Search

A synthesis of benzo[d]oxazoles by an N-deprotonation–O-SNAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward SNAr ring closure by C5 electron-withdrawing groups, were prepared and subjected to deprotonation–cyclization using 2 equiv. of K2CO3 in anhydrous DMF. Following deprotonation at nitrogen, the delocalized anion cyclized from the amide oxygen to give high yields of benzo[d]oxazoles. The temperature required for the cyclization of benzanilides correlated with the potency of the C5 activating group on the SNAr acceptor ring with nitro (most potent) reacting at 90 °C (1 h), cyano reacting at 115 °C (1 h), methoxycarbonyl reacting at 120 °C (2 h), and trifluoromethyl (least potent) reacting at 130 °C (3 h). Acetanilides were more difficult to cyclize but generally required 4–6 h at these same temperatures for completion. Product purification was accomplished by recrystallization or chromatography. [ABSTRACT FROM AUTHOR]

In order to study the competition between halogen bond acceptor sites of multifunctional N,O,X-based halogen bond acceptors (X = S, O, N or π aromatic ring) we have synthesized a family of oxazole derivatives and cocrystallized them with selected iodoperfluorinated benzenes as halogen bond donors. Out of 28 combinations, 19 experiments yielded crystals suitable for single-crystal X-ray diffraction. Structural analysis revealed that in all of the obtained cocrystals the most prominent supramolecular interaction is the I⋯Noxazole halogen bond with relative shortening values of up to 18%, comparable to I⋯Npyridine halogen bond shortening values. The acceptors are ditopic in 10 cocrystals and form additional I⋯N, I⋯O or I⋯π halogen bonds. A majority of cocrystals feature one donor molecule per one acceptor molecule. In order to rank the acceptor sites and establish how the electrostatic potential differences impact the supramolecular landscape around these molecules, the values of molecular electrostatic potentials (MEPs) were calculated on their optimized geometries. These calculations were in agreement with experimental observations, since the best (most negative MEP value) acceptor binding site in the series of used oxazoles is the oxazole nitrogen atom. Depending on the difference between MEP values of the oxazole oxygen atom and the peripheral functionalities, additional halogen bonds could potentially be formed with one of these acceptor sites, leading to the formation of two different types of halogen-bonded supramolecular chains. [ABSTRACT FROM AUTHOR]

A facile and efficient procedure is developed for H3PW12O40 catalyzed new and one-pot synthesis of highly functionalized oxazoles linked to benzo[a]phenazin derivatives using phenylenediamine derivatives, 2-hydroxy-1,4-naphthoquinone, arylglyoxals and acetonitrile via a multicomponent tandem cyclization Robinson-Gabriel reaction in a very short time and easy workup without any byproduct. Acetonitrile served not only as a solvent but also as the substrate in the reaction. [ABSTRACT FROM AUTHOR]

The van Leusen reaction utilizes p‐toluenesulfonylmethyl isocyanide as a versatile synthon for constructing nitrogen‐containing heterocycles, such as oxazoles, imidazoles, thiazoles, and pyrroles. In this study, the van Leusen imidazole reaction, employed for synthesizing potential Hsp90 inhibitors, yielded unexpected side products containing novel condensed tricycles, specifically 3a,8b‐dihydro‐1H‐benzofuro[2,3‐d]imidazoles. The mechanism behind the formation of this unprecedented fragment was further analyzed through quantum mechanical calculations and experimental investigations of the reaction outcome under different reaction conditions and with various substituents. Additionally, the stabilities of the products were evaluated. [ABSTRACT FROM AUTHOR]

A copper‐catalyzed one‐pot synthesis of substituted bis(benzoxazole)amine, N‐benzoxazole(benzoimidazole)amine, and N‐benzoxazole(benzothiazole)amine is described via intramolecular cyclization of iodophenol and 2‐amino benzimidazoles(thiazoles)(oxazoles)‐trichloroacetonitrile adduct under ultrasound irradiation in MeCN with good yields. The use of simple and readily available starting materials, no column chromatography, mild copper‐catalytic reaction conditions, good yields (74–84 %), applying the sonochemical methodology and short reaction times are remarkable specifications of this protocol. All the compounds synthesized in this design are new and their identities have been confirmed using IR, NMR, CHN and mass spectrometry techniques. [ABSTRACT FROM AUTHOR]

