Design, Synthesis, Antifungal Activity, and Action Mechanism of Pyrazole-4-carboxamide Derivatives Containing Oxime Ether Active Fragment As Succinate Dehydrogenase Inhibitors.

The dearomatization at the hydrophobic tail of the boscalid was carried out to construct a series of novel pyrazole-4-carboxamide derivatives containing an oxime ether fragment. By using fungicide-likeness analyses and virtual screening, 24 target compounds with theoretical strong inhibitory effects against fungal succinate dehydrogenase (SDH) were designed and synthesized. Antifungal bioassays showed that the target compound E1 could selectively inhibit the in vitro growth of R. solani, with the EC50 value of 1.1 µg/mL that was superior to that of the agricultural fungicide boscalid (2.2 µg/mL). The observations by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that E1 could reduce mycelial density and significantly increase the mitochondrial number in mycelia cytoplasm, which was similar to the phenomenon treated with boscalid. Enzyme activity assay showed that the E1 had the significant inhibitory effect against the SDH from R. solani, with the IC50 value of 3.3 µM that was superior to that of boscalid (7.9 µM). The mode of action of the target compound E1 with SDH was further analyzed by molecular docking and molecular dynamics simulation studies. Among them, the number of hydrogen bonds was significantly more in the SDH-E1 complex than that in the SDH-boscalid complex. This research on the dearomatization strategy of the benzene ring for constructing pyrazole-4-carboxamides containing an oxime ether fragment provides a unique thought to design new antifungal drugs targeting SDH.

Synthesis and Evaluation of diaryl ether modulators of the leukotriene A4 hydrolase aminopeptidase activity.

Activation of the aminopeptidase (AP) activity of leukotriene A4 hydrolase (LTA4H) presents a potential therapeutic strategy for resolving chronic inflammation. Previously, ARM1 and derivatives were found to activate the AP activity using the alanine-p-nitroanilide (Ala-pNA) as a reporter group in an enzyme kinetics assay. As an extension of this previous work, novel ARM1 derivatives were synthesized using a palladium-catalyzed Ullmann coupling reaction and screened using the same assay. Analogue 5, an aminopyrazole (AMP) analogue of ARM1, was found to be a potent AP activator with an AC50 of 0.12 µM. An X-ray crystal structure of LTA4H in complex with AMP was refined at 2.7 Å. Despite its AP activity with Ala-pNA substrate, AMP did not affect hydrolysis of the previously proposed natural ligand of LTA4H, Pro-Gly-Pro (PGP). This result highlights a discrepancy between the hydrolysis of more conveniently monitored chromogenic synthetic peptides typically employed in assays and endogenous peptides. The epoxide hydrolase (EH) activity of AMP was measured in vivo and the compound significantly reduced leukotriene B4 (LTB4) levels in a murine bacterial pneumonia model. However, AMP did not enhance survival in the murine pneumonia model over a 14-day period. A liver microsome stability assay showed metabolic stability of AMP. The results suggested that accelerated Ala-pNA cleavage is not sufficient for predicting therapeutic potential, even when the full mechanism of activation is known.

Design, Synthesis, Antifungal Activity, and 3D-QASR of Novel Oxime Ether-Containing Coumarin Derivatives as Potential Fungicides.

Structural modification of natural products is an effective approach for improving antifungal activity and has, therefore, been used extensively in the development of new agrochemical products. In this work, a series of novel coumarin derivatives containing oxime ether structures were designed, synthesized, and evaluated for antifungal activity. Some of the designed compounds exhibited promising antifungal activities against tested fungi, and compounds 4a, 4c, 5a, and 6b had EC50 values equivalent to those of commercial fungicides. Compound 6b was the most promising candidate fungicide against Rhizoctonia solani (EC50 = 0.46 µg/mL). In vivo antifungal bioassays suggested that compounds 5a and 6b could serve as novel agricultural antifungals. Furthermore, microscopy demonstrated that compound 6b induced the sprawling growth of hyphae, distorted the outline of cell walls, and reduced mitochondrial numbers. Additionally, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields were elucidated using an accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model. The results presented here will guide the discovery of potential novel fungicides for plant disease control in agriculture.

