Diphenyl Ether Derivatives Research Articles

Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug-susceptible and drug-resistant strains ofMycobacterium tuberculosis.

In our efforts to develop druggable diphenyl ethers as potential antitubercular agents, a series of novel diphenyl ether derivatives (5a-f, 6a-f) were designed and synthesized. The representative compounds showed promising in vitro activity against drug-susceptible, isoniazid-resistant, and multidrug-resistant strains of Mycobacterium tuberculosis with MIC values of 1.56μg/ml (6b), 6.25μg/ml (6a-d), and 3.125μg/ml (6b-c), respectively. All the synthesized compounds exhibited satisfactory safety profile (CC50 >300μg/ml) against Vero and HepG2 cells. Reverse phase HPLC method was used to probe the physicochemical properties of the synthesized compounds. This series of compounds demonstrated comparatively low logP values. pKa values of representative compounds indicated that they were weak acids. Additionally, in vitro human liver microsomal stability assay confirmed that the synthesized compounds possessed acceptable stability under study conditions. The present study thus establishes compound 6b as the most promising antitubercular agent with acceptable drug-likeness.

Pestalotilide A, a New Cytotoxic Diphenyl Ether Derivative from Pestalotiposis guepinii

A new diphenyl ether derivative, named pestalotilide A (1), along with four known compounds (2-5) have been isolated from the organic extracts of an endophytic fungus Pestalotiposis guepinii. Their structures were elucidated on the basis of HR-ESI-MS, 1D and 2D NMR spectroscopic data analyses. These isolates were evaluated for cytotoxicity against three cancer cell lines: Hela, HCT116 and A549; pestalotilide A exhibited weak in vitro anti-proliferative activities against the tested cell lines, with IC50 values of 23.8, 18.4 and 35.2 μM, respectively.

Diaporthols A and B: Bioactive diphenyl ether derivatives from an endophytic fungus Diaporthe sp.

Diaporthols A (1) and B (2), two diphenyl ether derivatives, were isolated from cultures of an endophytic fungus Diaporthe sp. ECN-137 obtained from the leaves of Phellodendron amurense. The structures of 1 and 2 were determined by extensive spectroscopic analyses, and the structure of 2 was confirmed by X-ray crystallographic analysis. Compounds 1 and 2 showed anti-migration activities in TGF-β1-elicited MDA-MB-231 breast cancer cells at a concentration of 20 μM.

Isopentylated diphenyl ether derivatives from the fermentation products of an endophytic fungus Phomopsis fukushii.

Three new isopentylated diphenyl ethers, (1-3), together with two known isopentylated diphenyl ethers derivatives (4 and 5) were isolated from the fermentation products of an endophytic fungus Phomopsis fukushii. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1-3 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results showed that compounds 1-3 showed strong activity with diameter of inhibition zone (IZD) of 21.8 ± 2.4 mm, 16.8 ± 2.2 mm, and 15.6 ± 2.0 mm, respectively.

Three new diphenyl ether derivatives from the fermentation products of an endophytic fungus Phomopsis fukushii

Three new diphenyl ethers (1-3), together with four known isopentylated diphenyl ethers derivatives (4-7), were isolated from the fermentation products of an endophytic fungus Phomopsis fukushii. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-3 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results revealed that compounds 1 and 2 showed strong inhibitions with inhibition zone diameters (IZD) of 20.2 ± 2.5 mm and 17.9 ± 2.2 mm, respectively. Compound 3 also showed good inhibition with IZD 15.2 ± 1.8 mm. The IZD data of compound 1 is close to that of positive control with IZD 21.9 ± 2.1 mm.

Sinopestalotiollides A–D, cytotoxic diphenyl ether derivatives from plant endophytic fungus Pestalotiopsis palmarum

Four new diphenyl ether derivatives, sinopestalotiollides A–D (1–4), one new natural α-pyrone product (11), as well as twelve known compounds (5–1 7), were obtained from the ethyl acetate extract of the endophytic fungus Pestalotiopsis palmarum isolated from the leaves of medicinal plant Sinomenium acutum (Thunb.) Rehd et Wils. The structures were elucidated by HR-ESI-MS and NMR spectrometry data. Bioassay experiments revealed that compounds 1–4 and 11 exhibited strong to weak cytotoxicities against three human tumor cell lines Hela, HCT116 and A549.

Bioactive Diphenyl Ethers and Isocoumarin Derivatives from a Gorgonian-Derived Fungus Phoma sp. (TA07-1).

Three new diphenyl ether derivatives—phomaethers A–C (1–3) and five known compounds—including a diphenyl ether analog, 2,3′-dihydroxy-4-methoxy-5′,6-dimethyl diphenyl ether (4); and four isocoumarin derivatives, diaportinol (5), desmethyldiaportinol (6), citreoisocoumarinol (7), and citreoisocoumarin (8)—were isolated from a gorgonian-derived fungus Phoma sp. (TA07-1). Their structures were elucidated by extensive spectroscopic investigation. The absolute configurations of 1 and 2 were determined by acid hydrolysis reactions. It was the first report to discover the diphenyl glycoside derivatives from coral-derived fungi. Compounds 1, 3, and 4 showed selective strong antibacterial activity against five pathogenic bacteria with the minimum inhibiting concentration (MIC) values and minimum bactericidal concentration (MBC) values between 0.156 and 10.0 μM.

