- Design and synthesis of sinomenine isoxazole derivatives via 1,3-dipolar cycloaddition reaction
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A novel structure of sinomenine isoxazole derivatives is synthesised from sinomenine hydrochloride and aromatic aldehydes and requires six steps. 19 target compounds have been obtained in good yields. The sinomenine hydrochloride transforms to 4-alkynyl sinomenine, which is a key intermediate product to synthesise the target sinomenine isoxazole compounds, after a neutralisation reaction with ammonia and substitution reaction with 3-chloropropyne. Another key intermediate product is 1,3-dipole, which can be obtained from aromatic aldehyde. After treatment with hydroxylamine hydrochloride and then sodium carbonate solution, aromatic aldehyde is converted to aldehyde oxime, which reacts with N-chlorosuccinimide (NCS) to afford aryl hydroximino chloride. 1,3-Dipole is eventually formed in situ while triethylamine (TEA) in DMF is added dropwise. Then 4-alkynyl sinomenine is added to provide the sinomenine isoxazole derivative via 1,3-dipolar cycloaddition reaction as the key step. All the target compounds are characterised by melting point, 1H NMR, 13C NMR, HRMS and FT-IR spectroscopy.
- Pan, Hongmei,Lu, Tong,Wu, Xuedan,Gu, Chengwen,Tao, Naili,Zhang, Biao,Wang, Ao,Chen, Guangmei,Zhang, Kehua,Cheng, Jie,Jin, Jie
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supporting information
p. 2360 - 2364
(2019/11/11)
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- 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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supporting information
(2021/05/10)
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- One pot synthesis of aryl nitriles from aromatic aldehydes in a water environment
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In this study, we found a green method to obtain aryl nitriles from aromatic aldehyde in water. This simple process was modified from a conventional method. Compared with those approaches, we used water as the solvent instead of harmful chemical reagents. In this one-pot conversion, we got twenty-five aryl nitriles conveniently with pollution to the environment being minimized. Furthermore, we confirmed the reaction mechanism by capturing the intermediates, aldoximes.
- Chen, Qingqing,Han, Hongwei,Lin, Hongyan,Ma, Xiaopeng,Qi, Jinliang,Wang, Xiaoming,Yang, Yonghua,Zhou, Ziling
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p. 24232 - 24237
(2021/07/29)
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- AN IMPROVED PROCESS FOR PREPARATION OF PURE ALDOXIME
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The present invention relates to an improved process for preparing aldoximes of formula (I) with high purity and high yield. The improved process for preparing aldoxime is fast, simple, highly efficient, and reproducible. The improved process for the preparation of aldoxime, which is synthesized in the higher yield under oximation reaction of aldehyde with hydroxylamine hydrochloride merely in aqueous medium using of in situ heat generation.
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Page/Page column 15-16
(2021/06/22)
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- On the mixed oxides-supported niobium catalyst towards benzylamine oxidation
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A series of mixed oxides-supported niobium-based catalysts has been synthesized and applied towards oxidation reactions of benzylamine derivatives. Under the optimized reaction conditions, the selectivity to oxime enhanced, leading to the main product with up to 72 %. Moreover, even α-substituted benzylamines were well tolerated and led to oximes in good isolated yields. It is important to mention; four equivalents of the harmless and inexpensive hydrogen peroxide were employed as oxidizing agent. Mechanism hypothesis suggested that the reaction proceed to selective benzylamine oxidation into nitroso intermediate, following by formation of the corresponding oxime tautomer mediated by an unstable water produced by NbOx supported catalyst. This consists the first mixed oxides-supported niobium-based catalyst for selective oxidation of benzylamines to oximes.
- Granato, álisson Silva,de Carvalho, Gustavo S. Gon?alves,Fonseca, Carla G.,Adrio, Javier,Leit?o, Alexandre A.,Amarante, Giovanni Wilson
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p. 118 - 125
(2020/09/11)
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- Design and Structural Optimization of Dual FXR/PPARδActivators
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Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δhave been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPAR?-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδactivator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδand was structurally refined to a potent and balanced FXR/PPARδactivator in a computer-aided fashion. The resulting dual FXR/PPARδmodulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.
- Schierle, Simone,Neumann, Sebastian,Heitel, Pascal,Willems, Sabine,Kaiser, Astrid,Pollinger, Julius,Merk, Daniel
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supporting information
p. 8369 - 8379
(2020/08/12)
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- Synthesis and SAR study of simple aryl oximes and nitrofuranyl derivatives with potent activity against Mycobacterium tuberculosis
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Background: Oximes and nitrofuranyl derivatives are particularly important compounds in medicinal chemistry. Thus, many researchers have been reported to possess antibacterial, antiparasitic, insecticidal and fungicidal activities. Methods: In this work, we report the synthesis and the biological activity against Mycobacterium tuberculosis H37RV of a series of fifty aryl oximes, ArCH=N-OH, I, and eight nitrofuranyl compounds, 2-nitrofuranyl-X, II. Results: Among the oximes, I: Ar = 2-OH-4-OH, 42, and I: Ar = 5-nitrofuranyl, 46, possessed the best activity at 3.74 and 32.0 μM, respectively. Also, 46, the nitrofuran compounds, II; X = MeO, 55, and II: X = NHCH2Ph, 58, (14.6 and 12.6 μM, respectively), exhibited excellent biological activities and were non-cytotoxic. Conclusion: The compound 55 showed a selectivity index of 9.85. Further antibacterial tests were performed with compound 55 which was inactive against Enterococcus faecalis, Klebisiella pneumonae, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhymurium and Shigel-la flexneri. This study adds important information to the rational design of new lead anti-TB drugs. Structure-activity Relationship (SAR) is reported.