Novel ether derivatives of 11-azaartemisinins with high order antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice.

This study investigates cutting-edge synthetic chemistry approaches for designing and producing innovative antimalarial drugs with improved efficacy and fewer adverse effects. Novel amino (-NH2) and hydroxy (-OH) functionalized 11-azaartemisinins 9, 12, and 14 were synthesized along with their derivatives 11a, 13a-e, and 15a-b through ART and were tested for their AMA (antimalarial activity) against Plasmodium yoelii via intramuscular (i.m.) and oral routes in Swiss mice. Ether derivative 13c was the most active compound by i.m. route, it has shown 100 % protection at the dose of 12 mg/kg × 4 days and showed 100 % clearance of parasitaemia on day 4 at dose of 6 mg/kg. Amine 11a, ether derivatives 13d, 13e and ether 15a also showed promising antimalarial activity. ß-Arteether gave 100 % protection at the dose of 48 mg/kg × 4 days and 20 % protection at 24 mg/kg × 4 days dose by oral route, while it showed 100 % protection at 6 mg/kg × 4 days and no protection at 3 mg/kg × 4 days by i.m. route.

Chemical and Antiplasmodial Investigations on Eremophila-Derived Alkaloids and Semisynthetic Ether Analogues.

Microthecaline A (1), the known antiplasmodial quinoline serrulatane alkaloid from the roots of Eremophila microtheca F. Muell. ex Benth. (Scrophulariaceae), was targeted for isolation and subsequent use in the generation of a semisynthetic ether library. A large-scale extraction and isolation yielded the previously undescribed quinoline serrulatane microthecaline B (2), along with crystalline 1 that enabled the first X-ray crystallographic analysis to be undertaken on this rare alkaloid structure class. The X-ray diffraction analysis of 1 supported the absolute configuration assignment of microthecaline A, which was originally assigned by ECD data analysis. Microthecaline A (1) was converted into 10 new semisynthetic ether derivatives (3-12) using a diverse series of commercially available alkyl halides. Chemical structures of the new serrulatane alkaloid and semisynthetic ether analogues were assigned by spectroscopic and spectrometric analyses. Antiplasmodial evaluations of 1-12 showed that the semisynthetic derivative 5 elicited the most potent activity with an IC50 value of 7.2 µM against Plasmodium falciparum 3D7 (drug-sensitive) strain.

Semisynthesis and Cytotoxic Evaluation of an Ether Analogue Library Based on a Polyhalogenated Diphenyl Ether Scaffold Isolated from a Lamellodysidea Sponge.

The known oxygenated polyhalogenated diphenyl ether, 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (1), with previously reported activity in multiple cytotoxicity assays was isolated from the sponge Lamellodysidea sp. and proved to be an amenable scaffold for semisynthetic library generation. The phenol group of 1 was targeted to generate 12 ether analogues in low-to-excellent yields, and the new library was fully characterized by NMR, UV, and MS analyses. The chemical structures for 2, 8, and 9 were additionally determined via single-crystal X-ray diffraction analysis. All natural and semisynthetic compounds were evaluated for their ability to inhibit the growth of DU145, LNCaP, MCF-7, and MDA-MB-231 cancer cell lines. Compound 3 was shown to have near-equivalent activity compared to scaffold 1 in two in vitro assays, and the activity of the compounds with an additional benzyl ring appeared to be reliant on the presence and position of additional halogens.

The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds.

The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure-activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure-activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.

The Protective Effects of Reineckia carnea Ether Fraction against Alzheimer's Disease Pathology: An Exploration in Caenorhabditis elegans Models.