The regiodivergent synthesis of 4‐ and 5‐sulfenyl oxazoles from 1,4,2‐dioxazoles and alkynyl thioethers has been achieved. Gold‐catalysed conditions are used to favour the formation of 5‐sulfenyl oxazoles via β‐selective attack of the nitrenoid relative to the sulfenyl group. In contrast, 4‐sulfenyl oxazoles are formed by α‐selective reaction under Brønsted acid conditions from the same substrates. The nature of stabilising gold‐sulfur interactions have been investigated by natural bond orbital analysis, showing that the S→Au interactions are significantly stronger in the intermediate that favours the 5‐sulfenyl oxazoles. A kinetic survey identifies catalyst inhibition processes. This study into the regiodivergent methods includes the development of telescoped annulation‐oxidation protocols for regioselective access to oxazole sulfoxides and sulfones. [ABSTRACT FROM AUTHOR]

Lupeol is one of the most important metabolite in the class of terpenoids and possess excellent anticancer, anti-inflammatory, anti-diabetic activities etc. In the present study, the different thiazoles and oxazoles bearing lupeol derivatives were prepared to enhance their biological activity. Initially, the in vitro cytotoxic activity results showed that the synthesized lupeol derivatives (9a–9j and 10a–10e) showed significant activity against various cancer cells and the compounds 9h and 10b exhibited excellent activity against CAL27 cells. Further, these compounds 9h and 10b arrest the cell cycle at S phase and induce the late apoptosis in CAL27 cells by downregulating the BcL2 and vimentin expression and upregulating the Bax gene expression. Moreover, the lupeol derivatives showed dose-dependent anti-inflammatory activity by inhibiting the secretion of IL-6 cytokines in LPS-induced Raw 264.7 cells. Together, these results clearly indicated that the thiazoles and oxazoles bearing lupeol derivatives can used as chemotherapeutic drugs against cancer and inflammatory diseases. [ABSTRACT FROM AUTHOR]

This article presents a new method for synthesizing 2,4-disubstituted oxazoles, which are important compounds with pharmaceutical and therapeutic applications. The authors propose a simple and efficient procedure using readily available materials and a copper catalyst. They successfully synthesized a variety of oxazoles with different functional groups. The method is versatile and can be used for late-stage installation of oxazoles into drug molecules and the synthesis of chiral ligands. The authors also suggest further exploration in carbene chemistry based on the mechanism proposed for the reaction. [Extracted from the article]

This review presents an outline of current advancements in the photochemical and electrochemical synthesis of oxazoles and isoxazoles. Oxazole and isoxazole are important building blocks for a variety of medicinally useful compounds. Therefore, the synthesis of these heterocycles via sustainable technologies is worth demanding. Photochemical and electrochemical are two among the few sustainable technologies. This review covers a brief discussion on reaction parameters like catalysts, substrates scope, reaction temperature, solvents, electrodes, electrolytes (in case of electrochemical process), light source (in case of photochemical process) for individual reaction. Detailed discussion on mechanistic insight for each reaction is also presented. Finally, summary, and future direction toward the development of effective electrochemical and photochemical methods for the reaction of oxazoles and isoxazoles is also presented. [ABSTRACT FROM AUTHOR]

With KI as the supporting electrolyte and a mediator, DMSO as the solvent and KHCO3 as the base, a convenient and efficient electrochemical route was developed for the synthesis of polysubstituted oxazoles from aromatic ketones and benzylamines. The electrosynthesis was smoothly carried out in an undivided cell at room temperature, affording the target products in moderate to high yields. [ABSTRACT FROM AUTHOR]

The recyclizations of 5‐amino‐ and 5‐hydrazine‐1,3‐oxazoles mainly with electron‐withdrawing group in 4th position are considered. The chemical behavior of these heterocycles is due to the presence of two hidden amide fragments; therefore, the recyclization processes include a stage of nucleophile attack on 2nd or 5th position of the oxazole cycle. When the nitrile group is present in 4th position, it is often involved in the recyclization forming α‐aminoazoles. 5‐Amino/hydrazine‐1,3‐oxazoles undergo recyclization both in nucleophilic (amines, hydrazine, thionating agents) and electrophilic medium ((trifluoro)acetic acid, other acylating agents). The numerous types of functionalized heterocycles can be easily obtained with the usage of these recyclizations, such as the derivatives of 3‐amino‐6,7‐dihydro‐5H‐pyrrolo[1,2–a]imidazole, imidazolidine‐2,4‐dione, 1H‐pyrazole‐3,4,5‐triamine, 5,6‐diamino‐2,3‐diphenylpyrimidin‐4(3H)‐one, 2‐(2‐R‐7‐oxo‐5‐(trifluoromethyl)oxazolo[5,4–d]pyrimidin‐6(7H)‐yl)acetic acid, 2‐R‐4‐(5‐R′‐1,3,4‐oxadiazol‐2‐yl)oxazol‐5‐amine, (amino(5‐amino‐1,3,4‐thiadiazol‐2‐yl)methyl)phosphonate. [ABSTRACT FROM AUTHOR]

