Two Unusual Rearranged Flavan Derivatives from Narcissus tazetta var. chinensis

Two unusual rearranged flavan derivatives with a rare bicyclo[3.3.1]non‐3‐ene‐2,9‐dione ring, tazettone A ( 1 ) and tazettone B ( 2 ), together with five known flavans, 3 – 7 , were isolated from the bulbs of Narcissus tazetta var. chinensis Roem . The structures of two new compounds were elucidated by spectroscopic analyses, including 1D‐ and 2D‐NMR spectroscopy. All of the isolated compounds were evaluated for their cytotoxicities against four human tumor cell lines A549, HCT116, SK‐BR‐3, and HepG2. Compounds 1 and 2 were almost inactive against all tested cell lines, while compounds 3 – 7 exhibited moderate or weak cytotoxicities against the tested cell lines.     

Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized 13C‐Labeled Molecular Probe

The γ‐glutamyl transpeptidase (GGT) enzyme plays a central role in glutathione homeostasis. Direct detection of GGT activity could provide critical information for the diagnosis of several pathologies. We propose a new molecular probe, γ‐Glu‐[1‐¹³C]Gly, for monitoring GGT activity in vivo by hyperpolarized (HP) ¹³C magnetic resonance (MR). The properties of γ‐Glu‐[1‐¹³C]Gly are suitable for in vivo HP ¹³C metabolic analysis since the chemical shift between γ‐Glu‐[1‐¹³C]Gly and its metabolic product, [1‐¹³C]Gly, is large (4.3 ppm) and the T₁ of both compounds is relatively long (30 s and 45 s, respectively, in H₂O at 9.4 T). We also demonstrate that γ‐Glu‐[1‐¹³C]Gly is highly sensitive to in vivo modulation of GGT activity induced by the inhibitor acivicin.     

Two Rare α‐Pyrone (=2H‐Pyran‐2‐one) Derivatives from Gentiana rhodantha Franchet

Two new rare α‐pyrone (=2H‐pyran‐2‐one) derivatives, rhodanthpyrones A and B ( 1 and 2 , resp.), together with fourteen known compounds, 3 – 16 , were isolated from the whole plants of Gentiana rhodantha. The structures of these compounds were elucidated by spectroscopic analyses. This is the first report on the occurrence of α‐pyrone derivatives in the genus Gentiana.     

Synthesis of Some New 2‐Oxo‐N‐[(10H‐phenothiazin‐10‐yl)alkyl] Derivatives of Azetidine‐1‐carboxamides

The synthesis of a new series of 4‐aryl‐3‐chloro‐2‐oxo‐N‐[3‐(10H‐phenothiazin‐10‐yl)propyl]azetidine‐1‐carboxamides, 4a – 4m , is described. Phenothiazine on reaction with Cl(CH₂)₃Br at room temperature gave 10‐(3‐chloropropyl)‐10H‐phenothiazine ( 1 ), and the latter reacted with urea to yield 1‐[3‐(10H‐phenothiazin‐10‐yl)propyl]urea ( 2 ). Further reaction of 2 with several substituted aromatic aldehydes led to N‐(arylmethylidene)‐N′‐[3‐(phenothiazin‐10‐yl)propyl]ureas 3a – 3m , which, on treatment with ClCH₂COCl in the presence of Et₃N, furnished the desired racemic trans‐2‐oxoazetidin‐1‐carboxamide derivatives 4a – 4m . The structures of all new compounds were confirmed by IR, and ¹H‐ and ¹³C‐NMR spectroscopy, FAB mass spectrometry, and chemical methods.     

New Efficient Route to the Synthesis of Enantiopure (+) and (−) Bicyclo[2.2.1]heptan‐syn‐2,7‐diol using Lipase‐Catalyzed Transesterifications

Abstract

Starting from racemic 7,7‐dimethoxy‐1,4,5,6‐tetrachlorobicyclo[2.2.1]hept‐5‐en‐2‐endo‐ol (±)‐7, using lipase‐catalyzed transesterification and a series of standard procedures, we prepared the enantiomers (+)‐(2R, 7S) and (?)‐(2S, 7R) bicyclo[2.2.1] heptan‐2,7‐syn‐diol 3 through a new alternative route with excellent yields and enantiomeric excess (up to 99%). These chiral bidentate compounds possess very rigid molecular structures and a favorable stereochemistry for metal coordination, thus becoming promising chiral ligands for asymmetric synthesis.     

