Oxime 5a Research Articles

Eudistomins Y-Inspired Design and Divergent Optimization of Heteroaryl Ketones for New Antifungal Leads.

The discovery of structurally distinct leads is imperative in modern agrochemical science. Inspired by eudistomins Y and the framework-related pharmaceuticals, aryl heteroaryl ketone was drawn as a common model intriguing the design and divergent synthesis of 14 kinds of heteroaryl ketones aligned with their oxime derivatives. Antifungal function-oriented phenotypical screen protruded benzothiazolyl-phenyl oxime 5a as a promising model, and the concomitant modification led to benzothiazolyl oxime 5am (EC50 = 5.17 μM) as a superior lead than fluoxastrobin (EC50 = 7.54 μM) against Sclerotinia sclerotiorum. Scaffold hopping of the phenyl subunit identified benzothiazolyl-pyridyl oxime as a novel antifungal scaffold accompanied by acquiring oxime 5bm with remarkable activity (EC50 = 3.57 μM) against Pyricularia oryzae. Molecular docking showed that candidate 5am could form more hydrogen bonds with the amino acid residues of actin than metrafenone. This compound also demonstrated better curative efficacy than that of fluoxastrobin and metrafenone in controlling the plant disease caused by S. sclerotiorum. These results rationalize the discovery of antifungal candidates based on aryl heteroaryl ketone.

Discovery of Dimethyl Shikonin Oxime 5a, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Type 2 Diabetes Mellitus.

Bombesin receptor subtype-3 (BB3, BRS-3) is an orphan Gαq protein-coupled receptor. The characterization of novel synthetic ligands for BB3 is an alternative and attractive strategy to study its diverse physiological functions. Here, we uncovered the intimate pairing of DMAKO-00 and its derivatives with BB3. Dimethyl shikonin oxime 5a (DSO-5a) was identified as the most potent agonist for BB3 (pEC50 = 8.422 in IP-1 accumulation), which was 898-fold more potent than DMAKO-00. Importantly, without brain penetration, DSO-5a improved glucose tolerance in C57BL/6 mice through BB3 and ameliorated glucose homeostasis in diabetic db/db mice. We further revealed that DSO-5a upregulated PPAR-gamma activity via BB3 through a quantitative proteomics approach. Collectively, our study demonstrated that DSO-5a, a representative compound of DMAKO-00 derivatives, is a potent, selective, and low-brain-penetrating agonist for BB3, and BB3 is a promising treatment target for type 2 diabetes mellitus.

Synthesis of pyrano isoxazoline/isoxazole annulated coumarins via intramolecular nitrile oxide cycloaddition and their cytotoxicity

An efficient and straight forward procedure for the syntheses of isoxazoline/isoxazole fused coumarin analogues 7a–7g and 8a–8g from the corresponding 7-O-allyloxy coumarin oximes 5a–5g and 7-O-propargyloxy coumarin oximes 6a–6g is presented. High yields and simple experimental procedures are important features of this methodology. This method is useful for the construction of many biologically active fused heterocycles. The structures of synthesized compounds are established on the basis of IR, NMR, and MS data. The products were tested for in vitro cytotoxic activity against three human cancer cell lines. All tested compounds demonstrated high cytotoxic activity.

Preparation and characterization of cyclopalladated complexes derived from l-(−)-fenchone

l-(−)-Fenchone 4 was reacted with RONH2·HCl (R = H or Me) and pyridine in ethanol to give l-fenchone oxime 5a and the corresponding O-methyl derivative 5b in 64 and 82% yields, respectively. Reactions of oximes 5a,b with Pd(OAc)2 in acetic acid at 80 °C followed by treatment with LiCl provided dimeric cyclopalladated complexes 7a,b in 65 and 49% yields. Compounds 7a,b were then converted to the mononuclear PPh3 derivatives 8a,b in 99 and 78% yields. The proposed structures of the synthesized complexes were supported by 1H, 13C{1H}, DEPT and 2D NMR spectra. Molecular structures of complexes 8a,b confirmed their trans-N,P geometry and the presence of the (sp3)C–Pd bond.