- Calixto, Stephane Lima,Carvalho, Guilherme da Silva Louren?o,Coimbra, Elaine Soares,Granato, Juliana da Trindade,Louren?o, Maria Cristina da Silva,Wardell, James,da Costa, Cristiane Fran?a,de Souza, Marcus Vinicius Nora
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- Adhesive functionalized ascorbic acid on CoFe2O4: A core-shell nanomagnetic heterostructure for the synthesis of aldoximes and amines
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This paper reports on the simple synthesis of novel green magnetic nanoparticles (MNPs) with effective catalytic properties and reusability. These heterogeneous nanocatalysts were prepared by the anchoring of Co and V on the surface of CoFe2O4 nanoparticles coated with ascorbic acid (AA) as a green linker. The prepared nanocatalysts have been identified by scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, X-ray atomic mapping, thermogravimetric analysis, X-ray powder diffraction, vibrating sample magnetometer analysis, coupled plasma optical emission spectrometry and Fourier transform infrared spectroscopy. The impact of CoFe2O4@AA-M (Co, V) was carefully examined for NH2OH·HCl oximation of aldehyde derivatives first and then for the reduction of diverse nitro compounds with sodium borohydride (NaBH4) to the corresponding amines under green conditions. The catalytic efficiency of magnetic CoFe2O4@AA-M (Co, V) nanocatalysts was investigated in production of different aldoximes and amines with high turnover numbers (TON) and turnover frequencies (TOF) through oximation and reduction reactions respectively. Furthermore, the developed environment-friendly method offers a number of advantages such as high turnover frequency, mild reaction conditions, high activity, simple procedure, low cost and easy isolation of the products from the reaction mixture by an external magnetic field and the catalyst can be reused for several consecutive runs without any remarkable decrease in catalytic efficiency.
- Sorkhabi, Serve,Ghadermazi, Mohammad,Mozafari, Roya
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p. 41336 - 41352
(2020/11/30)
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- A Synergic Activity of Urea/Butyl Imidazolium Ionic Liquid Supported on UiO-66-NH2 Metal–Organic Framework for Synthesis of Oximes
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An efficient supported ionic liquid catalyst is designed for condensation reaction of aldehydes and ketones. The Zr-based metal–organic framework (MOF), UiO-66-NH2, was initially functionalized with N,N′-dibutyl imidazolium ionic liquid (UiO-66-NH2-ILBr–), and then urea was attached to the ionic liquid (IL) to form a task-specific IL. Bromide was exchanged with tetrafluoroborate and the catalyst exhibits excellent performance for the synthesis of oximes. The ionic liquid/urea coupling showed a synergistic effect on the efficiency of the reaction. The supported catalyst system was recycled simply by filtration and reused for five times without significant decrease in its activity. The catalyst was characterized with PXRD, FTIR, TGA, XPS, BET, FE-SEM, EDS, elemental mapping and elemental analysis (CHN). Graphic Abstract: MOF/IL/urea catalytic system was used for the synthesis of oximes[Figure not available: see fulltext.].
- Askari, Saeed,Jafarzadeh, Mohammad,Christensen, David Benjamin,Kegn?s, S?ren
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p. 3159 - 3173
(2020/04/21)
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- Cu(II)–metformin immobilized on graphene oxide: an efficient and recyclable catalyst for the Beckmann rearrangement
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Abstract: In this study, for the first time, the copper(II) nanoparticles (NPs) have been immobilized on metformin-functionalized graphene oxide and then its catalytic applications have been investigated in synthesis of amides from aldoximes (Beckmann rearrangement). The chemical structure of prepared catalyst has been characterized by various analyses like FT-IR, TGA, TEM, SEM, EDX, and ICP. All analyses confirm the successful and stable immobilization of copper NPs on functionalized graphene oxide. This synthesized heterogeneous nanocatalyst showed excellent catalytic activity with high product yields and short reaction times. Also, the suggested catalyst could be recycled ten times without a drastic decrease in its catalytic activity. Graphic abstract: [Figure not available: see fulltext.].
- Solaiman Hamed, Ahmed,Mohammad Ali, Ehab
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p. 701 - 714
(2019/11/03)
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- Triazole alcohol derivative as well as preparation method and application thereof
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The invention relates to a triazole alcohol derivative as well as a preparation method and application thereof. The chemical structure of the triazole alcohol derivative is shown as a formula I, R1 represents a benzene ring or a substituted benzene ring, and substituent groups of the substituted benzene ring can be located at all positions of the benzene ring, can be mono-substituted or multi-substituted, and can be selected from a) halogen which is F and Cl; b) an electron withdrawing group which is cyano or trifluoromethyl; c ) a lower alkyl of 1-4 carbon atoms or a halogen substituted loweralkyl; and d) lower alkoxy of 1-4 carbon atoms or halogen substituted lower alkoxy. The compound of the invention has strong antifungal activity, has the advantages of low toxicity, wide antibacterial spectrum and the like, and can be used for preparing antifungal drugs.
