- Synthesis and in Vitro Cytotoxic Activity of Novel Triazole-Isoxazole Derivatives
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New derivatives of triazole-isoxazole were synthesized through a four-step reaction starting from various ethyl 4-aryl-2,4-dioxobutanoate derivatives. Finally, all compounds were examined by MTT assays for cytotoxic activity in two human breast cancer cell lines (MCF-7 and T-47D).
- Najafi, Zahra,Mahdavi, Mohammad,Safavi, Maliheh,Saeedi, Mina,Alinezhad, Heshmatollah,Pordeli, Mahboobeh,Kabudanian Ardestani, Sussan,Shafiee, Abbas,Foroumadi, Alireza,Akbarzadeh, Tahmineh
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- Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broad-spectrum antifungal agents
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To discover antifungal compounds with broad-spectrum and stable metabolism, a series of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. Compounds A30-A34 exhibited excellent broad-spectrum antifungal activity against Candida albicans with MIC values in the range of 0.03–0.5 μg/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25–2 μg/mL. In addition, compounds A31 and A33 showed high metabolic stability in human liver microsomes in vitro, with the half-life of 80.5 min and 69.4 min, respectively. Moreover, compounds A31 and A33 showed weak or almost no inhibitory effect on the CYP3A4 and CYP2D6. The pharmacokinetic evaluation in SD rats showed that compound A31 had suitable pharmacokinetic properties and was worthy of further study.
- Zhao, Liyu,Sun, Yin,Yin, Wenbo,Tian, Linfeng,Sun, Nannan,Zheng, Yang,Zhang, Chu,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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- Novel N-benzylpiperidine derivatives of 5-arylisoxazole-3-carboxamides as anti-Alzheimer's agents
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The complex pathophysiology of Alzheimer's disease (AD) has prompted researchers to develop multitarget-directed molecules to find an effective therapy against the disease. In this context, a novel series of N-(1-benzylpiperidin-4-yl)-5-arylisoxazole-3-ca
- Saeedi, Mina,Felegari, Peyman,Iraji, Aida,Hariri, Roshanak,Rastegari, Arezoo,Mirfazli, S. Sara,Edraki, Najmeh,Firuzi, Omidreza,Mahdavi, Mohammad,Akbarzadeh, Tahmineh
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- Design and synthesis of novel 5-arylisoxazole-1,3,4-thiadiazole hybrids as α-glucosidase inhibitors
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Background: α-Glucosidase inhibitors have occupied a significant position in the treatment of type 2 diabetes. In this respect, the development of novel and efficient non-sugar-based inhibitors is in high demand. Objective: Design and synthesis of new 5-arylisoxazole-1,3,4-thiadiazole hybrids possessing α-glucosidase inhibitory activity were developed. Methods: Different derivatives were synthesized by the reaction of various 5-arylisoxazole-3-carboxylic acids and ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)acetate. Finally, they were evalu-ated for their α-glucosidase inhibitory activity. Results: It was found that ethyl 2-((5-(5-(2-chlorophenyl)isoxazole-3-carboxamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5j) was the most potent compound (IC50 = 180.1 μM) compared with acarbose as the reference drug (IC50 = 750.0 μM). Also, the kinetic study of 5j revealed a competitive inhibition and docking study results indicated desired interactions of that compound with amino acid residues located close to the active site of α-glucosidase. Conclusion: Good α-glucosidase inhibitory activity obtained by the title compounds introduced them as an efficient scaffold, which merits to be considered in anti-diabetic drug discovery developments.