Synthesis of Sabina δ-Lactones and Sabina δ-Lactams from (+)-Sabinene

Two sabina δ-lactones (3 and 4) were obtained in a two-step synthesis from (+)-sabinene (1). The oxidation of (+)-sabinene (1) with potassium permanganate and sodium periodate to (–)-sabina ketone (2) was the first step. In the second step, the ketone obtained was subjected to chemical and microbial Baeyer–Villiger oxidation. Chemical Baeyer–Villiger oxidation of this ketone afforded two δ-lactones 3 and 4 whereas microbial Baeyer–Villiger oxidation afforded only ‘abnormal’ δ-lactone 4. (–)-Sabina ketone was also the starting material for the synthesis of new δ-lactams (7 and 8). They were obtained by Beckmann rearrangement of sabina ketone oximes 5a and 5b. An attempt to separate (–)-sabina ketone oximes 5a and 5b is also presented.

The alkylation of isatin‐derived oximes: Spectroscopic and X‐ray crystallographic structural characterization of oxime and nitrone products

Abstract magnified imageA series of isatin oximes was alkylated with alkyl halides and under Mitsunobu conditions to generate O‐alkylated oxime ether and N‐alkylated nitrone products. Alkylation of the sodium salts of oximes 5a and 5b with alkyl iodides produced predominantly the N‐alkylated nitrones (E)‐7 while alkylation of 5a and 5b with the harder electrophiles alkyl bromides and alkyl chlorides, gave mostly the O‐alkylated products, oxime ethers (E)‐6. Interestingly, alkylation of oxime 5b under Mitsunobu conditions with isopropyl alcohol produced the N‐alkylated nitrone (E)‐7bd as the major product. However, alkylation of oxime 5c, which incorporates a sterically bulky bromine substituent at the C‐4 position of the isatin heterocycle, with 2‐bromo‐ and 2‐iodo‐propane or with isopropyl alcohol under Mitsunobu conditions gave exclusively the O‐alkylated product, oxime ether (Z)‐6cd. The oxime ether and nitrone products (E)‐6 and (E)‐7, respectively, were characterized by LC/MS, 1H NMR, and 13C NMR. In addition, the structures of oxime ether (E)‐6bd and nitrone (E)‐7ad were determined by X‐ray crystallography. J. Heterocyclic Chem., 46, 432 (2009).

A novel photochemical synthesis of 5,6-dihydro-4H-1,2-oxazines by DCA-sensitized irradiation of γδ-unsaturated oximes

On DCA-sensitized irradiation 6,6-diphenylhex-5-en-2-one oxime 5a, 5,5-diphenylpent-4-enal oxime 5b and 2,2-dimethyl-5-phenylpent-4-enal oxime 5c undergo a novel photochemical cyclization yielding 3-methyl-6-diphenylmethyl-5,6-dihydro-4H-1,2-oxazine 9a, 6-diphenylmethyl-5,6-dihydro-4H-1,2-oxazine 9b and 6-benzyl-4,4-dimethyl-5,6-dihydro-4H-1,2-oxazine 9c, respectively.

The aza-di-π-methane rearrangement of β-γ-unsaturated oximes

Although previous studies have shown that acyclic β,γ-unsaturated oximes and oxime ethers do not undergo the aza-di-π-methane (ADPM) rearrangement, the 2-methyl-4,4-diphenyl-2-vinylbut-3-enal oxime 5a , its methyl ether 5b and the 2,2,4,4-tetraphenylbut-3-enal oxime 14 give the corresponding cyclopropyl derivatives 8a , 8b and 15 by the ADPM path, in a reaction that is controlled by the stability of the intermediate 1,3-biradical.

2-Cyanoethyl and p-nitrophenethyl α-hydroxyimino- and α-methoxyimino-phosphonates: potential precursors of metaphosphate anion

Methyl benzoylphosphonochloridate 3 reacted with 2-cyanoethanol or p-nitrophenethyl alcohol to yield methyl 2-cyanoethyl benzoylphosphonate 4a or methyl p-nitrophenethyl benzoylphosphonate 4b. Ketones 4a and 4b were converted into the corresponding oximes, 5a and 5b as a mixture of E and Z isomers, by hydroxylamine. Oximes 5a and 5b were demethylated by treatment with sodium iodide or lithium bromide to give the corresponding monester monosalts 6a and 6b. Reaction of lithium 2-cyanoethyl or p-nitrophenethyl benzoylphosphonate with methoxylamine afforded the respective oxime methyl ether salts 8a and 8b as predominantly E isomers. Base treatment of 6a and 6b caused their dealkylation to the anion of α-hydroxyiminobenzylphosphonic acid 9 which did not decompose further. In contrast, 8a and 8b in aqueous base gave the dianion of α-methoxyaminobenzylphosphonic acid 10, which slowly fragmented to benzonitrile and phosporic acid. The fragmentation is interpreted in terms of a dissociative mechanism involving the formation of metaphosphate anion.