- Dibenzazepine-linked isoxazoles: New and potent class of α-glucosidase inhibitors
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α-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33–54) was prepared using Nitrile oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their α-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against α-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 μM) using acarbose as a reference drug (IC50 = 875.75 ± 2.08 μM). Structure-activity relationship, kinetics and molecular docking studies of active isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48–50, and 54 showed binding interactions with critical amino acid residues of α-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.
- Umm-E-Farwa,Ullah, Saeed,Khan, Maria Aqeel,Zafar, Humaira,Atia-tul-Wahab,Younus, Munisaa,Choudhary, M. Iqbal,Basha, Fatima Z.
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- One-Pot Regioselective Synthesis of 7-Bromo-2H-Benzo[b][1,4]Oxazin-3(4H)-One Linked Isoxazole Hybrids as Anti-Cancer Agents and Their Molecular Docking Studies
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Abstract: Regioselective synthesis of some novel 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one linked isoxazole hybrids via copper(I) catalyzed one-pot reaction of various aromatic aldehydes with 7-bromo-4-(prop-2-yn-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one was developed. The structures of the compounds that are synthesized are confirmed by 1H NMR, 13C NMR, and mass spectra. All the hybrids have been tested for their in vitro anticancer activity against four human cancer cell lines, including HeLa, MCF-7, A549, and PC3. Three of the compounds exhibited remarkable anticancer activity compared to standard drug etoposide. Molecular docking studies with EGFR also strengthened the in vitro anticancer activity.
- Karthik, B.,Kumar, A. Kannan,Nukala, Satheesh Kumar,Ravinder, M.,Swamy, T. Narasimha
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p. 1269 - 1275
(2021/12/23)
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- One-pot Synthesis of Some Novel Xanthine Derived Isoxazoles as Potent Antibacterial Agents
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In search of better antibacterial agents, a series of novel xanthine derived 3,5-disubstituted isoxazole derivatives were synthesized (3a-3j) in one-pot using 8-chloro-1,3-dimethyl-7-(prop-2-yn-1-yl)-1H-purine-2,6(3H,7H)-dione and aromatic aldehydes and f
- Vidya
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p. 551 - 557
(2021/02/02)
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- One-pot synthesis of novel ether-linked diisoxazole derivatives via sequential O-propargylation and 1,3-dipolar cycloaddition from 2-bromohomoallylic alcohols
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A simple and efficient, one-pot approach for the synthesis of ether-linked diisoxazole derivatives has been developed through sequential reactions, which includes O-propargylation of 2-bromohomoallylic alcohols with propargyl bromide in the presence of so
- Zhang, Xiao-Lan,Wei, Mei-Hong,Chen, Jun-Min,Liu, Xiao-Ling
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- 1,3-Dipolar cycloaddition reactions of acyl phosphonates with nitrile oxides: synthesis of phosphonate-containing dioxazole derivatives
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New phosphonate-containing five-membered heterocyclic dioxazole derivatives are synthesized via 1,3-dipolar cycloaddition reactions of nitrile oxides used as dipole with acyl phosphonates under basic conditions. Herein, acyl phosphonates take part in the
- Polat-Cakir, Sidika
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p. 461 - 467
(2020/12/09)
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- One Pot Synthesis and Antitumor Activity of Isoxazole-Pyrimido[4,5-c]isoquinolines
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Abstract: A number of new isoxazole coupled pyrimido[4,5-c]isoquinolines has been synthesized in good to excellent yields by the one pot method. The Cu(I)-catalyzed cycloaddition reaction between the terminal alkyne 4 and various aldehydes has led to nitr
- Venkatesh,Narsimha,Kumar,Reddy
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p. 2444 - 2450
(2021/02/16)
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- Cu(I)-Catalysis of One-Pot Synthesis of Some Novel Regioselective Isoxazole-Benzimidazole Hybrids and Their In Vitro Anti-Cancer Evaluation
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Regioselective synthesis of some novel isoxazole-benzimidazole hybrids in high yields via Cu(I)-catalyzed tandem one-pot reaction of aromatic aldehydes with 1-prop-2-ynylbenzimidazole is developed. Structures of the synthesized compounds are confirmed by
- Ashok Kumar,Shanmukha Kumar Jagarlapudib
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p. 2512 - 2515
(2020/02/25)
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- An efficient protocol for the synthesis of six-membered N, O-heterocycles via a 1,3-dipolar (3+3) cycloaddition between nitrile oxide and α-diazo esters
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In this manuscript, we are reporting an efficient protocol for the construction of highly functionalized N, O-heterocyclic derivatives such as 1,2,4-oxadiazine and 1,4,2-dioxazine-6-carboxylate derivatives via a 1,3-dipolar (3 + 3) cycloaddition between nitrile oxide and unprotected α-diazo esters in the presence of 2 mol% Cu(OTf)2 catalyst. The expected N, O-heterocycles were obtained in excellent yields. These N, O-heterocycles are known to exhibit insecticidal and acaricidal properties.