- -
-
Paragraph 0131-0132
(2020/03/11)
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- Design, synthesis, and in vitro evaluation of novel triazole analogues featuring isoxazole moieties as antifungal agents
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In order to develop novel antifungal agents, based on our previous work, a series of (2R,3R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (a1-a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC80 values of 0.0313 μg/mL. In addition, compounds a6, a9, a12, a13 and a14 exhibited moderate inhibitory activities against fluconazole-resistant isolates with MIC80 values ranging from 8 μg/mL to 16 μg/mL. Furthermore, compounds a6, a12 and a23 exhibited low inhibition profiles for CYP3A4. Clear SARs were analyzed, and the molecular docking experiment was carried out to further investigate the relationship between a6 and the target enzyme CYP51.
- Chai, Xiaoyun,Ding, Zichao,Hao, Yumeng,Jiang, Yuanying,Jin, Yongsheng,Ni, Tingjunhong,Wang, Ruilian,Wang, Ruina,Wang, Ting,Xie, Fei,Yu, Shichong,Zhang, Dazhi
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supporting information
(2020/06/17)
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- Design, synthesis of novel 4,5-dihydroisoxazole-containing benzamide derivatives as highly potent FtsZ inhibitors capable of killing a variety of MDR Staphylococcus aureus
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Antibiotic resistance among clinically significant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. As a part of continuing effort to develop antibacterial agents, we rationally designed and synthesized two series of 4,5-dihydroisoxazol-5-yl and 4,5-dihydroisoxazol-3-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compound A16 possessing the 4,5-dihydroisoxazol-5-yl group showed outstanding antibacterial activity (MIC, ≤0.125–0.5 μg/mL) against various testing strains, including methicillin-resistant, penicillin-resistant and clinical isolated S. aureus strains. Besides, further mouse infection model revealed that A16 could be effective in vivo and non-toxic to Hela cells. Finally, a detailed discussion of structure-activity relationships was conducted, referring to the docking results. It is worth noting that substituting a 4,5-dihydroisoxazole ring for the isoxazole ring not only broadened the antibacterial spectrum but also resulted in a significant increase in antibacterial activity against S. aureus strains. Taken together, these results suggest a promising chemotype for the development of new FtsZ-targeting bactericidal agents.
- Song, Di,Bi, Fangchao,Zhang, Nan,Qin, Yinhui,Liu, Xingbang,Teng, Yuetai,Ma, Shutao
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supporting information
(2020/09/11)
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- Discovery of Natural Product-Based Fungicides (II): Semisynthesis and Biological Activity of Sarisan Attached 3-Phenylisoxazolines as Antifungal Agents
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Many phytopathogenic fungi cause severe damage to crop yields. In continuation of our research aimed at the discovery and development of natural products-based fungicides, a series of thirty-one sarisan attached 3-phenylisoxazolines were synthesized and evaluated for their antifungal activities against five phytopathogenic fungi (B. cinerea, C. lagenarium, A. solani, F. solani, and F. graminearum). Among all title sarisan derivatives, compounds IV2, IV14 and IV23 showed potent antifungal activity against some phytopathogenic fungi. In particular, compound IV2 exhibited a broad-spectrum and more potent antifungal activity against A. solani, F. solani, and F. graminearum than the commercial fungicide Hymexazol. In addition, compounds IV2, IV14 and IV23 also displayed relative low toxicity on normal NRK-52E cells. This work will give some insights into the development of sarisan derivatives as new fungicide candidates in plant protection.
- Liu, Zhiyan,Cao, Jiangping,Yan, Xiaoting,Cheng, Wanqing,Wang, Xiaoguang,Yang, Ruige,Guo, Yong
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- Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis
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Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.
- Li, Junyou,Liu, Mengqi,Li, Yazhou,Sun, Dan-Dan,Shu, Zhihao,Tan, Qian,Guo, Shimeng,Xie, Rongrong,Gao, Lixin,Ru, Hongbo,Zang, Yi,Liu, Hong,Li, Jia,Zhou, Yu
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p. 12748 - 12772
(2020/12/17)
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- Water mediated procedure for preparation of stereoselective oximes as inhibitors of MRCK kinase
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Stereoselective aldoximes, preferably Z form have been obtained from α-cyano substituted carbonyl conjugated alkenes. This reaction occurs through Michael addition type reaction followed by retro-Knoevenagel reaction without transition-metal catalysis via C–C bond cleavage. These oximes are evaluated against cancer cell lines employing mechanistic study. Two oximes showed significant cytotoxic activity, which through in silico studies were found to inhibit MRCK Kinase, responsible for metastatic spread of cancer mortality.
- Luqman, Suaib,Misra, Krishna,Pandey, Jyoti,Shrivash, Manoj Kumar,Shukla, Akhilesh Kumar,Singh, Shilipi
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- Synthesis and in vitro evaluation of neutral aryloximes as reactivators of Electrophorus eel acetylcholinesterase inhibited by NEMP, a VX surrogate
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Casualties caused by nerve agents, potent acetylcholinesterase inhibitors, have attracted attention from media recently. Poisoning with these chemicals may be fatal if not correctly addressed. Therefore, research on novel antidotes is clearly warranted. Pyridinium oximes are the only clinically available compounds, but poor penetration into the blood-brain barrier hampers efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in SAR studies, we synthesized and evaluated neutral aryloximes as reactivators for acetylcholinesterase inhibited by NEMP, a VX surrogate. Although few tested compounds reached comparable reactivation results with clinical standards, they may be considered as leads for further optimization.