This research focuses on the synthesis and in vitro anticancer evaluation of functionalized 2-aryl-5-(4-piperazin-1-yl)oxazoles and 5-[(4-arylsulfonyl) piperazin-1-yl]-2-phenyloxazoles. Oxazoles are a versatile class of compounds with diverse biological activities, making them attractive targets in medicinal chemistry. We incorporated amino and sulfonamide functionalities into the oxazole scaffold, as they have shown potential for interacting with biological targets. The synthesis of target oxazole derivatives was accomplished using 2-aroylamino-3,3-dichloroacrylonitriles as starting materials and employing efficient reaction conditions. The resulting compounds exhibited structural features that make them promising candidates for further chemical modifications and biological evaluations. Additionally, a series of sulfonamides were synthesized from 5-(piperazin-1-yl)oxazole-4-carbonitrile hydrochloride, offering diverse bioactivity and versatile structural characteristics. However, no potent inhibitors of malignant cell growth were identified among the tested compounds. Nevertheless, we categorized the investigated substances into two distinct groups based on their activity profile. Group A, comprising sulfonamides, displayed pronounced anticancer activity against breast cancer and melanoma cell lines. On the other hand, group B, the 2-aryl-5-(4-R-piperazin-1-yl)oxazole-4-carbonitriles, exhibited a moderate effect primarily on renal cancer cell lines. These findings provide valuable insights for further structural modifications in the quest for more potent anticancer agents. [ABSTRACT FROM AUTHOR]

Nitrile ylides are 1,3‐dipolar species with structures that are commonly described by propargylic and/or allenic resonance forms. Nevertheless, certain nitrile ylides exhibit a tendency to form dimers, suggesting the existence of structures characterized by an important carbenic contribution. To address the nitrile ylide carbenic nature, here we investigate two derivatives with OH and NH2 electron‐donating substituents. These nitrile ylides were generated in cryogenic matrices by UV‐irradiation of 3‐hydroxy‐ and 3‐amino‐isoxazole precursors and were found to photoisomerize to the corresponding oxazoles. The IR spectral characterization of the photogenerated nitrile ylides reveals the absence of the characteristic strong νas(CNC) absorption, which is associated with allenic and propargylic type structures. Computed geometries for the two experimentally investigated nitrile ylides and for analogues with different substituents at C3 and C1, together with NBO and NRT electronic structure analyses, performed at the CCSD(T) level of theory, reveal substantial carbenic character exclusively for nitrile ylides bearing OH and NH2 substituents at C3. As a whole, the results shed light on the factors determining the structural features of nitrile ylides, which play a major role in defining the reactivity of these important elusive compounds. [ABSTRACT FROM AUTHOR]

A first access to mono‐, di‐ and tri‐(Het)arylated pyrazolo[5,1‐b]oxazoles is reported. The series were generated from a library of 3‐(Het)arylpyrazolo[5,1‐b]oxazole platforms selectively functionalized through regioselective arylation procedures. The regioselective functionalization in C‐2 and C‐7 positions was investigated. Each Palladium‐catalyzed cross‐coupling condition was optimized and a representative library of the scope and limitations of the reactions was studied. [ABSTRACT FROM AUTHOR]

The search for new scaffolds is one of the important goals in the discovery of new pesticides, and the oxazoles as an important five‐membered heterocyclic compound are widely used in the discovery of new pesticides. Oxazoles ring are often used as the scaffolding structure or bridging chain to connect different reactive groups. In recent years, oxazoles have made rapid progress in the discovery of new pesticides, especially in the discovery of fungicides, insecticides, and acaricides. A systematic review of the recent research progress of oxazoles in the discovery of new pesticides is of interest. Therefore, we comprehensively reviewed the application of oxazole compounds in the discovery of new pesticides from 2003 to 2023; summarized the fungicidal, antibacterial, insecticidal, acaricidal, and herbicidal activities of oxazoles; and discussed the structure–activity relationship, physiochemical and mechanism of action, with the aim of providing inspiration and ideas for the discovery of oxazoles as novel agrochemicals. [ABSTRACT FROM AUTHOR]