The effect of O-nucleophiles structure on the features of halogen substitution in heterogeneous systems

The formation of diphenyl ether derivatives during interaction of 4-nitrochlorobenzene and substituted phenols in a heterogeneous system [DMF in the presence of potassium carbonate and iron(III) oxide] has been studied.

Design, Synthesis and Anti-tubulin Activity of Novel Dinitro Diphenyl Ether Derivatives as Potent Anticancer Agent

In this study, a series of Dinitrodiphenyl Ether derivatives (1b-5b) were synthesized and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3b (IC50=1.26 ± 0.84 μM) exhibited the most potent anti-proliferative activity of MCF-7 cancer cell line in vitro, which was comparable to that of colchicine (IC50=0.93 ± 0.46 μM) as reference. And it also showed the most potent growth inhibitory activity against tubulin (IC50=5.10 ± 0.81 μM), which was also compared with colchicine (IC50=3.42 ± 0.63 μM). Molecular docking simulation results demonstrated that 3b could bind to the colchicine binding site of tubulin and effectively inhibit tubulin polymerization. Moreover, the subsequent cell cycle arrest and apoptosis assay further confirmed that 3b could cause MCF-7 cell cycle arrest in the middle and later stages of mitosis and thus leading to cell apoptosis. To sum up, we recommend 3b as the best candidate of potential anti-cancer agent among these new compounds. Based on the preliminary results, compound 3b with potent inhibitory activity in tumor growth may be a potential anti-cancer agent.

A new diphenyl ether derivative from Mirabilis himalaica

One new compound, himalain A (1), together with 12 known compounds were isolated from Mirabilis himalaica. Their structures were determined by spectroscopic methods, including 2D NMR techniques, and the absolute configuration of the 1,2-diol moiety in 1 was defined through Riguera’s method. All isolated compounds were tested for their cytotoxic and antibacterial activities.

ChemInform Abstract: Recent Advances and Structural Features of Enoyl‐ACP Reductase Inhibitors of Mycobacterium tuberculosis

AbstractReview: 40 refs.

Antifouling phenyl ethers and other compounds from the invertebrates and their symbiotic fungi collected from the South China Sea.

Marine organism-derived secondary metabolites are promising potential sources for discovering environmentally safe antifouling agents. In present study, 55 marine secondary metabolites and their synthesized derivatives were tested and evaluated for their antifouling activities and security. These compounds include 44 natural products isolated from marine invertebrates and their symbiotic microorganisms collected from the South China Sea and 11 structural modified products derived from the isolated compounds. The natural secondary metabolites, covering phenyl ether derivatives, terpenoids, 9, 11-secosteroids, anthraquinones, alkaloids, nucleoside derivatives and peptides, were isolated from two corals, one sponge and five symbiotic fungi. All of the isolated and synthesized compounds were tested for their antifouling activities against the cyprids of barnacle Balanus (Amphibalanus) amphitrite Darwin. Noticeably, five phenyl ether derivatives (9, 11, 13–15) exhibited potent anti-larval settlement activity with the EC50 values lower than 3.05 μM and the LC50/EC50 ratios higher than 15. The study of structure–activity relationship (SAR) revealed that the introduction of acetoxy groups and bromine atoms to phenyl ether derivatives could significantly improve their antifouling activities. This is the first report on the SAR of phenyl ether derivatives on antifouling activity against barnacle B. amphitrite. The polybrominated diphenyl ether derivative, 2, 4, 6, 2′, 4′, 6′-hexabromo-diorcinol (13), which displayed excellent antifouling activity, was considered as a promising candidate of environmentally friendly antifouling agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s13568-016-0272-2) contains supplementary material, which is available to authorized users.

Recent Advances and Structural Features of Enoyl-ACP Reductase Inhibitors of Mycobacterium tuberculosis.

Mycobacterium tuberculosis enoyl-ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH-dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro-drug that needs activation to form the inhibitory INH-NAD adduct by KatG coding for catalase-peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug-resistant TB (MDR-TB). Hence, there is a need for new drugs that can combat MDR-TB. The rationale for the development of new drugs to combat MDR-TB strains is the design of InhA inhibitors that can bypass bioactivation by KatG. In the present review, special attention was paid to discuss the chemical nature and recent developments of direct InhA inhibitors. The InhA inhibitors reported here have significant inhibitory effects against Mtb InhA. The diphenyl ether derivatives have shown slow onset, a tight-binding mechanism, and high affinity at the InhA active site. However, some of the diphenyl ethers have significant in vitro efficacy, which fails to transform into in vivo efficacy. Among the InhA inhibitors, 4-hydroxy-2-pyridones have emerged as a new chemical class with significant InhA inhibitory activity and better pharmacokinetic parameters when compared to diphenyl ethers.

Rational design and synthesis of novel diphenyl ether derivatives as antitubercular agents.