Alzheimer's disease (AD) presents a significant challenge to global healthcare systems, with current treatments offering only modest relief and often bringing unwanted side effects, necessitating the exploration of more effective and safer drugs. In this study, we employed the Caenorhabditis elegans (C. elegans) model, specifically the AD-like CL4176 strain expressing the human Aß(1-42) protein, to investigate the potential of Reineckia carnea extract and its fractions. Our results showed that the Reineckia carnea ether fraction (REF) notably diminished the paralysis rates of CL4176 worms. Additionally, REF also attenuated the neurotoxicity effects prompted by Tau proteins in the BR5270 worms. Moreover, REF was observed to counteract the accumulation of Aß and pTau proteins and their induced oxidative stress in C. elegans AD-like models. Mechanistic studies revealed that REF's benefits were associated with the induction of autophagy in worms; however, these protective effects were nullified when autophagy-related genes were suppressed using RNAi bacteria. Together, these findings highlight Reineckia carnea ether fraction as a promising candidate for AD treatment, warranting further investigation into its autophagy-inducing components and their molecular mechanisms.

Benzene Amide Ether Scaffold is Active against Non-replicating and Intracellular Mycobacterium tuberculosis.

New drugs to treat tuberculosis which target intractable bacterial populations are required to develop shorter and more effective treatment regimens. The benzene amide ether scaffold has activity against intracellular Mycobacterium tuberculosis, but low activity against extracellular, actively replicating M. tuberculosis. We determined that these molecules have bactericidal activity against non-replicating M. tuberculosis but not actively replicating bacteria. Exposure to compounds depleted ATP levels in non-replicating bacteria and increased the oxygen consumption rate; a subset of molecules led to the accumulation of intrabacterial reactive oxygen species. A comprehensive screen of M. tuberculosis strains identified a number of under-expressing strains as more sensitive to compounds under replicating conditions including QcrA and QcrB hypomorphs. We determined the global gene expression profile after compound treatment for both replicating and nutrient-starved M. tuberculosis. We saw compound-dependent changes in the expression of genes involved in energy metabolism under both conditions. Taken together, our data suggest that the scaffold targets respiration in M. tuberculosis.

Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects 10 million people each year and the emergence of resistant TB augurs for a growing incidence. In the last 60 years, only three new drugs were approved for TB treatment, for which resistances are already emerging. Therefore, there is a crucial need for new chemotherapeutic agents capable of eradicating TB. Enzymes belonging to the type II fatty acid synthase system (FAS-II) are involved in the biosynthesis of mycolic acids, cell envelope components essential for mycobacterial survival. Among them, InhA is the primary target of isoniazid (INH), one of the most effective compounds to treat TB. INH acts as a prodrug requiring activation by the catalase-peroxidase KatG, whose mutations are the major cause for INH resistance. Herein, a new series of direct InhA inhibitors were designed based on a molecular hybridization approach. They exhibit potent inhibitory activities of InhA and, for some of them, good antitubercular activities. Moreover, they display a low toxicity on human cells. A study of the mechanism of action of the most effective molecules shows that they inhibit the biosynthesis of mycolic acids. The X-ray structures of two InhA/NAD+/inhibitor complexes have been obtained showing a binding mode of a part of the molecule in the minor portal, rarely seen in the InhA structures reported so far.

Synthesis and Insecticidal Activity Study of Azidopyridryl Containing Dichlorolpropene Ether Derivatives.