Rare C25 Steroids Produced by Penicillium chrysogenum P1X,a Fungal Endophyte of Huperzia serrata

Three new metabolites, norcyclocitrinol A ( 1 ), erythro‐11α‐hydroxyneocyclocitrinol ( 2 ), and pesudocyclocitrinol A ( 3 ), along with six known analogs, i.e., neocyclocitrinols A–D ( 4 – 7 , resp.), cyclocitrinol ( 8 ), and 24‐epicyclocitrinol ( 9 ), were isolated and identified from the culture broth of Penicillium chrysogenum P1X, a fungal endophyte of Huperzia serrata. Compounds 1 – 9 were identified by spectroscopic methods to share the same C₂₅‐steroid skeleton featuring an unusual bicyclo[4.4.1] A/B ring system. In particular, 1 represents the first example of a C₂₅ steroid with a bisnor C‐atom side chain. All compounds were evaluated for their cytotoxic activities against HeLa and HepG2 cell lines. However, none of them exhibited a significant cytotoxicity at a concentration of 20 μM .     

Water‐Soluble Non‐Classical Benzene Mimetics

A new generation of saturated benzene mimetics, 2‐oxabicyclo[2.1.1]hexanes, was developed. These compounds were designed as analogues of bicyclo[1.1.1]pentane with an improved water solubility. Crystallographic analysis of 2‐oxabicyclo[2.1.1]hexanes revealed that they occupy a novel chemical space, but, at the same time, resemble the motif of meta‐disubstituted benzenes.     

Indoloquinazoline Alkaloids from Araliopsis tabouensis

Three new indoloquinazolidine‐type alkaloids, 8,13‐dihydro‐2‐methoxyindolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolin‐5(7H)‐one ( 1 ), 8,13‐dihydro‐2‐methoxy‐13‐methylindolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolin‐5(7H)‐one ( 2 ), and 5,8,13,14‐tetrahydro‐2‐methoxy‐14‐methyl‐5‐oxo‐7H‐indolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolim‐6‐iun chloride ( 3 ) were isolated from Araliopsis tabouensis, together with three known compounds. The structures of the new compounds were determined primarily from 1D‐ and 2D‐NMR analysis. The antimalarial activities of compounds 1 – 5 were evaluated against Plasmodium falciparum D6 and W2 clones. The IC₅₀ values in antimalarial bioassay for compounds 2 – 5 varied from 1.8 to 4.7 μg/ml.     

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.     

Synthesis of Novel,Chiral Bicyclo[3.1.0]hex‐2‐ene Amino Acid Derivatives as Useful Synthons in Medicinal Chemistry

A short and concise synthesis of novel, chiral bicyclo[3.1.0]hex‐2‐ene amino acid derivatives 13 and 14 has been developed. The key step is a stereo‐ and regioselective allylic amination of exo‐ and endo‐methyl bicyclo[3.1.0]hex‐2‐ene‐6‐carboxylates 8 and 9 , which were prepared from 7,7‐dichlorobicyclo[3.2.0]hept‐2‐en‐6‐one ( 1 ). These amino acid derivatives are useful building blocks in medicinal chemistry and can be prepared as chiral compounds by using either (+)‐ 1 or (?)‐ 1 as starting material.     

Synthesis and Structural Characterisation of Derivatives of Tricyclo[5.2.1.02,6]Dec‐8‐Ene‐3,5‐Dione with an Expected Antimicrobial Activity

Anhydrides, imides, N‐ethylimides, N‐hydroxyimides and N‐aminoimides of 1,4,5,6‐tetramethyl‐bicyclo[5.2.1.0^2,6]hept‐5‐ene‐2,3‐dicarboxylic acid, 1,4,5,6,7‐pentamethyl‐bicyclo[5.2.1.0^2,6]hept‐5‐ene‐2,3‐dicarboxylic acid and 7‐ethyl‐1,4,5,6‐tetramethyl‐bicyclo[5.2.1.0^2,6]hept‐5‐ene‐2,3‐dicarboxylic acid were obtained. Antimicrobial activity of the newly obtained derivatives was tested against selected Gram‐positive and Gram‐negative bacteria and fungi of the Candida species. The structures of obtained compounds and their antimicrobial activity were compared. Structure of 1b, 2b and 1e were determined by an X‐ray analysis.     