Nitrogen‐containing heterocycles such as imidazoles, thiazoles, and oxazoles play a significant role in the fields of biological and pharmaceutical chemistry. These compounds were widely used for agrochemical, pesticide, medicinal, and industrial applications. Due to the wide spectrum of structural diversity as well as the biological and pharmaceutical activity of N‐heterocycles, a plethora of reports on their synthesis have appeared in the last few decades. However, developments in various bond‐forming strategies such as C−C, C−N, C−O, C−S, and N−N, as well as C−H activation, have been used as a powerful synthetic tool to derive copious N‐heterocycles. The most prominent and fascinating reports on the synthesis of imidazole, thiazole, oxazoles, and benzimidazole moieties by C−C and C−N coupling reactions, multi‐component and cycloaddition reactions, C−H activation, etc. are discussed in this study. These studies demonstrated the enormous potential of such methods for accelerating modern chemical synthesis and establishing molecular beauty through bonding. The various aspects of the methodologies, like optimized conditions, substrate scope, and mechanistic investigations, are discussed in detail. [ABSTRACT FROM AUTHOR]

This document is a research article that focuses on the total synthesis of ajudazol A, a natural product. The authors, researchers from the University of Bonn, provide detailed information about the experimental procedures and characterization data. The document is technical in nature and provides information relevant to organic chemistry and natural product synthesis. [Extracted from the article]

We have developed a photoinduced protocol for the synthesis of pharmaceutically important oxazole molecules using diazo‐ and nitrile‐containing reactants. The process involves the initial photolysis of the diazo compound to afford singlet carbenes, which are tapped by nitriles in a [3+2] cycloaddition fashion to give substituted oxazoles. With di‐nitrile compounds, useful bis‐oxazoles were obtained. The applicability of the transformation is showcased through the expedient synthesis of small‐molecule drugs and biologically relevant molecules such as felbinac, pimprinine, texamine, ugnenenazole etc. The protocol is also useful for the generation of 2H and 13C isotope labelled oxazoles. Merging photolysis with continuous‐flow chemistry was demonstrated for scaling up the reaction. The non‐requirement of metal catalysis or photosensitizers to harness the light energy with blue light sufficing the execution of the reaction makes it a versatile and general protocol for the synthesis of structurally diverse oxazoles [ABSTRACT FROM AUTHOR]

Syntheses of important classes of (heterocyclic) compounds, the sustainable generation of hydrogen, and the use of abundantly available metals are highly desirable. We introduce here a catalytic oxazole synthesis. Our reaction is a regio selective, one‐pot reaction and starts from esters and amino alcohols. Both are abundantly and diversely available and inexpensive starting materials. Hydrogen is liberated during the reaction and a molecular earth‐abundant metal catalyst, a Mn(I) compound, mediates the reaction most effectively ‐ and more efficiently than Ir and Ru catalysts. None of the oxazole derivatives synthesized, except the screening substrate and an active ingredient of a drug (an application), have been reported in literature yet. [ABSTRACT FROM AUTHOR]

The reactions of isoxazol-3-amine, thiazol-2-amine, benzo[d]thiazol-2-amine with 4-nitrobenzaldehyde and indole in the absence of a solvent under ball-milling conditions were studied. The reactions proceed through the in situ formation of a Schiff base and subsequent nucleophilic addition of indole at the C=N fragment to form the addition products, α,α-disubstituted azolyl-amines, in yields up to 80%. The structure of the products was proved by physicochemical methods. [ABSTRACT FROM AUTHOR]

The 1,3-dipolar cycloaddition of 1H-pyrrole-2,3-diones to azomethine ylides generated in situ by the condensation of L-proline and arylcarbaldehydes proceeds regio- and diastereoselectively to form substituted ethyl 1,2,5',6',7',7a'-hexahydro-3'H-spiro[pyrrole-3,2'-pyrrolo[2,1-b]oxazole]-4-carboxylates. The structure of the synthesized ethyl (3R*,3'R*,7a'S*)-3'-(4-bromophenyl)-2-oxo-1,5-diphenyl-1,2,5',6',7',7a'-hexahydro-3'H-spiro[pyrrole-3,2'-pyrrolo[2,1-b]oxazole]-4-carboxylate was confirmed by single crystal X-ray analysis. [ABSTRACT FROM AUTHOR]

A method has been developed for the selective C(2)H alkylation of (benz)oxazoles with tertiary alkyl chlorides and alkyl bromides under visible light-induced (460 nm) catalysis with the Pd(PPh3)4/[Bu4N]I system in N,N-dimethylacetamide. The tetraalkylammonium salt has a significant promoting effect on the reaction, which seems to be based on the stabilization of nanosized palladium species in the catalytic system. [ABSTRACT FROM AUTHOR]