- Akbarzadeh, Tahmineh,Eslami, Azadeh,Faramarzi, Mohammad Ali,Mahdavi, Mohammad,Mirfazli, Seyedeh Sara,Saeedi, Mina,Zardkanlou, Mahsa
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p. 436 - 444
(2021/10/04)
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- Mechanochemistry Enabled Construction of Isoxazole Skeleton via CuO Nanoparticles Catalyzed Intermolecular Dehydrohalogenative Annulation
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A dehydrohalogenative approach for isoxazole annulation by partnering β-vinyl halides and α-nitrocarbonyls under mechanochemical setting was accomplished. This chemistry is operative under the cooperative catalysis of cupric oxide nanoparticles (50 nm) a
- Vadivelu, Murugan,Sampath, Sugirdha,Muthu, Kesavan,Karthikeyan, Kesavan,Praveen, Chandrasekar
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p. 4941 - 4952
(2021/09/09)
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- Design and Synthesis of Novel Arylisoxazole-Chromenone Carboxamides: Investigation of Biological Activities Associated with Alzheimer's Disease
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A novel series of hybrid arylisoxazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman's method. Among synthesized compounds, 5-(3-nitrophenyl)-N-{4-[(2-oxo-
- Akbarzadeh, Tahmineh,Edraki, Najmeh,Firuzi, Omidreza,Hariri, Roshanak,Mahdavi, Mohammad,Mirfazli, Seyedeh Sara,Rastegari, Arezoo,Saeedi, Mina
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- Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment
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Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, w
- Johansson, Niklas G.,Turku, Ainoleena,Vidilaseris, Keni,Dreano, Lo?c,Khattab, Ayman,Ayuso Pérez, Daniel,Wilkinson, Aaron,Zhang, Yuezhou,Tamminen, Matti,Grazhdankin, Evgeni,Kiriazis, Alexandros,Fishwick, Colin W. G.,Meri, Seppo,Yli-Kauhaluoma, Jari,Goldman, Adrian,Boije Af Genn?s, Gustav,Xhaard, Henri
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supporting information
p. 605 - 610
(2020/03/10)
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- Discovery of 2-phenylthiazole-4-carboxylic acid, a novel and potent scaffold as xanthine oxidase inhibitors
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The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8, a potent XO inhibitor (IC50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors.
- Xu, Xue,Deng, Liming,Nie, Lu,Chen, Yueming,Liu, Yanzhi,Xie, Rongrong,Li, Zheng
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p. 525 - 528
(2019/01/09)
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- Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole-Phenylpiperazine Derivatives
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In this work, a novel series of arylisoxazole-phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5-(2-chlorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin
- Saeedi, Mina,Mohtadi-Haghighi, Dorrin,Mirfazli, Seyedeh Sara,Mahdavi, Mohammad,Hariri, Roshanak,Lotfian, Hania,Edraki, Najmeh,Iraji, Aida,Firuzi, Omidreza,Akbarzadeh, Tahmineh
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- Iron(iii)-catalyzed selective N-O bond cleavage to prepare tetrasubstituted pyridines and 3,5-disubstituted isoxazolines from: N -vinyl-α,β-unsaturated ketonitrones
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An iron(iii)-catalyst controlled cyclization and selective N-O bond cleavage of N-vinyl-α,β-unsaturated nitrones has been achieved under mild conditions to access tetrasubstituted pyridines and 3,5-disubstituted isoxazolines in moderate to good yields. The tetrasubstituted pyridines were afforded with FeCl3 as a catalyst while using FeCl3·6H2O combined with 1,10-phenanthroline delivered isoxazolines. The regioselectivity for cyclization of styrenyl groups in N-vinyl-α,β-unsaturated nitrones was completely different during the formation of pyridines and isoxazolines. A rational mechanism for the formation of pyridines and isoxazolines was proposed based on the further control experimental studies. The isoxazolines can be converted to a novel bidentate N-ligand over four steps and an epoxypyridine scaffold was obtained from N-vinyl nitrone when copper(ii) acetate in combination with the prepared bidentate N-ligand was used.
- Chen, Chun-Hua,Wu, Qing-Yan,Wei, Cui,Liang, Cui,Su, Gui-Fa,Mo, Dong-Liang
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supporting information
p. 2722 - 2729
(2018/06/29)
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- FIVE-MEMBERED HETEROCYCLIC AMIDES WNT PATHWAY INHIBITOR
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The present invention discloses a five-membered heterocyclic amide WNT pathway inhibitor, which belongs to a compound that regulates the activity of a Wnt signaling pathway, and provides a method for preparing such a compound, and the use of such a compound in preparing a medicament that antagonizes the Wnt signaling pathway. The five-membered heterocyclic amide WNT pathway inhibitor provided by the invention has a remarkable anti-tumor activity based on a target-based rational drug design of, and can be used for the development of a new generation of Wnt pathway inhibitors, and has a great clinical application value and considerable market potential.