Pyridalyl, as a novel insecticide with an unknown mode of action, has shown excellent control efficacy against lepidopterous larvae and thrips. Previous modifications of this compound have mostly focused on the pyridine moiety, with limited information available about modifications to other parts of pyridalyl. In this paper, we report the synthesis and insecticidal activity of a series of azidopyridryl-containing dichlorolpropene ether derivatives, based on modifications to the middle alkyl chain of pyridalyl. Screening results for insecticidal activity indicate that our synthesized compounds show moderate to high activities at the tested concentrations against P. xylostella. Particularly, compound III-10 exhibits a LC50 value of 0.831 mg L-1, compared to the LC50 value of pyridalyl at 2.021 mg L-1. Furthermore, compound III-10 also displays a relatively broad insecticidal spectrum against Lepidoptera pests M. separata, C. suppressalis, O. nubilalis, and C. medinalis. Finally, in field trials, III-10 demonstrates better control efficiency against Chilo suppressalis compared to pyridalyl. Overall, our findings suggest that the modification of the middle alkyl chain of pyridalyl may be a promising approach for developing insecticides with improved efficacy.

A New Class of Diaryl Ether Herbicides: Structure-Activity Relationship Studies Enabled by a Rapid Scaffold Hopping Approach.

We report on the development of a novel class of diaryl ether herbicides. After the discovery of a phenoxybenzoic acid with modest herbicidal activity, optimization led to several molecules with improved control of broadleaf and grass weeds. To facilitate this process, we first employed a three-step combinatorial approach, then pivoted to a one-step Ullmann-type coupling that provided faster access to new analogs. After determining that the primary target site of our benchmark diaryl ethers was acetolactate synthase (ALS), we further leveraged this copper-catalyzed methodology to conduct a scaffold hopping campaign in the hope of uncovering an additional mode of action with fewer documented cases of resistance. Our comprehensive and systematic investigation revealed that while the herbicidal activity of this area seems to be exclusively linked to ALS inhibition, our molecules represent a structurally distinct class of Group 2 herbicides. The structure-activity relationships that led us to this conclusion are described herein.

Inhibition of the hERG potassium ion channel by different non-nucleoside human cytomegalovirus polymerase antiviral inhibitor series and the exploration of variations on a pyrroloquinoline core to reduce cardiotoxicity potential.

Many non-nucleoside human cytomegalovirus (HCMV) inhibitors have been reported in patent and scientific literature, however, none have reached commercialization despite the urgent need for new HCMV treatments. Herein we report select compounds from different templates that all had low micromolar human ether-à-go-go (hERG) ion channel IC50 values. We also describe a series of pyrroloquinoline derivatives that were designed and synthesized to understand the effect of various substitution on human cytomegalovirus (HCMV) polymerase activity, antiviral activity, and hERG inhibition. These results demonstrated that hERG inhibition can be significantly altered based on the substitution on this template. An HCMV inhibitor with low hERG inhibition and reduced cytotoxicity is also described. The results suggest substitution can be fine tuned for the non-nucleoside polymerase inhibitors to reduce hERG inhibition and maintain HCMV antiviral potency.

Dichloroacetophenone biphenylsulfone ethers as anticancer pyruvate dehydrogenase kinase inhibitors in non-small cell lung cancer models.

Pyruvate dehydrogenase kinase 1 (PDK1) is an important metabolic enzyme which is often overexpressed in many types of cancers, including non-small-cell lung cancers (NSCLC). Targeting PDK1 appears to be an attractive anticancer strategy. Based on a previously reported moderate potent anticancer PDK1 inhibitor, 64, we developed three dichloroacetophenone biphenylsulfone ethers, 30, 31 and 32, which showed strong PDK1 inhibitions of 74%, 83% and 72% at 10 µM, respectively. Then we investigated the anticancer effects of 31 in two NSCLC cell lines, namely, NCI-H1299 and NCI-H1975. It was found that 31 exhibited sub-micromolar cancer cell IC50s, suppressed colony formation, induced mitochondrial membrane potential depolarization, triggered apoptosis, altered cellular glucose metabolism, with concomitant reductions in extracellular lactate levels and enhanced the generation of reactive oxygen species in NSCLC cells. Moreover, 31 significantly suppressed the tumor growth in an NCI-H1975 mouse xenograft model, outperforming the anticancer effects of 64. Taken together our results suggested that inhibition of PDK1 via dichloroacetophenone biphenylsulfone ethers may provide a novel direction leading to an alternative treatment option in NSCLC therapy.