SP 1 sp H NMR (500 MHz, CDCl SB 3 sb ): = 8.33 (d, I J i = 8.1 Hz, 1 H), 7.81 (d, I J i = 6.5 Hz, 1 H), 7.73 (d, I J i = 6.5 Hz, 1 H), 7.67 (d, I J i = 6.8 Hz, 1 H), 7.57 (s, 3 H), 7.48 (d, I J i = 6.8 Hz, 1 H), 7.36-7.27 (m, 4 H), 7.17 (t, I J i = 7.4 Hz, 4 H), 7.08 (s, 1 H), 6.92 (s, 1 H). Keywords: arylation; catalysis; P-ligand directed C-H activation; rhodium; trifluoromethylsulfonates; oxazoles EN arylation catalysis P-ligand directed C-H activation rhodium trifluoromethylsulfonates oxazoles 3589 3599 11 10/19/23 20231102 NES 231102 Graph Selective transition-metal-catalyzed C-H activation/functionalization reactions conducted with pseudo(halide) coupling partners obtained from renewable resources, such as alcohols and phenols, [1] complement advantageously the classical use of organic halides that are typically generated from fossil resources. Benchmark SP 1 sp I J i SB PSe sb value for Ph SB 3 sb P(Se) = 730 Hz; SP 31 sp P NMR (162 MHz, CDCl SB 3 sb ) for [(Ph SB 3 sb P)AuCl] = 57.1 ppm. Aryl Triflates in Phosphorus-Directed Rhodium(III)-Catalyzed C-H Activation. [Extracted from the article]

Acylethynylpyrroles, readily available from acylbromoacetylenes and pyrroles, smoothly undergo [3+2]-cyclization with ketones and aldehydes (room temperature) to give acylmethylidenepyrrolo[1,2-c]oxazoles. The reaction protocol meets the principles of the PASE (pot, atom, and step economy) paradigm to afford various pyrrolo[1,2-c]oxazoles, including spirocyclic ones, in up to 82% yield. [ABSTRACT FROM AUTHOR]

Photochemical functionalization of alkoxyoxazoles with trimethylsilyl azide and N,N-dimethylanilines is described. These C–N bond forming reactions proceed with concomitant oxidative ring-opening assisted by organic dyes as photocatalyst and molecular oxygen, providing access to novel chemical space. Unusual demethylative C–N bond formation in the case of N,N-dimethylanilines establishes a new reactivity pattern for these precursors. [ABSTRACT FROM AUTHOR]

New all-oral regimens for rifampin-resistant tuberculosis (RR-TB) are being scaled up globally. Measurement of drug concentrations in hair assesses long-term drug exposure. Delamanid (DLM) is likely to be a key component of future RR-TB treatment regimens, but a method to describe its quantification in hair via liquid chromatography-tandem mass spectrometry (LC-MS/MS) has not previously been described. We developed and validated a simple, fast, sensitive, and accurate LC-MS/MS method for quantifying DLM and its metabolite DM-6705 in small hair samples. We pulverized and extracted two milligrams of hair in methanol at 37 °C for two hours, and diluted 1:1 with water. A gradient elution method eluted DLM, DM-6705, and the internal standard OPC 14714 within 3 min, bringing overall analysis time to 5.5 min. The method has limits of detection (LOD) of 0.0003 ng/mg for DLM and 0.003 ng/mg for DM-6705. The established linear dynamic ranges are 0.003-2.1 ng/mg and 0.03-21 ng/mg for DLM and DM-6705, respectively. Eleven of 12 participant hair samples had concentrations within DLM's linear dynamic range, while all 12 samples had concentrations within the quantifiable range for DM-6705. The ranges of concentrations observed in these clinical samples for DLM and DM-6705 were 0.004-0.264 ng/mg hair and 0.412-12.041 ng/mg hair respectively. We demonstrate that while DLM was detected in hair at very low levels, its primary metabolite DM-6705 had levels approximately 100 times higher. Measuring DM-6705 in hair may accurately reflect long-term adherence to DLM-containing regimens for drug-resistant TB.

Adenosine deaminase (ADA) is a human mononuclear Zn2+ metalloenzyme that converts adenosine to inosine. ADA is a validated drug target for cancer, but there has been little recent work on the development of new therapeutics against this enzyme. The lack of new advancements can be partially attributed to an absence of suitable assays for high-throughput screening (HTS) against ADA. To facilitate more rapid drug discovery efforts for this target, an in vitro assay was developed that utilizes the enzymatic conversion of a visibly emitting adenosine analogue to the corresponding fluorescent inosine analogue by ADA, which can be monitored via fluorescence intensity changes. Utilizing this assay, a library of ∼350 small molecules containing metal-binding pharmacophores (MBPs) was screened in an HTS format to identify new inhibitor scaffolds against ADA. This approach yielded a new metal-binding scaffold with a Ki value of 26±1 μM.