- Cavalcante, Samir F. de A.,Kitagawa, Daniel A.S.,Rodrigues, Rafael B.,Bernardo, Leandro B.,da Silva, Thiago N.,dos Santos, Wellington V.,Correa, Ana Beatriz de A.,de Almeida, Joyce S.F.D.,Fran?a, Tanos C.C.,Ku?a, Kamil,Simas, Alessandro B.C.
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- Substituted aromatic diisooxazoline-containing aromatic amidine compounds, and preparation method and application thereof
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The invention discloses substituted aromatic diisooxazoline-containing aromatic amidine compounds represented by the general formula F-1, and the structural formulas and substituents of the compoundsare shown in the specification. The invention also provides a preparation method of the compounds. The compounds provided by the invention are suitable for controlling plant diseases, such as powderymildew, rust disease, downy mildew, epidemic disease, leaf blight and the like.
- -
-
Paragraph 0089-0093
(2018/06/04)
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- 7-Oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-Dioxides: Mechanochemical Synthesis by Tandem Michael Addition–1,3-Dipolar Cycloaddition of Aldoximes and Evaluation of Antibacterial Activities
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A solvent-free, green, and efficient mechanochemical method for the synthesis of a series of bridged bicyclo aza-sulfone derivatives, namely 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxides through tandem Michael addition–1,3-dipolar cycloaddition of aldoximes was developed. Mechanochemical grinding/milling facilitates quick formation of aldoximes from corresponding aldehydes and hydroxylamine, which upon reaction with divinyl sulfone in a mixer mill affords 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxide derivatives in good overall yields. The newly synthesized bicyclo aza-sulfone derivatives 4 were screened for antibacterial activities. Mostly bicyclo aza-sulfones derived from electron-rich aromatic aldehydes inhibit the growth of Mycobacterium smegmatis (mc2155) and those from aliphatic aldehydes the growth of Escherichia coli (DH5α) in moderate to good effect. However, butyraldehyde-derived compound 4r was very effective against both M. smegmatis and E. coli. The key advantages of this mechanochemical method are catalyst- and solvent-free conditions, shorter reaction time, and formation of a new series of 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxide derivatives, which are good antibacterial agents against M. smegmatis and E. coli.
- Bhutia, Zigmee T.,Das, Avijit,Biswas, Malabika,Chatterjee, Amrita,Banerjee, Mainak
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p. 506 - 514
(2018/02/09)
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- Synthesis and biological activity of ethyl 2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylate
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A series of novel ethyl 2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylates I-1-6 were synthesized. The structures of all target compounds were characterized by 1H NMR, 13C NMR, IR,MS and elemental analyses. Their fungicidal and herbicidal activities were evaluated. The results of preliminary bioassays show that the title compounds I-4 possess 20-50% inhibition against most of the tested plants at the dosage of 150 g ai/ha, while the title compounds I-1-5 possess 32-58% inhibition against FusaHum graminearum, Thanatephorus cucumeris, Botrytis cinereapers and Fusarium oxysporum in vitro at the concentration of 100 mg/L.
- Wang, Wei,Wang, Lie-Ping,Mao, Min-Zhen,Zhang, Xiao-Guang,Zheng, Xiao-Rui,Huang, Xiao-Ying,Xue, Chao,Ning, Bin-Ke
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p. 164 - 167
(2017/11/20)
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- Efficient synthesis of 1,2,4-oxadiazine-5-ones via [3+3] cycloaddition of in situ generated aza-oxyallylic cations with nitrile oxides
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1,2,4-Oxadiazin-5-ones were prepared via [3+3] cycloaddition of in situ generated aza-oxyallylic cations with nitrile oxides in good yields and excellent functional group compatibility. This efficient transformation is metal-free and is promoted by an inorganic base Cs2CO3. In addition, this reaction features simple-operation, mild conditions, and high regioselectivity.
- Wang, Gangqiang,Chen, Rongxing,Zhao, Sen,Yang, Liangfeng,Guo, Haibing,Sun, Shaofa,Wang, Jian,Domena, Justin,Xing, Yalan
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supporting information
p. 2018 - 2020
(2018/04/25)
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- Novel design of recyclable copper(II) complex supported on magnetic nanoparticles as active catalyst for Beckmann rearrangement in poly(ethylene glycol)
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Copper complex-functionalized magnetic core–shell nanoparticles (Fe3O4@SiO2-Lig-Cu) were prepared and characterized using various techniques. The activity of the new catalyst was tested for the Beckmann rearrangement. The reaction conditions allow for the conversion of a wide variety of aldoximes, including aromatic and heterocyclic ones, to amides in good to excellent yields. High efficiency, mild reaction conditions, easy work-up, use of poly(ethylene glycol) as a green medium and simple purification of products are important advantages of this system. Moreover, the eco-friendly heterogeneous nanocatalyst could be easily recovered from the reaction mixture using an external magnet and reused several times.