A Comparison of the Antibacterial Efficacy of Carbohydrate Lipid-like (Thio)Ether, Sulfone, and Ester Derivatives against Paenibacillus larvae.

Paenibacillus larvae is the causative agent of American foulbrood (AFB), the most serious bacterial disease affecting developing honeybee larvae and pupas. In this study, a library of 24 (thio)glycosides, glycosyl sulfones, 6-O-esters, and ethers derived from d-mannose, d-glucose, and d-galactose having C10 or C12 alkyl chain were evaluated for their antibacterial efficacy against two P. larvae strains. The efficacy of the tested compounds determined as minimal inhibitory concentrations (MICs) varied greatly. Generally, dodecyl derivatives were found to be more potent than their decylated analogs. Thioglycosides were more efficient than glycosides and sulfones. The activity of the 6-O-ether derivatives was higher than that of their ester counterparts. Seven derivatives with dodecyl chain linked (thio)glycosidically or etherically at C-6 showed high efficacy against both P. larvae strains (MICs ranged from 12.5 µM to 50 µM). Their efficacies were similar or much higher than those of selected reference compounds known to be active against P. larvae-lauric acid, monolaurin, and honeybee larval food components, 10-hydroxy-2-decenoic acid, and sebacic acid (MICs ranged from 25 µM to 6400 µM). The high efficacies of these seven derivatives suggest that they could increase the anti-P. larvae activity of larval food and improve the resistance of larvae to AFB disease through their application to honeybee colonies.

Novel 1-Indanone derivatives containing oxime and oxime ether moieties as immune activator to resist plant virus.

BACKGROUND: Vegetable viruses are difficult to prevent and control in the field, causing massive economic losses of agricultural production in the world. A new natural product-based antiviral agent would be an effective means to control viral diseases. As a class of natural products, 1-indanones present various pharmacologically actives, while their application in agriculture remains to be found. RESULTS: A series of novel 1-indanone derivatives were designed and synthesized and the antiviral activities were systematically evaluated. Bioassays showed that most compounds exhibited good protective activities against cucumber mosaic virus (CMV), tomato spotted wilt virus (TSWV), and pepper mild mottle virus (PMMoV). Notably, compound 27 exhibited the best protective effects against PMMoV with EC50 values of 140.5 mg L-1 , superior to ninanmycin (245.6 mg L-1 ). Compound 27 induced immunity responses through multilayered regulation on mitogen-activated protein kinase, plant hormone signal transduction and phenylpropanoid biosynthesis pathways. CONCLUSION: These 1-indanone derivatives especially compound 27 can be considered as potential immune activators to resist plant virus. © 2023 Society of Chemical Industry.

Design, Synthesis, and Insecticidal and Fungicidal Activities of Ether/Oxime-ether Containing Isoxazoline Derivatives.

The existing agricultural insecticides have developed drug resistance from long-term use. Isoxazoline derivatives are new insecticides discovered in the 21st century. Because of their unique insecticidal mechanism, high selectivity, safety, and no significant cross resistance with the existing pesticides on the market, they have become a hot spot in the field of pesticide research. Herein, a series of novel isoxazoline derivatives containing ether and oxime-ether structures were designed and synthesized by a scaffold-hopping strategy using the pesticide fluralaner as a template structure. Through the investigation of insecticidal activity and the systematic structure-activity relationship, a series of compounds with high insecticidal activities were found, and compounds I-4, II-9, and II-13 with LC50 values of 0.00008-0.00036 mg/L against diamondback moth emerged as novel insecticide candidates. These compounds also exhibited broad spectrum fungicidal activities against 14 plant fungi. The current work provides a reference for the design of new isoxazoline compounds based on the scaffold-hopping strategy.