Keywords: fluoroalkyl substituents; carboxylic acid anhydrides; N -propargylic amides; oxazoles; cyclization EN fluoroalkyl substituents carboxylic acid anhydrides N -propargylic amides oxazoles cyclization 1984 1995 12 06/16/23 20230704 NES 230704 Because of the unique properties of fluorine atoms, organic fluorine-containing compounds have been applied to various medicines and pesticides. [23] In the transformation of 4,5-disubstituted I N i H-1,2,3-triazoles with fluorinated acid anhydrides, the cyclization of -acyloxy enamide intermediates occurred after elimination of a nitrogen molecule under heating conditions, leading to fluoroalkylated oxazoles (Scheme 1c). The optimized reaction conditions with propargylic amide B 1a b was applied to the cyclization of propargylic amide B 1b b , which has a biphenyl group at the propargylic position, and the corresponding trifluoromethylated oxazole was generated in 98% yield (entry 7). [Extracted from the article]

In this study, we report the development of efficient synthetic strategies for the preparation of novel 2'-carboxyl isoflavones and their recyclization products, pyrazoles and oxazoles. Utilizing readily accessible starting materials and mild reaction conditions, the synthesis affords valuable compounds with good to excellent yields. The presence of diverse functional groups, including hydroxyl, carboxyl, and carboxamido moieties, renders these molecules attractive for biological screening and targeted structural modifications. This work unveils new avenues for the design of compounds exhibiting a wide range of beneficial properties and opens new opportunities for future research into intramolecular interactions of proximal functional groups. [ABSTRACT FROM AUTHOR]

Feasible, scalable, and cost-effective method for the synthesis of low-molecular 2-(trifluoroacetyl)oxazoles from the corresponding oxazoles and trifluoroacetic anhydride was elaborated. The procedure was scaled up to 70 g of the desired ketones in a single run. Tolerance of the oxazole core to various functional group transformations was demonstrated. Thus, synthesis of various building blocks approved the possibility of using 2-(trifluoroacetyl)oxazoles as a starting materials for medicinal chemistry. [ABSTRACT FROM AUTHOR]

An environmentally benign, efficient, practically applicable and C(sp3)−H functionalization of primary amines for the synthesis of highly substituted oxazoles from easily available internal alkynes was developed. This synthesis is toxic chemicals, transition‐metal free as well as mild and regioselective. This one‐pot methodology with broad substrate scope unlocks a green avenue for the synthesis of highly functionalized oxazole derivatives with excellent yields. [ABSTRACT FROM AUTHOR]

An efficient method is developed for synthesizing new pyrazole‐linked oxazoles through a palladium‐catalyzed Sonogashira coupling reaction. In this method, from the reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐N‐(prop‐2‐phenyl)‐1H‐pyrazole‐4‐carboxamide with aryl iodides having nitro group and aryl iodides with electron‐donating groups, pyrazole‐linked oxazole derivatives and 5‐chloro‐3‐methyl‐1‐phenyl‐N‐(3‐arylprop‐2‐yn‐1‐yl)‐1H‐pyrazole‐4‐carboxamide derivatives were obtained respectively. The prepared products were characterized using FT‐IR, 1HNMR, and 13CNMR spectroscopies. [ABSTRACT FROM AUTHOR]

The synthesis of substituted isoxazole–oxazole hybrids by the noncatalytic reaction of methyl 2-diazo-2-(alkyl/aryl/hetarylisoxazol-5-yl)acetates with alkyl and aryl cyanides has been reported. According to DFT calculations, the reaction proceeds through the intermediate formation of a nitrile ylide and its subsequent cyclization at the carbonyl oxygen. The reaction of acrylonitrile with methyl 2-diazo-2-(isoxazol-5-yl)acetate proceeds quite differently and leads to a mixture of the cis and trans isomers of cyclopropanes, which, according to DFT calculations, are formed by the cycloaddition of a diazo-derived carbene to the C=C bond of acrylonitrile. The hetero-Diels–Alder reaction of the 5-alkoxyoxazole moiety of isoxazole–oxazole hybrids makes it possible to obtain isoxazole–pyridine hybrids, albeit in low yield. [ABSTRACT FROM AUTHOR]

A novel approach to various trisubstituted oxazoles (28 examples, up to 88% yield) has been developed via 9H‐thioxanthen‐9‐one (TX) mediated oxidative annulation of N‐acetyl enamide under visible light irradiation in the presence of BF3 ⋅ Et2O (2.0 equiv) and 40 mol% of PhNO2. This metal‐free procedure features high atom and step economy, green and mild conditions and broad substrate scope. [ABSTRACT FROM AUTHOR]

