‘Click Synthesis’ of Some Novel Benzimidazol Oxime Ethers Containing Heterocycle Residues as Potential ß‐Adrenergic Blocking Agents

The ‘click synthesis’ of some novel O‐substituted oximes, 5a – 5j , which contain heterocycle residues, as new analogs of ß‐adrenoceptor antagonists is described (Scheme 1). The synthesis of these compounds was achieved in four steps. The formation of (E)‐2‐(1H‐benzo[d]imidazol‐1‐yl)‐1‐phenylethanone oxime, followed by their reaction with 2‐(chloromethyl)oxirane, afforded mixture of oil compounds 3 and 4 , which by a subsequent tetra‐n‐butylammonium bromide (TBAB)‐catalyzed reaction with N H heterocycle compounds (Scheme 1), led to the target compounds 5a – 5j in good yields.     

Novel Delta‐Opioid‐Receptor‐Selective Ligands in the 14‐Alkoxy‐Substituted Indolo‐ and Benzofuromorphinan Series

Several new indolo‐ and benzofuromorphinans substituted at the positions 5 and 14 were prepared and tested in vitro by means of opioid‐receptor binding and functional ([³⁵S]GTPγS binding) assays. All compounds 1 – 11 displayed high affinity for δ opioid‐binding sites (Table 1). Compound 4 proved to be an agonist, and all other compounds were antagonists. The presence of a Me group at position 5 induced no change in δ affinity (see 1 vs. 3 ), but decreased the μ and κ affinities. An EtO group at position 14 conferred a very high affinity and also high selectivity to δ opioid receptors (see 2 and 10 ). Chain elongation of the 14‐alkoxy group resulted in compounds with reduced δ affinity and selectivity (see 4 and 11 and also 5 – 9 ). The results of the present study indicate that the 5‐ and 14‐positions of indolo‐ and benzofuromorphinans represent critical sites that could be a trigger to develop new compounds with increased δ affinity and/or selectivity.     

Novel Cytostatic Lanostanoid Triterpenes from Ganoderma australe

Two new compounds 1 and 2 , together with the known sterols ergosterol, 5,6‐dehydroergosterol, and ergosterol peroxide, and four polyoxygenated lanostanoid triterpenes named applanoxidic acid A ( 3 ), C ( 4 ), F ( 5 ), and G ( 6 ) were isolated from the fungus Ganoderma australe. The structures of the new compounds were elucidated by means of spectroscopic techniques, while the known triterpenoids 3 – 6 were identified by comparing their spectral data with those reported in the literature. Compounds 1 – 6 inhibited the viability and growth of the HL‐60 cell line.     

Synthesis and Characterization of New Thebaine Derivatives as Potential Opioid Agonists and Antagonists: 2‐[N‐(1H‐Tetrazol‐5‐yl)‐6,14‐endo‐etheno‐6,7,8,14‐tetrahydrothebaine‐7α‐yl]‐5‐phenyl‐1,3,4‐oxadiazoles

In this study, we report the synthesis a series of novel 2‐[N‐(1H‐tetrazol‐5‐yl)‐6,14‐endo‐etheno‐6,7,8,14‐tetrahydrothebaine‐7α‐yl]‐5‐phenyl‐1,3,4‐oxadiazole derivatives ( 7a – e ) which have potential opioid antagonist and agonist. The substitution reaction of 6,14‐endo‐ethenotetrahydrothebaine‐7α‐carbohydrazide with corresponding benzoyl chlorides gave diacylhydrazine compounds 4a – e in good yields. The treatment of compounds 4a – e with POCl₃ caused the conversion of side‐chain of compounds 5a – e into 1,3,4‐oxadiazole ring at C(7) position; thus, compounds 5a – e were obtained. Subsequently, cyanamides ( 6a – e ) were prepared from compounds 5a – e and then compounds 7a – e were synthesized by the azidation of 6a – e with NaN₃. The structures of the compounds were established on the basis of their IR, ¹H NMR, ¹³C APT, 2D‐NMR (COSY, NOESY, HMQC, HMBC) and high‐resolution mass spectral data.     