- Keyhaniyan, Mahdi,Shiri, Ali,Eshghi, Hossein,Khojastehnezhad, Amir
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- Design, synthesis and structure-based optimization of novel isoxazole-containing benzamide derivatives as FtsZ modulators
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Antibiotic resistance among clinically significant bacterial pathogens is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. Utilizing computational docking method and structure-based optimization strategy, we rationally designed and synthesized two series of isoxazol-3-yl- and isoxazol-5-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compounds B14 and B16 that possessed the isoxazol-5-yl group showed strong antibacterial activity against various testing strains, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. aureus. Further molecular biological studies and docking analyses proved that the compound functioned as an effective inhibitor to alter the dynamics of FtsZ self-polymerization via a stimulatory mechanism, which finally terminated the cell division and caused cell death. Taken together, these results could suggest a promising chemotype for development of new FtsZ-targeting bactericidal agent.
- Bi, Fangchao,Song, Di,Zhang, Nan,Liu, Zhiyang,Gu, Xinjie,Hu, Chaoyu,Cai, Xiaokang,Venter, Henrietta,Ma, Shutao
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- Synthesis of new coumarin tethered isoxazolines as potential anticancer agents
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A series of new coumarin tethered isoxazolines (7a-l) were synthesized and evaluated for their cytotoxic potency against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Preliminary results revealed that some of these coumarin tethered isoxazolines 7b, 7c, 7f and 7j exhibited significant antiproliferative effect against human melanoma cancer (UACC 903) with IC50 values of 8.8, 10.5, 9.2 and 4.5 μM respectively. However, compound 7c was non-toxic to normal human cells at the tested concentration. Further, we have chosen compound 7c to check its efficacy in Ehrlich Ascites Carcinoma animal model in-vivo for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature such as regression of tumor volume. The present study indicates the scope of developing into potent anticancer drug in near future.
- Lingaraju, Gejjalagere S.,Balaji, Kyathegowdanadoddi S.,Jayarama, Shankar,Anil, Seegehalli M.,Kiran, Kuppalli R.,Sadashiva, Maralinganadoddi P.
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supporting information
p. 3606 - 3612
(2018/11/06)
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- Synthesis and Antibacterial Evaluation of Benzofuran Based 3,5-Disubstituted Isoxazoles
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A series of novel benzofuran-isoxazole 7a–7j hybrid heterocyclic molecules are synthesized. The structures of compounds 7a–7j are assessed by IR, NMR, MASS spectroscopy and elemental analysis. The target compounds 7a–7j are screened for their antibacterial activity and demonstrated excellent to moderate activity against gram-positive and gram-negative bacteria.
- Sunitha,Kumar, A. Kishore,Lincoln, Ch. Abraham,Jalapathi,Reddy, V. Gopal
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p. 2669 - 2674
(2019/04/04)
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- A mild system for synthesis of aldoximes and ketoximes in the presence of N-hydroxyphthalimide in aqueous system
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An efficient method for synthesis of oximes from aldehydes or ketones with N-hydroxyphthalimide or N-hydroxysuccinimide in water has been described. It is the first time to utilize NHPI as an oximation reagent to synthesize aldoximes and ketoximes from the corresponding organic carbonyl compounds without other reagents. The reaction tolerates various functional groups and affords the corresponding oximes in 76%–98% yields. The by-product phthalic acid can be recycled from the system. In addition, this method has been successfully applied to the synthesis of the precursor of some pharmacologically active amide molecules.
- Jiang, Xiaoying,Xu, Xiaohe,Lin, Yuyan,Yan, Yiyan,Li, Pingping,Bai, Renren,Xie, Yuanyuan
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supporting information
p. 5879 - 5885
(2018/09/06)
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- Preparation technology for 3-aryl-4-nitro isoxazole compound
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The invention discloses a preparation technology for a 3-aryl-4-nitro isoxazole compound. The preparation technology comprises the following steps: synthesizing a compound shown as formula II through the nucleophilic addition of hydroxylamine hydrochloride and the compound shown as formula I used as the raw material; acquiring the compound shown as formula III through the substitution reaction of the compound shown as formula II and N-chlorosuccinimide; preparing 1-dimethyl amino-2-nitro ethylene through the reaction of N,N-dimethylformamide dimethyl acetal and nitromethane used as the raw material; and acquiring a target product 3-aryl-4-nitro isoxazole compound through the cyclization reaction of the compound shown as formula III and 1-dimethyl amino-2-nitro ethylene. The raw materials in the synthesis route are low in cost and easily acquired, the operation condition is mild and is easily controlled, the product is easily purified and the preparation technology is a new method for synthesizing the 3-aryl-4-nitro isoxazole compound.
- -
-
Paragraph 0046; 0047
(2018/03/01)
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- Ultrasonic-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles via various terminal acetylenes and azide and their quorum sensing inhibition
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An efficient synthesis of 1,4-disubstituted 1,2,3-triazole derivatives was studied. 1,4-Disubstituted 1,2,3-triazoles containing isoxazole and thymidine structures were synthesized in 84–96% yields starting from various terminal isoxazole ether alkynes and β-thymidine azide derivatives via a 1,3-dispolar cycloaddition using copper acetate, sodium ascorbate as the catalyst under ultrasonic assisted condition. All the target compounds were characterized by HRMS, FT-IR, 1H NMR and 13C NMR spectroscopy. Furthermore, the quorum sensing inhibitory activities of synthesized compounds were evaluated with Chromobacterium violaceum (C. Violaceum CV026) based on their inhibition of violacein production, with compound C10-HSL as a positive control. The compounds 8a, 8c and 8f exhibited considerable levels of inhibitory activity against violacein production, and IC50 values were 217?±?19, 223?±?20 and 42.8?±?4.5?μM, respectively, which highlighted the potential of these compounds as lead structures for further research towards the development of novel QS inhibitors.