PurposeIn the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs.Patients and methodsPatients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease.ResultsThere were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03).ConclusionIn patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

[3H]Diazonamide A ([3H]DZA), prepared from the natural product isolated from Diazona angulata, bound to tubulin in larger aberrant assembly products (>500 kDa by sizing HPLC) but not to the αβ-tubulin heterodimer. The binding reaction was rapid, but stoichiometry was low. Stoichiometry was enhanced up to 8-fold by preincubating the tubulin in the reaction mixture prior to adding the [3H]DZA. Although Mg2+ did not affect binding stoichiometry, the cation markedly increased the number of tubulin rings (diameter about 50 nm) observed by negative stain electron microscopy. Bound [3H]DZA did not dissociate from the tubulin oligomers despite extensive column chromatography but did dissociate in the presence of 8 M urea. With preincubated tubulin, a superstoichiometric amount of [3H]DZA appeared to bind to the tubulin oligomeric structures, consistent with observations that neither nonradiolabeled DZA nor DZA analogues inhibited binding of [3H]DZA to the tubulin oligomers. Only weak inhibition of binding was observed with multiple antimitotic compounds. In particular, no inhibition occurred with vinblastine, and the best inhibitors of those examined were dolastatin 10 and cryptophycin 1. We compared the aberrant assembly reaction induced by DZA to those induced by other antimitotic peptides and depsipeptides, in particular dolastatin 10, cryptophycin 1, and hemiasterlin, but the results obtained varied considerably in terms of requirements for maximal reactions, polymer morphology, and inhibitory effects observed with antimitotic compounds.

Difluorocarbene is a simple and versatile one-carbon unit for synthesizing acyclic and cyclic organofluorine compounds. However, the use of difluorocarbene in organic synthesis has been relatively limited because of the harsh conditions required for its generation, the toxicity of the precursors, and undesired dimerization. This feature article provides an account of (i) the generation of free and metal difluorocarbenes from trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) or BrCF2CO2Li/Na and (ii) their application to the facile synthesis of valuable organofluorine compounds. The difluorocarbenes thus generated react with (thio)carbonyl compounds and silyl dienol ethers to provide a wide variety of products such as (a) difluoromethyl (thio)ethers, (b) fluorinated thiophenes, (c) fluorinated thia/oxazoles, (d) fluorinated cyclopentanones and (e) difluoroalkenes. [ABSTRACT FROM AUTHOR]

We report a palladium‐catalyzed intramolecular direct heteroarylation of oxazole tethered β‐naphthols to access corresponding tetracyclic 4H‐benzo[5,6]chromeno[3,4‐d]oxazoles. Various functional groups are well tolerated and furnished the desired products in good to excellent yields under the present reaction conditions. The scale‐up reaction and synthetic utility of the resulting molecules have been demonstrated. Moreover, UV/vis absorption and fluorescence emission properties have been evaluated for these polyheterocyclic compounds. [ABSTRACT FROM AUTHOR]

A new series of amide derivatives (9a–j) have been synthesized and their chemical structures characterized by the 1HNMR, 13CNMR, and mass spectroscopic techniques. The synthesized amide derivatives (9a–j) were evaluated for their in vitro anti-proliferative activity against four human cancer cell lines, including PC3 (prostate cancer), A549 (lung cancer), MCF7 (breast cancer), and A2780 (ovarian cancer) cells by employing the MTT assay. Results were expressed as IC50 values and were compared with the clinical drug, etoposide, used as a positive control. Among the synthesized amide derivatives, five compounds 9a, 9b, 9c, 9d, and 9g revealed potent anti-proliferative potential toward all cell lines. Primarily, two compounds 9a and 9b possessed the most promising anticancer activities. [ABSTRACT FROM AUTHOR]

The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.

Colloidal drug aggregates have been a nuisance in drug screening, yet, because they inherently comprise drug-rich particles, they may be useful in vivo if issues of stability can be addressed. As the first step toward answering this question, we optimized colloidal drug aggregate formulations using a fluorescence-based assay to study fulvestrant colloidal formation and stability in high (90%) serum conditions in vitro. We show, for the first time, that the critical aggregation concentration of fulvestrant depends on media composition and increases with serum concentration. Excipients, such as polysorbate 80, stabilize fulvestrant colloids in 90% serum in vitro for over 48 h. Using fulvestrant and an investigational pro-drug, pentyloxycarbonyl-( p-aminobenzyl) doxazolidinylcarbamate (PPD), as proof-of-concept colloidal formulations, we demonstrate that the in vivo plasma half-life for stabilized colloids is greater than their respective monomeric forms. These studies demonstrate the potential of turning the nuisance of colloidal drug aggregation into an opportunity for drug-rich formulations.