A series of triclosan mimic diphenyl ether derivatives have been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The binding mode of the compounds at the active site of enoyl-acyl carrier protein reductase of M. tuberculosis has been explored. Among them, compound 10b was found to possess antitubercular activity (minimum inhibitory concentration =12.5 µg/mL) comparable to triclosan. All the synthesized compounds exhibited low levels of cytotoxicity against Vero and HepG2 cell lines, and three compounds 10a, 10b, and 10c had a selectivity index more than 10. Compound 10b was also evaluated for log P, pKa, human liver microsomal stability, and % protein binding, in order to probe its druglikeness. Based on the antitubercular activity and druglikeness profile, it may be concluded that compound 10b could be a lead for future development of antitubercular drugs.

Synthesis and Antiviral Bioassay of New Diphenyl Ether-based Compounds.

A set of diphenyl ether derivatives bearing different heterocycles were synthesized from 4-phenoxybenzohydrazide 1 in good yield. Synthesized compounds were screened against a broad panel of viruses in different cell cultures and some of the synthesized compounds showed promising antiviral properties.

Secondary Metabolites from the Culture of the Marine Sponge-Associated Fungi Talaromyces tratensis and Sporidesmium circinophorum.

Wortmin (1), meso-1,4-bis(4-methoxybenzyl)-2,3-butanediol (2), and a new isocoumarin derivative tratenopyrone (3) were isolated from the marine sponge-associated fungus Talaromyces tratensis KUFA 0091. A new diphenyl ether derivative, circinophoric acid (4), was isolated, together with the previously reported anthraquinones catenarin and physcion, the benzophenone monomethylsoluchrin, and β-ergosterol-5,8-endoperoxide, from the marine sponge-associated fungus Sporidesmium circinophorum KUFA 0043. The structures of the new compounds were established based on an extensive analysis of 1D and 2D NMR spectra, and, in the case of compounds 2-4, also by X-ray analysis. All of the isolated compounds were tested for their antibacterial activity against Gram-positive and Gram-negative bacteria, and multidrug-resistant isolates from the environment, as well as for their anti-quorum sensing based on the pigment production of Chromobacterium violaceum ATCC 31523. None of the compounds exhibited either antibacterial (MIC > 256 µg/mL) or anti-quorum sensing activities. The compounds were also inactive in the antifungal (MIC > 512 µg/mL) and cancer cell line (GI50 > 150 µM) assays.

Penicillanthone and penicillidic acids A–C from the soil-derived fungus Penicillium aculeatum PSU-RSPG105

A new xanthone (penicillanthone, 1) and three new diphenyl ether derivatives (penicillidic acids A–C, 2–4) together with 14 known compounds (5–18) were isolated from the soil-derived fungus Penicillium aculeatum PSU-RSPG105.

Polyketide butenolide, diphenyl ether, and benzophenone derivatives from the fungus Aspergillus flavipes PJ03-11.

Five new polyketides including three new butenolides (1-3), one new diphenyl ether (4), and one new benzophenone (5), together with eleven known compounds (6-16) were isolated from a wetland fungus Aspergillus flavipes PJ03-11. Their structures were elucidated on the basis of detailed spectroscopic analysis. All the isolated compounds were tested for their α-glucosidase inhibitory activities. The results showed that compounds 1-3, 6, 7, 11, 15 and 16 exhibited stronger inhibitory activities than acarbose. And the preliminary structure-activity relationships of aspulvinone and diphenyl ether compounds on the α-glucosidase inhibitory activity were reported.

Design, synthesis and evaluation of antitubercular activity of Triclosan analogues

Novel Triclosan mimic diphenyl ether derivatives 4a–k were designed and synthesized with lipophilicity considerably lesser than that of Triclosan. The binding mode of the compounds at the active site of enoyl-ACP reductase was analysed using docking method. The syntheses were carried out with one-pot reductive amination reaction and were characterized by spectral techniques. The synthesized compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain by Microplate Alamar Blue assay. Compounds 4h and 4j were the most active compounds with MIC equal to 25μg/mL against M. tuberculosis H37Rv strain. All compounds were also examined for their cytotoxic potential against VERO and HepG2 cell lines and were safe even at 300μg/mL. LogP of all the synthesized compounds was evaluated by RPHPLC and was significantly lesser than Triclosan.

Azaphilone and Diphenyl Ether Derivatives from a Gorgonian-Derived Strain of the Fungus Penicillium pinophilum.

Three new azaphilone derivatives, pinophilins D-F (1-3), and one new diphenyl ether derivative, hydroxypenicillide (10), together with nine known compounds (4-9, 11-13), were isolated from the gorgonian-derived fungus Penicillium pinophilum XS-20090E18. Their structures including absolute configurations were determined by spectroscopic data, chemical conversions, the ECD exciton chirality method, and ECD calculations. Compounds 10-13 exhibited inhibitory activity against the larval settlement of the barnacle Balanus amphitrite at nontoxic concentrations. Compounds 10 and 11 showed cytotoxicity against Hep-2, RD, and HeLa cell lines.