Synthesis of Some Novel Pyrido[2,3‐d]pyrimidine and Pyrido[3,2‐e][1,3,4]triazolo and Tetrazolo[1,5‐c]pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

A novel series of pyrido[2,3‐d]pyrimidines 3a – d , 4a – d , 5a – d , 6a – d , and 7a – d ; pyrido[3,2‐e][1,3,4]triazolo; and tetrazolo[1,5‐c]pyrimidines 10a – d and 11a – d was synthesized through different chemical reactions starting from 2‐amino‐3‐cyano‐4,6‐diarylpyridines. The newly synthesized heterocycles were characterized by elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral data. Compounds have been screened for their antibacterial and antifungal activities. The data showed that the presence of electron‐donating group such as p‐methoxyphenyl increases the antimicrobial activity. Also, the compounds have shown anticancer activity for colon and liver cancer cells.     

Microwave‐Assisted Beckmann Rearrangement: Convenient Synthesis of 1,3‐Diaza‐bicyclo[3.2.2]nonane

Small heterocyclic amines such as 1,3‐diaza‐bicyclo[3.2.2]nonane are known to be key components of biologically active molecules. A convenient synthesis of this compound utilizing a key Beckmann rearrangement of (Z)‐1‐aza‐bicyclo[2.2.2]octan‐3‐one oxime (6) with conc. H₂SO₄ under microwave irradiation was achieved. The desired compound (1) was obtained in 20% yield overall.     

Microwave‐Assisted Synthesis of Novel Spiro Phosphonyl Thiazolo Pyrazole Glycosides as Potential Nematicidal Agents

A series of novel dimethyl 7‐((3aR,5S,6S,6aR)‐6‐((1‐(4‐chlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐2,2‐dimethyltetrahydrofuro[2,3‐d][1,3]dioxol‐5‐yl)‐4‐(4‐fluorophenyl)‐9‐oxo‐8‐phenyl‐6‐thia‐1,2,8‐triazaspiro[4.4]non‐2‐en‐3‐ylphosphonate 2a – g were synthesized by the reaction of chalcone derivatives of 2‐((3aR,5S,6S,6aR)‐6‐((1‐(4‐chlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐2,2‐dimethyltetrahydrofuro[2,3‐d][1,3]dioxol‐5‐yl)‐3‐phenylthiazolidin‐4‐one 1 with Bestmann–Ohira reagent. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS, and elemental analysis. The compounds 2a – g were evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans; compounds 2b , 2c , 2g , and 2f showed appreciable nematicidal activity.     

Synthesis and Antimicrobial Studies of New Spiropyran Quinazolinone Derivatives with Amide,Urea, and Sulfonamide Moieties

Three new series of quinazolinone derivatives containing amide, urea, and sulfonamide were synthesized through multistep synthesis. The required intermediates 4‐[(4′‐oxo‐2,3,3′,4′,5,6‐hexahydro‐1′H ‐spiro[pyran‐4,2′‐quinazolin]‐1′‐yl)methyl]benzoic acid 4 and 1′‐(3‐aminobenzyl)‐2,3,5,6‐tetrahydro‐1′H ‐spiro[pyran‐4,2′‐quinazolin]‐4′(3′H )‐one 8 were prepared by hydrolysis of ester and reduction of nitro intermediates. Three different series of compounds were synthesized from these two scaffolds. The key scaffolds 4 and 8 were successfully converted to target molecules via amides 5a – k , urea 9a – f , and substituted sulfonamides 10a – e . The chemical structures of newly synthesized compounds were characterized by spectral analysis. The structure of 5d was confirmed by X‐ray crystallography study. These newly synthesized compounds were screened for antibacterial studies against Staphylococcus epidermidis , Salmonella typhi , Proteus mirabilis , and Shigella sonnei and for the antifungal activity against Aspergillus niger and Candida albicans . Among all the compounds, 9b – d showed excellent activities against S. typhi . Compound 9a showed moderate activity against all fungi stains, and 5I showed moderate activity against P. mirabilis , while the other derivatives showed fairly good activities.     

2-Chlorobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2-chlorobicyclo[2.2.1]heptane-2-carboxamide as precursors of bicyclo[2.2.1]hept-5-en-2-one and bicyclo[2.2.1]heptan-2-one: resolution,absolute configuration and hydrogen-bonding properties