Bengazoles A⁻G from the marine sponge Jaspis sp. exhibit potent in vitro antifungal activity against Candida spp. and other pathogenic fungi. The mechanism of action (MOA) of bengazole A was explored in Candida albicans under both liquid culture and surface culture on Mueller-Hinton agar. Pronounced dose-dependent synergistic antifungal activity was observed with bengazole A in the presence of bengamide A, which is also a natural product from Jaspis sp. The MOA of bengazole A was further explored by monitoring the sterol composition of C. albicans in the presence of sub-lethal concentrations of bengazole A. The GCMS of solvent extracts prepared from liquid cultures of C. albicans in the presence of clotrimazole-a clinically approved azole antifungal drug that suppresses ergosterol biosynthesis by the inhibition of 14α-demethylase-showed reduced cellular ergosterol content and increased concentrations of lanosterol and 24-methylenedihydrolanosterol (a shunt metabolite of ergosterol biosynthesis). No change in relative sterol composition was observed when C. albicans was cultured with bengazole A. These results eliminate an azole-like MOA for the bengazoles, and suggest that another as-yet unidentified mechanism is operative.

Background & aimsIncreased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH.MethodsIn an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis.ResultsThe contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF.ConclusionIn an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555.

Background & aimsDe novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH.MethodsWe analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastography measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy.ResultsA relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P = .004 vs placebo), 23% given GS-0976 5 mg (P = .43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P = .002). Changes in magnetic resonance elastography-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was observed in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were observed in patients given GS-0976.ConclusionsIn a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555.

A novel Rh(III)‐catalyzed cascade C−H activation/annulation/nucleophilic attack/Michael addition of 2‐phenyloxazoles with maleimides for highly‐selective construction of pyrroloisoquinoline derivatives through conditions control is reported. In this reaction, oxazoles were used both as the directing group and potential functionalized reagents, H2O was the nucleophile. The notable features of this protocol include atom economy and highly regioselectivity. [ABSTRACT FROM AUTHOR]

An interaction of 6-aryl-1,2,4-triazine-5-carbonitriles with 2‑amino-4-aryl-substituted thiazoles and oxazoles has been studied. The difference in the reactivity of these aminoheterocycles depending on the presence of an oxygen or a sulfur atom in their composition has been demonstrated. Previously, the 4-aryl-3-hydroxy-2,2′-bipyridines were obtained as products of aza-Diels−Alder reaction between 6-aryl-3-(2-pyridyl)-1,2,4-triazine-5-carbonitriles and 2-amino-4-aryloxazoles. It was shown that the reaction of 6-aryl-1,2,4-triazine-5-carbonitriles with 2-aminothiazoles led to the products of ipso-substitution of cyano group. The aza-Diels−Alder reaction of these compounds with 2,5-norbornadiene gave (2,2′-bi)pyridines with the 2-aminothiazolyl at alpha-position. [ABSTRACT FROM AUTHOR]

A new synthetic protocol for the preparation of oxazole N‐oxides in the form of stable boron trifluoride complexes has been developed. It is based on the condensation of α‐diketone monooximes with an appropriate aldehyde component in the presence of an equimolar amount of boron trifluoride. The method opens access to a broad scope of derivatives including previously unknown 2‐unsubstituted oxazole N‐oxides. Its abilities were demonstrated via the synthesis of 25 diverse oxazole derivatives in 14–89 % yields. [ABSTRACT FROM AUTHOR]

An efficient method for the C(2)−H arylation of (benz)imidazoles and (benz)oxazoles with aryl chlorides and aryl bromides under Ni/NHC catalysis has been developed. The main benefit of the method is the in situ generation of active Ni/NHC complexes from the air‐tolerant bench‐stable precursors NiCl2Py2, IMes⋅HCl, and potassium tert‐butoxide, which plays a dual role as base and Ni(II) to Ni(0) reductant. The approach represents a user‐friendly alternative for procedures relying on the use of toxic phosphine ligands or unstable air‐sensitive Ni(cod)2. The concept highlighted in the present study shows that mapping a competitive picture of catalyst dynamics and revealing the competitive processes towards the destruction and stabilization of catalytically active species enables a highly efficient catalytic system to be built under simple conditions. [ABSTRACT FROM AUTHOR]