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Paragraph 0159-0161
(2018/10/19)
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- Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo
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Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here the structure-based design of selective MptpB inhibitors that reduce survival of multidrug-resistant tuberculosis strains in macrophages and enhance killing efficacy by first-line antibiotics. Monotherapy with an orally bioavailable MptpB inhibitor reduces infection burden in acute and chronic guinea pig models and improves the overall pathology. Our findings provide a new paradigm for tuberculosis treatment.
- Vickers, Clare F.,Silva, Ana P. G.,Chakraborty, Ajanta,Fernandez, Paulina,Kurepina, Natalia,Saville, Charis,Naranjo, Yandi,Pons, Miquel,Schnettger, Laura S.,Gutierrez, Maximiliano G.,Park, Steven,Kreiswith, Barry N.,Perlin, David S.,Thomas, Eric J.,Cavet, Jennifer S.,Tabernero, Lydia
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p. 8337 - 8352
(2018/09/18)
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- 1,2,3-Triazole-isoxazole based acetylcholinesterase inhibitors: Synthesis, biological evaluation and docking study
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In this work, a series of derivatives containing 1,2,3-triazole and isoxazole were synthesized. All of them were evaluated as novel dual AChE inhibitors. Most of synthesized compounds showed moderate to good inhibitory potency toward AChE. Among them, N-(
- Najafi, Zahra,Mahdavi, Mohammad,Saeedi, Mina,Sabourian, Reyhaneh,Khanavi, Mahnaz,Safavi, Maliheh,Tehrani, Maliheh Barazandeh,Shafiee, Abbas,Foroumadi, Alireza,Akbarzadeh, Tahmineh
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- Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents
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To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability.
- Zhao, Shizhen,Zhang, Xiangqian,Wei, Peng,Su, Xin,Zhao, Liyu,Wu, Mengya,Hao, Chenzhou,Liu, Chunchi,Zhao, Dongmei,Cheng, Maosheng
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- Fatty Acid Cysteine-Based Conjugates and Their Use in Treating Medical Disorders
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The invention relates to fatty acid cysteine-based conjugates, compositions comprising a fatty acid cysteine-based conjugates, and methods for using such conjugates and compositions to treat disease, such as a disease caused by dysregulation of autophagy
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- ISOXAZOLE COMPOUNDS AND METHODS FOR THE TREATMENT OF CYSTIC FIBROSIS
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The invention relates to a compound of Formula (I) and methods of treating cystic fibrosis comprising the step of administering a therapeutically effective amount of a compound of Formula (I) or II to a patient in need thereof: Formula (I) and Formula (II). The invention relates to the use of substituted oxazole and substituted thiazole compounds in the treatment of cystic fibrosis transmembrane conductance regulator (CFTR) mediated diseases.
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- FATTY ACID CYSTEAMINE CONJUGATES OF CFTR MODULATORS AND THEIR USE IN TREATING MEDICAL DISORDERS
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The invention relates to fatty acid cysteamine conjugates of a CFTR modulator, compositions comprising a fatty acid cysteamine conjugate of a CFTR modulator, and methods for using such conjugates and compositions to treat disease, such as a disease caused
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- Development of variously functionalized nitrile oxides
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N-Methylated amides (N,4-dimethylbenzamide and N-methylcyclohexanecarboxamide) were systematically subjected to chemical transformations, namely, N-tosylation followed by nucleophilic substitution. The amide function was converted to the corresponding carboxylic acid, esters, amides, aldehyde, and ketone upon treatment with hydroxide, alkoxide, amine, diisobutylaluminium hydride and Grignard reagent, respectively. In these transformations, N-methyl-N-tosylcarboxamides behave like a Weinreb amide. Similarly, N-methyl-5-phenylisoxazole-3-carboxamide was converted into 3-functionalized isoxazole derivatives. Since the amide was prepared by the cycloaddition reaction of ethynylbenzene and N-methylcarbamoylnitrile oxide, the nitrile oxide served as the equivalent of the nitrile oxides bearing a variety of functional groups such as carboxy, alkoxycarbonyl, carbamoyl, acyl and formyl moieties.