Two New Flavonoids from Retama raetam

Two new furanoflavonoids, retamasins A and B ( 1 and 2 , resp.), along with five known flavonoids, 3 – 7 , were isolated from the aerial parts of Retama raetam. Their structures were determined on the basis of extensive spectroscopic (IR, MS, and 1D‐ and 2D‐NMR) analyses and by comparison with the literature data. This is the first report of the isolation of new furanoflavonoids 1 and 2 from Retama genus, while compounds 3, 5 , and 6 were found for the first time from R. raetam. Antioxidant and anti‐inflammatory activities of the isolated compounds were also evaluated. Compounds 2, 3 , and 5 – 7 exhibited potent inhibitions of iNOS activity with IC₅₀ values of 2.9, 5.0, 3.1, 1.2, and 4.8 μg/ml, respectively. All compounds inhibited NF‐κB except 1 and 5 . Compound 6 was most active in inhibiting iNOS and NF‐κB activity, as well as in decreasing oxidative stress.     

Synthesis and Cyclization of 8‐Formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic Acids

A facile synthesis of a series of new quinoline‐8‐carbaldehyde compounds, namely 8‐formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic acids ( 4a – 4h ) and 13‐oxo‐6,13‐dihydro[1]benzoxepino[3,4‐b]quinoline‐8‐carbaldehyde ( 5a – 5g ) is described, involving the one‐pot synthesis reaction of ethyl 2‐(chloromethyl)‐8‐formylquinoline‐3‐carboxylate ( 3 ) with substituted phenols followed by the intramolecular cyclization reaction via the treatment with polyphosphoric acid (PPA). Quinoline‐8‐carbaldehydes 4a – 4h and 5a – 5g are novel and their structures were supported by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis.     

Synthesis and Cytotoxicity Evaluation of Metal‐Chelator‐Bearing Flavone,Carbazole, Dibenzofuran,Xanthone, and Anthraquinone

2‐(Aryloxymethyl)‐5‐benzyloxy‐1‐methyl‐1H‐pyridin‐4‐ones 8a – 8g , 2‐(aryloxymethyl)‐5‐hydroxy‐4H‐pyran‐4‐ones 9a – 9g , and 2‐(aryloxymethyl)‐5‐hydroxy‐1‐methyl‐1H‐pyridin‐4‐ones 10a – 10g were prepared from the known 5‐benzyloxy‐2‐(hydroxymethyl)pyran‐4‐one ( 3 ) in a good overall yield. These compounds were evaluated in vitro against a three‐cell lines panel consisting of MCF7 (breast), NCI‐H460 (lung), and SF‐268 (CNS), and the active compounds passed on for evaluation in the full panel of 60 human tumor cell lines derived from nine cancer cell types. The results indicated that 5‐hydroxy derivatives are more favorable than their corresponding 5‐benzyloxy precursors ( 10a – 10g vs. 8a – 8g ), and 1‐methyl‐1H‐pyridin‐4‐ones are more favorable than their corresponding pyran‐4(1H)‐ones ( 10a – 10g vs. 9a – 9g ). Among these three types of compounds, 2‐(aryloxymethyl)‐5‐hydroxy‐1‐methyl‐1H‐pyridin‐4‐ones 10a – 10g were the most cytotoxic; they inhibited the growth of almost all the cancer cells tested. On the contrary, compound 8a (a mean GI₅₀=27.8 μM ), 8b (38.5), 8d (11.0), and 8e (30.5) are especially active against the growth of SK‐MEL‐5 (a melanoma cancer cell) with a GI₅₀ of <0.01, 5.65, 0.55, and 0.03 μM , respectively (cf. Table 2).     

Antioxidative Cassane Diterpenoids from the Seeds of Caesalpinia minax

Five new cassane diterpenoids, caesalmins I–M ( 1 – 5 ), and 23 known analogs were isolated from the seeds of Caesalpinia minax. Their structures were elucidated by spectroscopic methods and comparison with reported data. The antioxidant properties of 1 – 28 were determined by the method of oxygen radical absorbance capacity of fluorescein (ORAC‐FL), and 14 compounds exhibited good antioxidant activities with ORAC‐FL values of 2.24–4.89 Trolox equivalents. The structure? activity relationship of the active compounds was also discussed.     

Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

Synthesis and Characterization of New (Z)‐5‐((1H‐1,2,4‐Triazol‐1‐yl)methyl)‐3‐arylideneindolin‐2‐ones

Ten compounds of new (Z)‐5‐((1H‐1,24‐triazol‐1‐yl)methyl)‐3‐arylideneindolin‐2‐ones ( 5a – j ) have been synthesized by the Knoevenagel condensation of 5‐((1H‐1,2,4‐triazol‐1‐ylmethyl)indolin‐2‐one ( 3 ) with 4‐substituted aromatic aldehydes ( 4a – j ).     