- Kuruba, Bharath Kumar,Vasanthkumar, Samuel
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p. 3860 - 3865
(2017/06/14)
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- Synthesis, antimalarial activity, and target binding of dibenzazepine-tethered isoxazolines
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Malaria, a complex and deadly parasitic infectious disease, is a huge public health problem in many endemic countries around the globe. The prevailing extensive resistance of malaria parasites to traditional drugs and emergence of resistance to the currently used frontline artemisinin-based chemotherapy calls for the development of new drugs. Towards this objective and since compounds containing the dibenzazepine moiety are effective in treating both gametocyte and asexual stage malaria parasites, including multi drug resistant parasites, a library of dibenzazepine tethered 3,5-disubstituted isoxazolines was synthesised via 1,3-dipolar cycloaddition reaction. An additional diversified group of dibenzazepine derivatives were accessed by Suzuki coupling of one of the above dibenzazepine derivatives with various organoboronic acids. All compounds were structurally characterized and were evaluated for their antimalarial activity. They exhibited good to excellent inhibitory activity against the growth of drug-sensitive Plasmodium falciparum 3D7 strain with IC50 values ranging from 0.2 to 7.7 μM. About 50% of the compounds were either minimally or not toxic to human cell lines. Five of the compounds (6j, 6k, 8c, 8k and 8l) that highly inhibited the parasite growth were further assessed for antimalarial activity using an additional chloroquine-sensitive (D6) and two chloroquine-resistant (W2 and 7G8) P. falciparum strains. These compounds were effective against all four strains (3D7, D6, W2 and 7G8), exhibiting IC50 values of 0.1 to 1.75 μM. The dibenzazepines were identified to target the metalloamino-peptidase of parasites. Molecular docking and dynamics simulation studies were performed to understand the binding mode and binding strengths of the selected compounds with the enzyme. In agreement with their excellent antimalarial activity, the data suggested that the compounds can strongly bind to the active site of the enzyme.
- Vinay Kumar, Koravangala S.,Lingaraju, Gejjalagere S.,Bommegowda, Yadaganahalli K.,Vinayaka, Ajjampura C.,Bhat, Pritesh,Pradeepa Kumara, Challanayakanahally S.,Rangappa, Kanchugarakoppal S.,Gowda, D. Channe,Sadashiva, Maralinganadoddi P.
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p. 90408 - 90421
(2015/11/16)
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- A facile one-pot synthesis of 3,5-disubstituted isoxazole derivatives using hydroxy (tosyloxy) iodobenzene
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Hydroxy (tosyloxy) iodobenzene (HTIB), a hypervalent iodine reagent, has been extensively used for oxidative transformations. We have developed a one-pot synthesis wherein aldoximes when reacted with alkynes in the presence of HTIB result in the direct formation of isoxazoles. This simple and straightforward reaction allows for ease of purification while leading to the formation of high purity 3,5-disubstituted isoxazoles in moderate yields.
- Jadhav, Ravindra D.,Mistry, Hitesh D.,Motiwala, Hashim,Kadam, Kishorkumar S.,Kandre, Shivaji,Gupte, Amol,Gangopadhyay, Ashok K.,Sharma, Rajiv
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p. 774 - 780
(2013/08/23)
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- PYRIDINONE AND PYRIMIDINONE DERIVATIVES AS FACTOR XIA INHIBITORS
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The present invention provides compounds of the general formula (I), their salts and N- oxides, and solvates and prodrugs thereof (wherein the characters are as defined in the description). The compounds of the general formula (I) are inhibitors of Factor XIa, so that they are useful in the prevention of and/or therapy for thromboembolic diseases.