- Zhang, Da-wei,Zhang, Yu-min,Li, Jing,Zhao, Tian-qi,Gu, Qiang,Lin, Feng
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p. 343 - 353
(2016/12/23)
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- Poly(ethylene glycol)–bound sulfonyl chloride as an efficient catalyst for transformation of aldoximes to nitriles
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An operationally simple, efficient, and environmentally benign preparation of nitriles in good to excellent yields from various aldoximes in the presence of recyclable poly(ethylene glycol)–bound sulfonyl chloride is described.
- Zhang, Xiao-Lan,Liu, Xiao-Ling,Sang, Xiao-Yan,Sheng, Shou-Ri
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p. 232 - 237
(2017/01/22)
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- Synthesis of 3,5-Disubstituted isoxazoles containing privileged substructures with a diverse display of polar surface area
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We designed and synthesized the molecular framework of 3,5-disubstituted isoxazoles containing privileged substructures with various substituents which uniquely display polar surface area in a diverse manner. A library of 3,5-disubstituted isoxazoles were systematically prepared via 1,3-dipolar cycloaddition of alkynes with nitrile oxides prepared by two complementary synthetic routes; method A utilized a halogenating agent with a base and method B utilized a hypervalent iodine reagent. Through the biological evaluation of corresponding isoxazoles via three independent phenotypic assays, the different pattern of biological activities was shown according to the type of privileged substructure and substituent. These results demonstrated the significance of molecular design via introducing privileged substructures and various substituents to make a diverse arrangement of polar surface area within a similar 3-dimensional molecular framework.
- Kim, Mingi,Hwang, Yoon Soo,Cho, Wansang,Park, Seung Bum
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supporting information
p. 407 - 413
(2017/06/19)
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- Novel Compounds
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The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C- terminal hydrolase 30 or Ubiquitin Specific Peptidase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and cancer. Compounds of the invention include compounds having the formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R1c, R1d, R1e, R1f, R1g, R2, X, L and A are as defined herein.
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Page/Page column 63
(2017/07/06)
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- Iron-catalyzed synthesis of benzoxazoles by oxidative coupling/cyclization of phenol derivatives with benzoyl aldehyde oximes
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An iron-catalyzed oxidative coupling/cyclization reaction for the synthesis of benzoxazoles at room temperature is reported. This reaction was enabled by an inexpensive iron(iii) catalyst by treating readily available phenol derivatives with benzoyl aldehyde oximes. Mechanistic studies show that benzoyl aldehyde oxime is not only used as a substrate, but also serves as an ancillary ligand to support the iron salt in the promotion of the transformation.
- Gao, Sen,Gao, Liming,Meng, Hong,Luo, Meiming,Zeng, Xiaoming
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supporting information
p. 9886 - 9889
(2017/09/11)
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- Constructing novel dihydrofuran and dihydroisoxazole analogues of isocombretastatin-4 as tubulin polymerization inhibitors through [3+2] reactions
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[3+2] reactions play a key role in constructing various pharmaceutical moleculars. In this study, using Mn(OAc)3 mediated and 1,3-dipolar [3+2] cyclization reactions, 38 novel dihydrofuran and dihydroisoxazole analogues of isoCA-4 were synthesized as inhibitors of tubulin polymerization. Among them, compound 6g was found to be the most potent cytotoxic agents against PC-3 cells with IC50 value of 0.47 μM, and compound 5p exhibted highest activity on HeLa cells with IC50 vaule of 2.32 μM. Tubulin polymerization assay revealed that 6g was a dose-dependent and effective inhibitor of tubulin assembly. Immunohistochemistry studies and cell cycle distribution analysis indicated that 6g severely disrupted microtubule network and significantly arrested most cells in the G2/M phase of the cell cycle in PC-3 cells. In addition, molecular docking studies showed that two chiral isomers of 6g can bind efficiently and similarly at colchicine binding site of tubulin.
- Song, Ming-Yu,Cao, Chen-Yu,He, Qiu-Rui,Dong, Qing-Miao,Li, Ding,Tang, Jiang-Jiang,Gao, Jin-Ming
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p. 5290 - 5302
(2017/10/06)
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- Direct preparation of oximes and Schiff bases by oxidation of primary benzylic or allylic alcohols in the presence of primary amines using Mn(III) complex of polysalicylaldehyde as an efficient and selective heterogeneous catalyst by molecular oxygen
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The present work introduced the new strategy for direct preparation of Schiff base as well as oxime compounds through oxidation of primary benzylic or allylic alcohols in the presence of amines by complexation of Mn(III) to a polymeric Schiff base ligand based on polysalicylaldehyde (PSA-Schiff base-Mn(III) complex). As a new environmentally benign protocol, manganese heterogeneous polymeric catalytic system demonstrated promising oxidation of alcohols in ethanol using molecular oxygen. PSA was synthesized through polycondensation reaction of 2-hydroxy-5-chloromethyl-benzaldehyde and then treated with 2-aminophenol to form polymeric ligand. Average molecular weight of PSA was studied by an analytical method as well as GPC analysis. Formation of the catalyst was characterized step by step by FTIR, UV–Vis, 1H NMR, TGA, CHN and EDX analyses. Loading amounts of metal ions as well as leaching amount of the catalysis were studied by ICP-OES instrument. The catalyst shows up to high yields for oxidation of primary and secondary primary benzylic or allylic alcohols to carbonyl compounds, especially direct imine formation in a mild, inexpensive and efficient method which can be successfully recovered from the reaction mixture and reused for several times without any remarkable reactivity loss. Effect of solvent, temperature, catalyst amount and oxygen donors along with some blank experiments to elucidation of catalyst activity was evaluated in this work. Also chemoselectivity behavior of the catalyst was investigated with some combinations.
