their natural products has led to a diminished probability of discovering novel bioactive compounds from this group. Consequently, our research focus has shifted towards less explored actinomycetes, beyond Streptomyces, with particular emphasis on Kitasatospora setae (K. setae). The genome of K. setae was annotated and analyzed through whole-genome sequencing using multiple bio-informatics tools, revealing an 8.6 Mbp genome with a 74.42% G + C content. AntiSMASH analysis identified 40 putative biosynthetic gene clusters (BGCs), approximately half of which were recessive and unknown. Additionally, metabolomic mining utilizing mass spectrometry demonstrated the potential for this rare actinomycete to generate numerous bioactive compounds such as glycosides and macrolides, with bafilomycin being the major compound produced. Collectively, genomics- and metabolomics-based techniques confirmed K. setae's potential as a bioactive secondary metabolite producer that is worthy of further exploration.

Marchaetoglobins A-D: Four Cytochalasans with Proangiogenic Activity from the Marine-Sponge-Associated Fungus Chaetomium globosum 162105.

Four new cytochalasans, marchaetoglobins A-D (1-4), along with five known compounds (5-9), were isolated from the marine-sponge-associated fungus Chaetomium globosum 162105. Compounds 1-4 represent examples of 19,20-seco-chaetoglobosins, of which compound 1 is the first furan-containing cytochalasan. Their structures and absolute configurations were elucidated by extensive spectroscopic analyses and electronic circular dichroism calculations. Compounds 5, 8, and 9 displayed weak to moderate antibacterial activities against Bacillus thuringiensis, Edwardsiella piscicida, Vibrio alginolyticus, and Pseudomonas syringae pv. actinidiae with minimum inhibitory concentration values ranging from 5 to 25 µg/mL. In addition, compounds 2, 3, and 5 showed potent in vivo proangiogenic activity in transgenic zebrafish, comparable to the positive control.

Design of Balanced Cyclooxygenase Inhibitors Based on Natural Anti-inflammatory Ascidian Metabolites and Celecoxib.

The serious adverse effects caused by non-selective and selective cyclooxygenase-2 (COX-2) inhibitors remain significant concerns for current anti-inflammatory drugs. In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6 m, exhibiting potent balanced inhibition, was selected for subsequent in vitro anti-inflammatory assays. Treatment with 6 m effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, resulting in reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, as well as decreased production of prostaglandin E2 (PGE2 ), nitric oxide (NO), and reactive oxygen species (ROS). However, 6 m has no effect on the MAPK signaling pathway. Therefore, due to its potent in vitro anti-inflammatory activity coupled with lack of cytotoxicity, 6 m represents a promising candidate for further development as a new lead compound targeting inflammation.

Actinomycins produced by endophyte Streptomyces sp. GLL-9 from navel orange plant exhibit high antimicrobial effect against Xanthomonas citri susp. citri and Penicillium italicum.

BACKGROUND: Citrus canker and citrus blue mold are two severe diseases in citrus plants, which are mainly caused by Xanthomonas citri susp. citri (Xcc) and Penicillium italicum, respectively. The currently widely used pesticides for these two diseases are harmful to human health and the environment. Therefore, searching for novel antimicrobial agents, especially from natural resources, is getting increasing interest. RESULTS: In this study, the crude extract of Streptomyces sp. GLL-9, an endophyte from a navel orange tree, was found to exhibit excellent antimicrobial effects against Xcc and P. italicum. Bioassay-guided isolation led to the discovery of three actinomycins (Acts), actinomycin X2 (Act-X2 ), actinomycin D (ActD), and actinomycin XOß (Act-XOß ). The MIC (minimum inhibitory concentration) values of Act-X2 , ActD, and Act-XOß were 31.25, 62.50, and 62.50 µg mL-1 against Xcc, respectively, while 62.50 (Act-X2 ) and 125.00 µg mL-1 (ActD) against P. italicum, being better or comparable to the positive controls. The highest yield of Acts was obtained by solid-state fermentation with rice containing 1% L-tryptophan as a culture medium, being 6.03, 3.07, and 1.02 mg g-1 , for Act-X2 , ActD, and Act-XOß , respectively. The ethyl acetate extract of Streptomyces sp. GLL-9 cultivated under the optimal fermentation conditions (EAE-1) can efficiently control these two citrus diseases by excessively producing reactive oxygen species (ROS) in both pathogens, damaging the cell membranes of P. italicum, and inhibiting the growth of Xcc. In addition, Act-X2 , ActD, and EAE-1 displayed broad-spectrum antifungal activity. CONCLUSION: EAE-1 and Acts produced by Streptomyces sp. GLL-9 have high potential as novel antimicrobial agents against plant pathogens. © 2023 Society of Chemical Industry.

Structure-guided design of novel HEPT analogs with enhanced potency and safety: From Isopropyl-HEPTs to Cyclopropyl-HEPTs.

Members of the HEPT class are potential non-nucleoside inhibitors of HIV-1 reverse transcriptase. Our previously disclosed one representative HEPT analog 2 produced potent inhibitory activity against wild-type HIV-1 (EC50 = 63.0 nM), but its high cytotoxicity and low selectivity index still needs to be improved (CC50 = 34.0 µM, SI = 565). In this work, a series of novel cyclopropyl-substituted HEPT analogs were developed by substituting a cyclopropyl ring for the isopropyl group at the C-5 position of 2 with the purpose of improving its potency and safety. Of this series, the most potent compound 9h featuring a 2,5-fluoro substitution on the C-6 benzene ring exerted significantly increased inhibitory activity toward wild-type HIV-1 (EC50 = 0.017 µM), which was 4-fold more active than the lead compound 2. The cytotoxicity of 9h was also reduced with much higher selectivity index (SI > 2328). This compound possessed good pharmacokinetics profiles and potential safety: (1) No obvious in vitro inhibition effect toward CYP enzyme and hERG was observed in 9h; (2) The single-dose acute toxicity test did not induce mice death and obvious pathological damage; (3) Excellent oral bioavailability of 9h (F= 86%) in rats was unveiled. These results provide valuable guidance for further development of HEPT anti-HIV-1 drugs.