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Page/Page column 261
(2013/07/05)
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- Discovery, synthesis, and biological evaluation of a novel group of selective inhibitors of filoviral entry
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Herein, we report the development of an antifiloviral screening system, based on a pseudotyping strategy, and its application in the discovery of a novel group of small molecules that selectively inhibit the Ebola and Marburg glycoprotein (GP)-mediated infection of human cells. Using Ebola Zaire GP-pseudotyped HIV particles bearing a luciferase reporter gene and 293T cells, a library of 237 small molecules was screened for inhibition of GP-mediated viral entry. From this assay, lead compound 8a was identified as a selective inhibitor of filoviral entry with an IC50 of 30 μM. To analyze functional group requirements for efficacy, a structure-activity relationship analysis of this 3,5-disubstituted isoxazole was then conducted with 56 isoxazole and triazole derivatives prepared using "click" chemistry. This study revealed that while the isoxazole ring can be replaced by a triazole system, the 5-(diethylamino)acetamido substituent found in 8a is required for inhibition of viral-cell entry. Variation of the 3-aryl substituent provided a number of more potent antiviral agents with IC50 values ranging to 2.5 μM. Lead compound 8a and three of its derivatives were also found to block the Marburg glycoprotein (GP)-mediated infection of human cells.
- Yermolina, Maria V.,Wang, Jizhen,Caffrey, Michael,Rong, Lijun L.,Wardrop, Duncan J.
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experimental part
p. 765 - 781
(2011/04/15)
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- Design and synthesis of spiro derivatives of parthenin as novel anti-cancer agents
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Several novel spiro derivatives of parthenin (1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene- γ-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their in vitro cytotoxicity against three human cancer cell lines viz., SW-620, DU-145 and PC-3. In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of α,β-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with in vivo and western blotting experiments has been described.
- Reddy, Doma Mahendhar,Qazi, Naveed A.,Sawant, Sanghpal D.,Bandey, Abid H.,Srinivas, Jada,Shankar, Mannepalli,Singh, Shashank K.,Verma, Monika,Chashoo, Gousia,Saxena, Arpita,Mondhe, Dilip,Saxena, Ajit K.,Sethi,Taneja, Subhash C.,Qazi, Gulam N.,Sampath Kumar
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body text
p. 3210 - 3217
(2011/07/31)
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- Synthesis and pharmacological evaluation of 1,3,4-oxadiazole bearing bis(heterocycle) derivatives as anti-inflammatory and analgesic agents
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A series of novel ether-linked bis(heterocycle)s have been synthesized via [3 + 2]-cycloaddition reaction of nitrile oxide with allyl alcohol followed by intramolecular 1,3-diploar cycloaddition reaction of nitrile imine with carbonyl group. All the newly
- Jayashankar,Lokanath Rai,Baskaran,Sathish
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experimental part
p. 3898 - 3902
(2009/12/09)
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- Reactivity of arylnitrile oxides and C-aroyl-N-phenylnitrones with 3-methylenedihydro-(3H)-furan-2-one and itaconic anhydride
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1,3-dipolar cycloaddition is a powerful route for the synthesis of five-membered heterocycles. The [3+2] cycloadditions of some α-methylene-γ-buryrolactones, namely 3-methylenedihydro-(3H)-furan-2-one (1) and itaconic anhydride (2) were studied. Their rea
- Roussel, Christophe,Ciamala, Kabula,Vebrel, Jo?l,Riche, Claude
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p. 1977 - 1991
(2016/10/24)
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- Efficient synthesis and utilization of phenyl-substituted heteroaromatic carboxylic acids as aryl diketo acid isosteres in the design of novel HIV-1 integrase inhibitors
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Three new types of aryl diketo acid (ADK) isosteres were designed by conversion of the biologically labile 1,3-diketo unit into heteroaromatic motif such as isoxazole, isothiazole, or 1H-pyrazole to improve the physicochemical property of ADK-based HIV-1 integrase (IN) inhibitors. The synthesis of the heteroaromatic carboxylic acids was established by employing phenyl β-diketoester or benzaldehyde as the starting material and 1,3-dipolar cycloaddition as the key reaction. Of the compounds tested, the 3-benzyloxyphenyl-substituted isoxazole carboxylic acid displayed the best IN inhibitory and antiviral activities, with N-hydroxylamidation enhancing the in vitro and in vivo potency. These findings are important for further optimization of ADK-based IN inhibitors.