‘Click Synthesis’ of Some Novel O‐Substituted Oximes Containing 1,2,3‐Triazole‐1,4‐diyl Residues as New Analogs of β‐Adrenoceptor Antagonists

The ‘click synthesis’ of some novel O‐substituted oximes, 7a – 7t , which contain 1,2,3‐triazolediyl residues, as new analogs of β‐adrenoceptor antagonists is described (Schemes 1–4). The synthesis of these compounds was achieved in four to five steps. The formation of oximes of 9H‐fluoren‐9‐one and benzophenone, i.e., 9a and 9b , respectively, followed by their reaction with propargyl bromide, afforded O‐propargyl oximes 10a and 10b , respectively, which by a subsequent CuI‐catalyzed Huisgen cycloaddition with prepared β‐azido alcohols 11a – 11j (Schemes 2 and 3), led to the target compounds 7a – 7t in good yields.     

Synthesis and Reactions of Pyrido[2,1‐a]isoquinolin‐4‐yl Formimidate Derivatives and Antimicrobial Activities of Isolated Products

Treatment of arylidene malononitriles 2A – C with 1‐cyanomethylisoquinoline 1 afforded 4‐amino‐2‐arylpyrido[2,1‐a ]isoquinoline‐1,3‐dicarbonitrile derivatives 5A – C , which converted to formimidates 6A – C via reaction with triethylorthoformate. Treatment of the latter compounds with hydrazine hydrate gave the corresponding amino–imino compounds 7A – C , which underwent Dimroth rearrangement to afford 13‐aryl‐1‐hydrazinylpyrimido[5′,4′:5,6]pyrido[2,1‐a ]isoquinoline‐12‐carbonitrile 8A – C . The latter reacted with aldehyde to give 9a – i . Oxidative cyclization of the latter compounds 9a – i gave [1,2,4]triazolo[4″,3″:1′,6′]‐pyrimido[5′,4′:5,6]pyrido[2,1‐a ]isoquinolines 10a , d , g . Such compounds isomerized to the thermodynamically more stable isomers [1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:5,6]‐pyrido[2,1‐a ]isoquinolines 11a , d , g . Antimicrobial activities for some compounds were studied.     

Three New Phenyl Ether Derivatives from Aspergillus carneus HQ889708

Three new phenyl ether derivatives, 3‐hydroxy‐5‐(3‐hydroxy‐5‐methylphenoxy)benzoic acid ( 1 ), 3,4‐dihydroxy‐5‐(3‐hydroxy‐5‐methylphenoxy)benzoic acid ( 2 ), 3‐[3‐hydroxy‐5‐(hydroxymethyl)phenoxy]‐5‐methylphenol ( 3 ), and three known compounds 4 – 6 were obtained from the fermentation broth of Aspergillus carneus HQ889708, which was isolated from sea water from South China Sea. The structures of compounds 1 – 3 were established on the basis of spectroscopic methods including ESI‐MS and NMR. Compounds 4 – 6 were reported before as synthesized products, herein, they are reported from nature for the first time.     

Synthesis,In Vitro Biological Screening,and In Silico Computational Studies of Some Novel Imidazole‐2‐thiol Derivatives

Substituted imidazole analogues 2‐((5‐acetyl‐4‐methyl‐1‐phenyl‐1H‐imidazole‐2‐yl)thio)‐N‐phenylacetamides ( 3a – 3m ) have been synthesized from 1‐[1‐(phenyl)‐2‐mercapto‐4‐methyl‐1H‐imidazol‐5‐yl]‐ethanone ( 1a – 1e ) and 2‐chloro‐N‐phenylacetamide ( 2a – 2i ) in the presence of potassium carbonate as a catalyst in dimethylformamide under microwave irradiation as well as conventional method. Structures of the obtained compounds have been confirmed by advance spectroscopic techniques such as IR, ¹H NMR, ¹³C NMR, and mass spectrometry. All the synthesized compounds were tested for their in vitro antimicrobial and antituberculosis activities. Good antibacterial molecules were further screened for the bacterial resisted cell line, from which compound 3b shows maximum inhibition. In silico molecular docking study was carried out to discover the binding affinity of synthesized compounds with active site of transferase (PDB ID: 1HNJ) and antibiotic resistance (PDB ID: 1W3R) protein. Moreover, molecular dynamics study of the 3b ‐1W3R complex has also been performed, as 3b has a good antibacterial activity as compared with other.     