- Asahara, Haruyasu,Arikiyo, Keita,Nishiwaki, Nagatoshi
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p. 1241 - 1245
(2015/08/18)
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- O-iodoxy benzoic acid–mediated synthesis of 3,5-diarylisoxazoles and isoxazole-3-carboxylic acids
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A new, convenient, ecofriendly synthesis of 3,5-diarylisoxazoles is reported from a,b-unsaturated ketoximes. Similarly, a novel synthesis of isoxazole carboxylic acids is also reported. Both the methods use efficient, environmentally friendly, and nontoxic iodoxybenzoic acid (IBX) as an oxidative cyclizing reagent. Easy procedure, environmentally benign reaction conditions, and nontoxicity are advantages to the methodology.
- Desai, Vidya G.,Naik, Sneha R.,Dhumaskar, Kashinath L.
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p. 1453 - 1460
(2016/09/23)
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- 3-Carboxamido-5-aryl-isoxazoles as new CB2 agonists for the treatment of colitis
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Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new selective CB2 receptor agonists without psychotropic side effects associated to CB1 receptors. In this purpose, a new series of 3-carboxamido-5- aryl-isoxazoles, never described previously as CB2 receptor agonists, was designed, synthesized and evaluated for their biological activity. The pharmacological results have identified great selective CB2 agonists with in vivo anti-inflammatory activity in a DSS-induced acute colitis mouse model.
- Tourteau, Aurélien,Andrzejak, Virginie,Body-Malapel, Mathilde,Lemaire, Lucas,Lemoine, Amélie,Mansouri, Roxane,Djouina, Madjid,Renault, Nicolas,El Bakali, Jamal,Desreumaux, Pierre,Muccioli, Giulio G.,Lambert, Didier M.,Chavatte, Philippe,Rigo, Beno?t,Leleu-Chavain, Natascha,Millet, Régis
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p. 5383 - 5394
(2013/09/02)
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- Synthesis and anticancer activity of heteroaromatic linked 4β-amido podophyllotoxins as apoptotic inducing agents
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A series of different heteroaromatic linked 4β-amidopodophyllotoxin conjugates (16a-i, 17a-i and 18a-d) were synthesized and evaluated for anticancer activity against five human cancer cell lines. Among the series, one of the compound 17g showed significant antiproliferative activity in A549 (lung cancer) cell line. Flow cytometric analysis showed that 17g arrested the cell cycle in the G2/M phase leading to caspase-3 dependent apoptotic cell death. Further, Hoechst 33258 staining and DNA fragmentation assay also suggests that 17g induces cell death by apoptosis.
- Kamal, Ahmed,Tamboli, Jaki R.,Vishnuvardhan,Adil,Nayak, V. Lakshma,Ramakrishna
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p. 273 - 280
(2013/02/25)
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- Synthesis of novel 5-substituted isoxazole-3-carboxamide derivatives and cytotoxicity studies on lung cancer cell line
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A series of novel 5-substituted isoxazole-3-carboxamide derivatives 6 have been prepared by coupling of 5-substituted isoxazole-3-carboxylic acids 3 with substituted-3-benzyloxyaniline 5 using DCC/HOBT as coupling agent. The products 6 have been evaluated for cytotoxicity on A549 lung cancer cell line and compounds 6a, 6b, 6e, 6j are found to show moderate proliferative activity and low cytotoxicity.
- Veeraswamy,Kurumurthy,Santhosh Kumar,Sambasiva Rao,Thelakkat, Kavya,Kotamraju, Srigiridhar,Narsaiah
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p. 1369 - 1375
(2012/11/13)
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- Synthesis of hydroxybenzaldehyde derivatives containing an isoxazole heteroring
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5-Phenyl(p-tolyl)isoxazole-3-carboxylic acids were synthesized starting from 3-hydroxyiminomethyl-5-phenyl(p-tolyl)isoxazoles, and their reactions with p-hydroxybenzaldehyde, vanillin, isovanillin, o-vanillin, and ethyl vanillin gave the corresponding esters. The latter were brought into condensation with aromatic amines to obtain Schiff bases which were reduced to amines. Pleiades Publishing, Ltd., 2012.