- Zeng, Li-Fan,Zhang, Hu-Shan,Wang, Yun-Hua,Sanchez, Tino,Zheng, Yong-Tang,Neamati, Nouri,Long, Ya-Qiu
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scheme or table
p. 4521 - 4524
(2009/04/08)
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- One-pot copper(I)-catalyzed synthesis of 3,5-disubstituted isoxazoles
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3,5-Disubstituted isoxazoles are obtained in good yields by a convenient one-pot, three-step procedure utilizing a regioselective copper(I)-catalyzed cycloaddition reaction between in situ generated nitrile oxides and terminal acetylenes. Most functional
- Hansen, Trond V.,Wu, Peng,Fokin, Valery V.
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p. 7761 - 7764
(2007/10/03)
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- One-Pot Synthesis of 3-Substituted Isoxazoles from Phenyl Vinylic Selenide
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Phenyl vinylic selenide was adopted for 1,3-dipolar cycloaddition to nitrile oxides and subsequent oxidation-elimination furnished 3-substituted isoxazoles with good yields in a one-pot, two-step transformation.
- Sheng, Shou-Ri,Liu, Xiao-Ling,Xu, Qu,Song, Cai-Sheng
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p. 2763 - 2764
(2007/10/03)
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- Diastereoselective [3+2] cycloadditions of a camphor-derived chiral N- acryloylhydrazide with nitrile oxides: The preparation of optically pure δ2-isoxazolines
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Reaction of a novel chiral N-acryloylhydrazide with various nitrile oxides proceeded smoothly to afford the cycloadduct with high diastereoselectivity (99:1). The auxiliary can be easily removed from the cycloadducts under mild conditions. (C) 2000 Elsevier Science Ltd.
- Yang, Kung-Shuo,Lain, Jung-Chaing,Lin, Chun-Hui,Chen, Kwunmin
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p. 1453 - 1456
(2007/10/03)
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- Ketoken gem-dithiols and trithiones: Synthesis and study of the behavior towards dipole reagents; Synthesis of some nitrogen heteroaromatics
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The behavior of ketoken gem-dithiols towards active methylene and methyl groups resulted in the formation of thiopyrano-dihydrocaumarine derivatives IIIa,b via cyclocondensation reaction between substituted 4-dihydrocyclohexanone Ia.b. N-phenylpyrazoline
- Zayed, Salem E.
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- Substituent Effects on 1,3-Dipolar Cycloadditions to Some 1,1-Diphenyl-2-Aza-1,3-Butadiene Derivatives.
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The reactivity and in particular the siteselectivity of electrocyclic additions to 1,1-diphenyl-2-aza-1,3-butadienes, substituted or not on the terminal carbon with methyl and phenyl, and with a 3-carbomethoxyl group, have been investigated with the
- Balsamini, Cesarino,Bedini, Annalida,Spadoni, Gilberto,Burdisso, Marina,Capelli, Anna Maria
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p. 3773 - 3784
(2007/10/02)
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- Cycloadditions, 18: 5-Aminoisoxazoles by Cycloaddition of Nitrile Oxides to Ynamines
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Ten differently substituted ynamines 1a-j react with five nitrile oxides 3a-e to give the 5-aminoisoxazoles 4a-z.The stannyl-substituted ynamine 1k furnishes the same compounds (e.g. 4a-d) by reaction with the hydroximoyl chlorides 2a-d.Two representatives of 4 - b and p - can be transformed into the corresponding 1-azirine-3-carboxamides 6a and b.