Computationally identified novel diphenyl- and phenylpyridine androgen receptor antagonist structures

We have identified and profiled a set of androgen receptor (AR) binding compounds representing two nonsteroidal scaffolds from a public chemical database supplied by Asinex with virtual screening procedure incorporating our recently published 3D QSAR model of AR ligands. The diphenyl- and phenylpyridine-based compounds act as antagonists in wild-type AR in CV1 cells and also retain this antagonistic character in CV1 cells expressing T877A mutant receptor. This mutation is frequently associated with prostate cancer. Two of the compounds repress the androgen-dependent cell growth of LNCaP prostate cancer cells expressing the T877A AR mutant. Molecular modeling of the observed in vitro antagonism with induced fit docking suggests that W741 and M895 could be mechanistically involved in the initiation of the antagonism. The results indicate finding of nonsteroidal AR antagonist compounds from a public chemical database with computational methods. Compounds could serve as a novel platform to develop more potent AR antagonists with inhibitory activity in both wild-type and T877A mutant AR.     

Silver ion chromatography enables the separation of 2-methylalkylresorcinols from alkylresorcinols

Alkylresorcinols (∑ARs) is the generic term for a highly varied class of lipids found mainly in cereals. These bioactive compounds consist mainly of 5-alkylresorcinols (ARs), which differ in length, unsaturation, and substituents on the alkyl side chain on C-5. In addition, 2-methyl-5-alkylresorcinols (mARs) are scarcely studied minor compounds that are supposed to exist with the same structural diversity. In the first step, ∑ARs were enriched by solid-phase extraction from wheat grain and quinoa seed extracts. The subsequent application of silver ion chromatography (SIC), silica gel, coated with 20% AgNO₃, then deactivated with 1% water) enabled an unprecedented full separation of saturated mARs from conventional ARs. Specifically, saturated mARs were eluted with n-hexane/ethyl acetate (92:8, v/v), and conventional ARs with n-hexane/ethyl acetate (80:20, v/v). The unpreceded separation indicated that the SIC method could be useful not only for separations according to the degree of unsaturation, but also in the case of steric hindrance by additional (alkyl) substituents. Continued fractionation enabled the collection of unsaturated ARs in wheat and quinoa extracts. In this way, 35 ∑ARs (including five mARs) were detected by gas chromatography/mass spectrometry analysis in wheat and 45 ∑ARs (including 21 mARs) in quinoa. These included several low abundant and partly unknown ∑ARs such as 1,3-dihydroxy-5-tricosadienylbenzene.     

4‐Hydroxy‐3‐carboxycoumarin as an efficient building block for new ruthenium(II) complexes: synthesis,characterization, antibacterial,antioxidant and anti‐inflammatory activities

A new 4‐hydroxy‐3‐carboxycoumarin ligand and its ruthenium(II) complexes ( 1 – 5 ) have been synthesized, characterized and screened for their in vitro antibacterial activity against a range of Gram‐positive and Gram‐negative bacteria. In addition, compounds 1 – 5 were investigated for antioxidant activities using superoxide radical, 2,2‐diphenyl‐1‐picrylhydrazyl radical and hydroxyl radical scavenging assays, in which most of them displayed significant antioxidant activities. Furthermore, compounds 1 – 5 were evaluated for anti‐inflammatory activity using indirect haemolytic and lipoxygenase inhibition assays and revealed good activity. The new complexes were characterized using spectroscopic methods in addition to elemental analysis.     

Eupatozansins A – C,Sesquiterpene Lactones from Eupatorium chinense var. tozanense

Phytochemical investigation of Eupatorium chinense var. tozanense has resulted in the isolation of three new germacranolides, designated as eupatozansins A–C ( 1 – 3 ), along with five known compounds, (5S,6R,7R,8R)‐8‐angeloyloxy‐2‐oxoguaia‐1(10),3,11(13)‐trien‐12,6‐olide ( 4 ), costunolide ( 5 ), leptocarpin ( 6 ), 2α‐hydroxyeupatolide 8‐O‐angelate ( 7 ), and quercetin ( 8 ). The structures of the new compounds were identified by 1D and 2D NMR experiments, as well as high‐resolution mass spectrometry. The in vitro cytotoxic activities of compounds 1 – 8 were evaluated.     

Secoatisane‐ and Isopimarane‐Type Diterpenoids from the Chinese Mangrove Excoecaria agallocha L.

Phytochemical investigations of the stems and leaves of the Chinese mangrove Excoecaria agallocha L. yielded one new secoatisane‐type diterpenoid, agallochaol C ( 1 ), three new isopimarane‐type diterpenoids, agallochaols D–F ( 2 – 4 ), along with four known diterpenoids 5 – 8 . The structures of new compounds 1 – 4 were determined on the basis of spectroscopic‐data interpretation and chemical evidence.