Synthesis and Antiproliferative Activity of Steroidal Diaryl Ethers.

Novel 13α-estrone derivatives have been synthesized via direct arylation of the phenolic hydroxy function. Chan-Lam couplings of arylboronic acids with 13α-estrone as a nucleophilic partner were carried out under copper catalysis. The antiproliferative activities of the newly synthesized diaryl ethers against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231, HeLa, SiHa) were investigated by means of MTT assays. The quinoline derivative displayed substantial antiproliferative activity against MCF-7 and HeLa cell lines with low micromolar IC50 values. Disturbance of tubulin polymerization has been confirmed by microplate-based photometric assay. Computational calculations reveal significant interactions of the quinoline derivative with the taxoid binding site of tubulin.

Synthesis and biological activities of novel chalcone derivatives containing pyrazole oxime ethers.

A series of novel chalcone derivatives containing pyrazole oxime ethers were designed and synthesized. The structures of all the target compounds were determined by NMR and HRMS. The structure of H5 was further confirmed via single-crystal X-ray diffraction analysis. The results of biological activity test showed that some of the target compounds exhibited significant antiviral and antibacterial activities. The test results of EC50 value against tobacco mosaic virus showed that H9 had the best curative and protective effect, and the EC50 value of curative activity of H9 was 166.9 µg/mL, which was superior to ningnanmycin (NNM) 280.4 µg/mL, the EC50 value of protective activity of H9 was 126.5 µg/mL, which was superior to ningnanmycin 227.7 µg/mL. Microscale thermophoresis (MST) experiments demonstrated that H9 (Kd = 0.0096 ± 0.0045 µmol/L) exhibited a strong binding ability with tobacco mosaic virus capsid protein (TMV-CP), which was far superior to ningnanmycin (Kd = 1.2987 ± 0.4577 µmol/L). In addition, molecular docking results showed that the affinity of H9 to TMV protein was significantly higher than ningnanmycin. The results of against bacterial activity showed that H17 has a good inhibiting effect against Xanthomonas oryzae pv. oryzae (Xoo), the EC50 value of H17 was 33.0 µg/mL, which was superior to the commercial drugs thiodiazole copper (68.1 µg/mL) and bismerthiazol (81.6 µg/mL), and the antibacterial activity of H17 was verified by scanning electron microscopy (SEM).

Engineering Multifunctional Polyether Ether Ketone Implant: Mechanics-Adaptability, Biominerialization, Immunoregulation, Anti-Infection, Osteointegration, and Osteogenesis.

Polyether ether ketone (PEEK) has become one of the most promising polymer implants in bone orthopedics, due to the biocompatibility, good processability, and radiation resistance. However, the poor mechanics-adaptability/osteointegration/osteogenesis/antiinfection limits the long-term in vivo applications of PEEK implants. Herein, a multifunctional PEEK implant (PEEK-PDA-BGNs) is constructed through in situ surface deposition of polydopamine-bioactive glass nanoparticles (PDA-BGNs). PEEK-PDA-BGNs exhibit good performance on osteointegration and osteogenesis in vitro and in vivo, due to their multifunctional properties including mechanics-adaptability, biominerialization, immunoregulation, anti-infection, and osteoinductive activity. PEEK-PDA-BGNs can show the bone tissue-adaptable mechanic surface and induce the rapid biomineralization (apatite formation) under a simulated body solution. Additionally, PEEK-PDA-BGNs can induce the M2 phenotype polarization of macrophages, reduce the expression of inflammatory factors, promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), and improve the osseointegration and osteogenesis ability of the PEEK implant. PEEK-PDA-BGNs also show good photothermal antibacterial activity and can kill 99% of Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA), suggesting their potential antiinfection ability. This work suggests that PDA-BGNs coating is probably a facile strategy to construct multifunctional (biomineralization, antibacterial, immunoregulation) implants for bone tissue replacement.