- Himbert, Gerhard,Kuhn, Hildegard,Barz, Michael
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p. 403 - 407
(2007/10/02)
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- Organic Curing Agents for Polysulfide Sealants. II. Additions of Thiols to Nitrile Oxides: Scope, Relative Reactivities and Application to the Cure of Polysulfide Sealants
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Efficient addition between various nitrile oxides and both short (C2) and long chain (C16) alkyl thiols, aliphatic dithiols and aryl thiols occurred rapidly at ambient temperature with the formation of thiohydroximic acid derivatives.Competitive experiments with bis(nitrile oxides) showed that for terephthalonitrile oxide the second addition proceeded more readily than the first whereas with anthracene-9,10-bis(carbonitrile oxide) elevated temperatures were needed to obtain the diadduct.Relative reactivities of a number of thiols with nitrile oxides were also determined spectroscopically.Reaction between prop-2-ene-1-thiol and p-nitrobe nzonitrile oxide afforded products resulting from both cycloaddition and 1,3-addition with the latter predominating.The polysulfide prepolymer LP-2 was cured effectively at ambient temperatures by both terephthalonitrile oxide and 4,4'-sulfonylbisbenzonitrile dioxide at CNO to SH ratios of 1.5 and higher giving tack-free products within 0.5 h and 90percent cure in under 4 h.For the less highly cross-linked LP-32 based sealants, curing was a little slower.Unreinforced sealants produced in this manner were firm elastomers with hardness of 35-40 (Rex A).The naphthalenebis(carbonitrile oxides) afforded softer products while anthracene-9,10-bis(carbonitrile oxide) was ineffective.One-part formulations involving in situ generation of nitrile oxide from hydroximoyl chlorides and barium hydroxide (formed by action of water vapour on barium oxide) were also produced.
- Hanhela, Peter J.,Paul, D. Brenton
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p. 1257 - 1272
(2007/10/02)
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- SYNTHESIS OF 3-ARYL-4,5-DIHYDRO-5-HYDROXY-1,2-OXAZOLES BY REACTION OF SUBSTITUTED BENZONITRILE OXIDES WITH THE ENOLATE ION OF ACETALDEHYDE.
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By reaction of substituted benzonitrile oxides with the enolate ion of acetaldehyde (quantitatively generated by the known cycloreversion of THF in the presence of n-butyllithium) a number of 3-aryl-4,5-dihydro-5-hydroxy-1,2-oxazoles (previously unknown or, in two cases, only synthesized by different procedures) have been isolated in high yields.Treatment of such hydroxy-isoxalines with some common bases allows their conversion in high yields into the corresponding isoxazoles.
- Di Nunno, L.,Scilimati, A.
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p. 2181 - 2190
(2007/10/02)
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- SITE SELECTIVITY IN THE REACTIONS OF 1,3-DIPOLES WITH NORBORNADIENE DERIVATIVES
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The cycloadditions of arylazides, benzonitrile oxides and diphenylnitrile imine to norbornadiene derivatives 1a-c showed varying degree of site- and stereo-selectivity.With dipolarophile 1a arylazides and benzonitrile oxides attack, preferentially, the electron-poor tetrasubstituted double bond, while in the case of 1b and 1c is the substituted double bond which enters the cycloaddition.By contrast, 2-diazopropane and C-phenyl-N-methylnitrone react with the sole tetrasubstituted double bond of 1a-c in stereo- and site-specific cycloadditions.The quantitative evaluation of the two possible reaction paths was performed by glc analysis.The compounds detected were those arising from Diels-Alder cycloreversions of the thermally labile intermediate adducts 2 and 3 (Scheme 1).The results were rationalized on the basis of a qualitative perturbation treatment which considers frontier orbital interactions only.
- Cristina, D.,Amici, M. De,Micheli, C. De,Gandolfi, R.
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p. 1349 - 1357
(2007/10/02)
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- SYNTHESIS AND PROPERTIES OF AZOLS AND THEIR DERIVATIVES. PART II. REACTION OF N-OXIDES OF AROMATIC NITRILES WITH UNCONJUGATED NITROOLEFINES AND SOME CONVERSION OF ADDUCT OBTAINED
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The reaction of 1,3-dipolar cycloaddition of 3-nitro-2-methylpropene-1, 3,3-dinitrobutene-1 or 3-nitropropene-1 with N-oxides of aromatic nitriles (RC6H4CN->O, R = H, m-NO2, p-NO2, p-CH3O) and likewise some chemical properties of 3-phenyl-5-nitromethyl
- Baranski, Andrzej,Shvekhgeimer, Genrikh A.,Kirillova, Natalia I.
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