- Kazemnejadi, Milad,Shakeri, Alireza,Mohammadi, Mohammad,Tabefam, Marzieh
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p. 1917 - 1933
(2017/08/15)
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- Ir(III)-Catalyzed Synthesis of Isoquinoline N-Oxides from Aryloxime and α-Diazocarbonyl Compounds
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An efficient Ir(III)-catalyzed C-H activation and annulations of aryloxime with α-diazocarbonyl compounds has been developed for the synthesis of substituted isoquinoline N-oxides. The reaction proceeds under mild atmospheric conditions, without any external oxidants and releases N2 and H2O as the byproducts. In addition, synthetic applications of the N-oxide products have been established by performing further functionalization. An interesting dimeric iridacyclic complex allied through a bis-silver carboxylate bridge has been isolated that efficiently catalyzed the reaction.
- Phatake, Ravindra S.,Patel, Pitambar,Ramana, Chepuri V.
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supporting information
p. 292 - 295
(2016/02/03)
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- Effect of novel triazole-amino acid hybrids on growth and virulence of Candida species: in vitro and in vivo studies
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The increasing incidence of human candidiasis and the tendency of Candida species to become resistant to existing chemotherapies are well-recognized health problems. The present study demonstrates the successful synthesis of novel triazole-amino acid hybrids with potent in vitro and in vivo inhibitory activity against Candida species. Particularly, compounds 68 and 70 showed potent in vitro activity against fluconazole (FLC) resistant as well as sensitive clinical isolates of Candida albicans. Time kill curve analysis of lead inhibitors 68 and 70 showed their fungistatic nature. Secretion of hydrolytic enzymes, mainly proteinases and phospholipases, decreased considerably in the presence of 68 and 70 indicating their interference in fungal virulence. TEM analysis of Candida cells exposed to compounds 68 and 70 clearly showed morphological changes and intracellular damage as their possible mode of action. A preliminary mechanistic study carried out on the two most effective inhibitors (68 and 70) revealed the inhibition of ergosterol biosynthesis thereby causing the cells to lose their integrity and viability. The selected compounds did not show significant cytotoxicity up to a concentration of 200 μg mL?1 in the HEK293 cell line. An in silico analysis of 68 and 70 binding to a modeled C. albicans CYP51 showed critical H-bonding as well as hydrophobic interactions with the important active site residues indicating the basis of their anti-Candida role. Studies on the larvae of Galleria mellonella showed that the selected inhibitors (68 and 70) were non-toxic, did not provoke an immune response and significantly reduced Candida proliferation in vivo.
- Aneja, Babita,Irfan, Mohammad,Kapil, Charu,Jairajpuri, Mohamad Aman,Maguire, Ronan,Kavanagh, Kevin,Rizvi, M. Moshahid A.,Manzoor, Nikhat,Azam, Amir,Abid, Mohammad
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p. 10599 - 10619
(2016/11/30)
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- Monocyclic β-lactam and unexpected oxazinone formation: synthesis, crystal structure, docking studies and antibacterial evaluation
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Novel monocyclic β-lactam derivatives bearing aryl, phenyl and heterocyclic rings were synthesized as possible antibacterial agents. Cyclization of imines (3h, 3t) with phenylacetic acid in the presence of phosphoryl chloride and triethyl amine did not afford the expected β-lactams. Instead, highly substituted 1,3-oxazin-4-ones (4h, 4t) were isolated as the only product and confirmed by single crystal X-ray analysis of 4t. The results of antibacterial activity showed that compound 4l exhibited considerable antibacterial activity with MIC and MBC values of 62.5 μg/mL against Klebsiella pneumoniae. Cytotoxicity assay on Chinese Hamster Ovary (CHO) cell line revealed non-cytotoxic behavior of compounds 4d, 4h, 4k and 4l up to 200 μg/mL conc. Molecular docking was performed for compound 4l with penicillin binding protein-5 to identify the nature of interactions. The results of both in silico and in vitro evaluation provide the basis for compound 4l to be carried as a potential lead molecule in the drug discovery pipeline against bacterial infections.