The absolute configuration of bicyclo[2.2.1]heptan-2-one has not been correlated with a crystal structure of a chemical precursor. The only chemical correlation available had an ambiguity, which could have reversed the assignment. Herein, we report the resolution of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide on a cellulose triacetate column and the crystal structures of the enantiomerically pure and racemic α-chloroamide. We found the absolute configuration (1R,2R,4R) for the (+)-enantiomer of the α-chloroamide. This compound was converted to (+)-bicyclo[2.2.1]hept-5-ene-2-one by base hydrolysis, and the 5,6-unsaturated compounds converted to the saturated congeners. This is the first unambiguous experimental determination of the absolute configuration of bicyclo[2.2.1]heptan-2-one and of bicyclo[2.2.1]hept-5-ene-2-one. The three crystal structures of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide reported herein reveal H-bonded dimers, with two distinct orientations of the bicyclic portion relative to the carboxamide dimer. In the racemic crystal, each dimer is composed of two enantiomers, and the bicyclic portions have their bridge carbon atom (C-7) on opposite sides of the H-bonded carboxamide dimer moiety. In the enantiomerically pure crystals, the major dimer had both C-7 atoms on the same side of the carboxamide dimer moiety while the minor dimer had the C-7 atoms on opposite sides. The dimers are present in solution, and can be easily monitored.     

Andhraxylocarpins A–E: Structurally Intriguing Limonoids from the True Mangroves Xylocarpus granatum and Xylocarpus moluccensis

Five new limonoids, including andhraxylocarpins A and B ( 1 and 2 ) which contain a 9‐oxa‐tricyclo[3.3.2.1^{7, 10}]undecane‐2‐ene motif, andhraxylocarpins C and D ( 3 and 4 ), which contain a (Z)‐bicyclo[5.2.1]dec‐3‐en‐8‐one substructure, and andhraxylocarpin E ( 5 ), which contains a tricyclo[3.3.1.1^{3, 6}]decane‐9‐one scaffold, were isolated from the seeds of two true mangroves, Xylocarpus granatum and Xylocarpus moluccensis, that were collected in the estuaries of Andhra Pradesh, India. The absolute configurations of these compounds were determined by extensive NMR investigations, single‐crystal X‐ray diffraction analysis, and by circular dichroism and optical rotatory dispersion spectroscopy, in combination with quantum‐chemical calculations. The pronounced structural diversity of limonoids from these mangroves might originate from environmental factors.     

Synthesis and Microbial Studies of New Pyridine Derivatives-Ill

2-Amino substituted benzothiazole 4a--4I and p-acetamidobenzenesulfonyl chloride 2 were used to prepare 2-（p-aminophenylsulfonamido） substituted benzothiazole 6a--6I using mixture of pyridine and acetic anhydride which formed an electrophilic complex （N-acetyl pyridinium） to facilitate condensation to give desired product by removal of HC1. 2-{p-[（3-Carboxypyrid-2-y1）amino]phenylsulfonamido}benzothiazoles 8a--81 were synthesized from 2-chloropyridine-3-carboxylic acid 7 and 6a--6I in 2-ethoxy ethanol using Cu-powder and K2CO3. Acid chlorides 9a--91 were condensed with 2-hydroxyethyl piperazine 10 and 2,3-dichloropiperazine 11 for amide deriva- tives 2-（p-（（3-（4-（2-hydroxyethy1）piperazin-1-ylcarbonyl）pyrid-2-y1）amino）phenylsulfonamido）benzothiazoes 12a -121 and 2-{p-[3-（2,3-dichloropiperazin-l-ylcarbonyl）pyrid-2-ylamino]phenylsulfonamido}benzothiazoles 13a- 131 respectively. The structures of the new compounds have been established on the basis of their chemical analysis and spectral data （IR, 1↑H NMR and mass）. All the compounds have been screened for their antibacterial and antifungal activities.     

Isolation and Structural Elucidation of Armeniaspirols A–C: Potent Antibiotics against Gram‐Positive Pathogens

In an antibiotic lead discovery program, the known strain Streptomyces armeniacus DSM19369 has been found to produce three new natural products when cultivated on a malt‐containing medium. The challenging structural elucidation of the isolated compounds was achieved by using three independent methods, that is, chemical degradation followed by NMR spectroscopy, a computer‐assisted structure prediction algorithm, and X‐ray crystallography. The compounds, named armeniaspirol A–C ( 2 – 4 ), exhibit a compact, hitherto unprecedented chlorinated spiro[4.4]non‐8‐ene scaffold. Labeling experiments with [1‐¹³C] acetate, [1,2‐¹³C2] acetate, and [U‐¹³C] proline suggest a biosynthesis through a rare two‐chain mechanism. Armeniaspirols displayed moderate to high in vitro activities against Gram‐positive pathogens such as methicillin‐resistant S. aureus (MRSA) or vancomycin resistant E. faecium (VRE). As analogue 2 was active in vivo in an MRSA sepsis model, and showed no development of resistance in a serial passaging experiment, it represents a new antibiotic lead structure.