- Potkin,Gadzhily,Dikusar,Petkevich,Zhukovskaya,Aliev,Nagieva
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p. 127 - 136
(2012/05/20)
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- New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold that protect against experimental colitis
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Growing evidence suggests a role for the endocannabinoid (EC) system, in intestinal inflammation and compounds inhibiting anandamide degradation offer a promising therapeutic option for the treatment of inflammatory bowel diseases. In this paper, we repor
- Andrzejak, Virginie,Muccioli, Giulio G.,Body-Malapel, Mathilde,El Bakali, Jamal,Djouina, Madjid,Renault, Nicolas,Chavatte, Philippe,Desreumaux, Pierre,Lambert, Didier M.,Millet, Regis
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experimental part
p. 3777 - 3786
(2011/08/03)
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- Synthesis of 2,3 and 4,5-dihydro-hydroxy-isoxazoles and isoxazoles under different pH conditions
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Reaction between aryl 1,3-diketoesters 2a-e and hydroxylamine hydrochloride has been investigated under different experimental conditions. Whereas acid conditions gave principally 3,5-isoxazole esters (3a-e), reactions under neutral and basic conditions l
- Andrzejak, Virginie,Millet, Regis,Bakali, Jamal El,Guelzim, Abdelhalim,Gluszok, Sebastien,Chavatte, Philippe,Bonte, Jean-Paul,Vaccher, Claude,Lipka, Emmanuelle
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body text
p. 32 - 38
(2010/08/05)
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- Use of the Nitrile Oxide Cycloaddition (NOC) reaction for molecular probe generation: A new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6
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A series of hydroxamate based HDAC inhibitors containing a phenylisoxazole as the CAP group has been synthesized using nitrile oxide cycloaddition chemistry. An HDAC6 selective inhibitor having a potency of ～2 picomolar was identified. Some of the compounds were examined for their ability to block pancreatic cancer cell growth and found to be about 10-fold more potent than SAHA. This research provides valuable, new molecular probes for use in exploring HDAC biology.
- Kozikowski, Alan P.,Tapadar, Subhasish,Luchini, Doris N.,Ki, Hwan Kim,Billadeau, Daniel D.
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supporting information; experimental part
p. 4370 - 4373
(2009/05/30)
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- Analogs of 4-hydroxyisoleucine and uses thereof
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The invention relates to analogs of 4-hydroxyisoleucine, and to lactones, pharmaceutically acceptable salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. The analogs of the invention stimulate both glucose uptake and insulin secretion, and may thus be useful for the prevention and treatment of disorders of carbohydrate or lipid metabolism, including diabetes mellitus (type 1 and type 2 diabetes), pre-diabetes, and Metabolic Syndrome.
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Page/Page column 45
(2008/06/13)
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- Compounds and compositions for use in the prevention and treatment of obesity and related syndromes
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The invention relates to 4-hydroxyisoleucine, isomers, analogs, lactones, salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. More particularly, the invention relates to the use of those compounds in the prevention and treatment of obesity and related syndromes.
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Page/Page column 58
(2010/11/24)
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- Ramoplanin derivatives possessing antibacterial activity
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Novel ramoplanin derivatives are disclosed. These ramoplanin derivatives exhibit antibacterial activity. As the compounds of the subject invention exhibit potent activities against gram positive bacteria, they are useful antimicrobial agents. Methods of synthesis and of use of the compounds are also disclosed.
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Page/Page column 39; 56
(2010/11/23)
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- CARBOXYLIC ACID DERIVATIVES AND DRUGS CONTAINING THE SAME
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The present invention provides a novel carboxylic acid compound, a salt thereof or a hydrate of them useful as an insulin-resistant improver, and a medicament comprising the compound as an active ingredient. That is, the present invention provides a carboxylic acid compound represented by the following formula (I), a salt thereof, an ester thereof or a hydrate of them. In the formula, R1 represents hydrogen atom, hydroxyl group or a C1-6 alkyl group etc. which may have one or more substituents; L represents a single or double bond or a C1-6 alkylene group etc. which may have one or more substituents; M represents a single bond or a C1-6 alkylene group etc. which may have one or more substituents; T represents a single bond or a C1-3 alkylene group which may have one or more substituents; W represents carboxyl group or a group represented by the formula -CON(Rw1)Rw2 (wherein Rw1 and Rw2 are the same as or different from each other and each represents hydrogen atom, formyl group etc.) etc.; represents a single or double bond; X represents oxygen atom or a C2-6 alkenylene group etc. which may have one or more substituents; Y represents a C5-12 aromatic hydrocarbon group etc. which may have one or more substituents and which may have one or more heteroatoms; and ring Z represents a C5-6 aromatic hydrocarbon group which may have 0 to 4 substituents and which may have one or more heteroatoms.
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