- Aneja, Babita,Irfan, Mohammad,Hassan, Md. Imtaiyaz,Prakash, Amresh,Yadava, Umesh,Daniliuc, Constantin G.,Zafaryab, Md.,Rizvi, M. Moshahid A.,Azam, Amir,Abid, Mohammad
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p. 834 - 852
(2016/07/07)
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- Seeking potent anti-tubercular agents: Design, synthesis, anti-tubercular activity and docking study of various ((triazoles/indole)-piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole derivatives
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A series of thirty eight novel 3-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole and 1-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl/1,4-diazepan-1-yl)-2-(1H-indol-3-yl)substituted-1-one analogues were synthesised, characterised using various analytical techniques and evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two 'wild' strains Spec. 210 and Spec. 192. The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 6.16 to >200 μM. Among the tested compounds, 7i, 7y and 7z exhibited moderate activity (MIC = 24.03-29.19 μM) and 7j exhibited very good anti-tubercular activity (MIC = 6.16 μM). Furthermore, 7i, 7j, 7y and 7z were found to be non-toxic against mouse macrophage cell lines when screened for toxicity. All the synthesised compounds were docked to pantothenate synthetase enzyme site to know deferent binding interactions with the receptor.
- Naidu, Kalaga Mahalakshmi,Srinivasarao, Singireddi,Agnieszka, Napiórkowska,Ewa, Augustynowicz-Kope?,Kumar, Muthyala Murali Krishna,Chandra Sekhar, Kondapalli Venkata Gowri
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p. 2245 - 2250
(2016/04/20)
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- An efficient one-pot protocol for the conversion of benzaldehydes into tetrazole analogs
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An efficient protocol has been developed for the one-pot synthesis of tetrazole derivatives in moderate to good yields starting from substituted benzaldehydes and proceeding via non-isolated oxime and nitrile intermediates. The structures of the desired products were confirmed by IR, and NMR spectroscopy as well as mass spectrometry. A plausible reaction mechanism is also discussed.
- Khan, Khalid Mohammed,Fatima, Itrat,Saad, Syed Muhammad,Taha, Muhammad,Voelter, Wolfgang
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p. 523 - 524
(2016/01/20)
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- An efficient solvent-free synthesis of isoxazolyl-1,4-dihydropyridines on solid support SiO2 under microwave irradiation
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An efficient synthesis of 1,4-dihydropyridines was developed. 1,4-Dihydropyridines were synthesized starting from various 3-substituted isoxazolyl-5-carbaldehydes, ethyl acetoacetate, and ammonium acetate under microwave irradiation and solvent-free conditions (86–96?%), and were characterized by HRMS, FT-IR, 1H NMR, and 13C NMR spectroscopy. Solid support SiO2 was found to possess favorable catalysis and dispersancy for the condensation reaction. The merits of the method included the environmental friendly reaction conditions, simple operation, extensive substrates, good yields and reuse of the SiO2. Moreover, the crystal structure of compound diethyl 4-[3-(2-methoxyphenyl)isoxazol-5-yl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate in orthorhombic Pbca space group was presented. Graphical abstract: [Figure not available: see fulltext.]
- Zhang, Dawei,Chen, Xiaodong,Guo, Xue,Zhang, Yumin,Hou, Yaya,Zhao, Tianqi,Gu, Qiang
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p. 1605 - 1614
(2016/08/16)
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- Optimization and Structure-Activity Relationships of Phosphinic Pseudotripeptide Inhibitors of Aminopeptidases That Generate Antigenic Peptides
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The oxytocinase subfamily of M1 aminopeptidases, consisting of ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2), and insulin-regulated aminopeptidase (IRAP), plays critical roles in the generation of antigenic peptides and indirectly regulates human adaptive immune responses. We have previously demonstrated that phosphinic pseudotripeptides can constitute potent inhibitors of this group of enzymes. In this study, we used synthetic methodologies able to furnish a series of stereochemically defined phosphinic pseudotripeptides and demonstrate that side chains at P1′ and P2′ positions are critical determinants in driving potency and selectivity. We identified low nanomolar inhibitors of ERAP2 and IRAP that display selectivity of more than 2 and 3 orders of magnitude, respectively. Cellular analysis demonstrated that one of the compounds that is a selective IRAP inhibitor can reduce IRAP-dependent but not ERAP1-dependent cross-presentation by dendritic cells with nanomolar efficacy. Our results encourage further preclinical development of phosphinic pseudotripeptides as regulators of adaptive immune responses.
- Kokkala, Paraskevi,Mpakali, Anastasia,Mauvais, Francois-Xavier,Papakyriakou, Athanasios,Daskalaki, Ira,Petropoulou, Ioanna,Kavvalou, Sofia,Papathanasopoulou, Mirto,Agrotis, Stefanos,Fonsou, Theodora-Markisia,Van Endert, Peter,Stratikos, Efstratios,Georgiadis, Dimitris
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supporting information
p. 9107 - 9123
(2016/10/22)
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- Five-membered azole heterocyclic compound and its preparation method, pharmaceutical composition and use thereof
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The present invention relates to a five-membered azole heterocycle compound represented by the following general formula (I), a preparation method of the five-membered azole heterocycle compound, a drug composition of the five-membered azole heterocycle compound, and a use of the five-membered azole heterocycle compound in preparation of drugs for prevention or treatment of TGR5-mediated diseases. The formula (I) is represented by the instruction.
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Paragraph 0235; 0236; 0266; 0267
(2017/02/28)
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- Br?nsted acid catalyzed transoximation reaction: Synthesis of aldoximes and ketoximes without use of hydroxylamine salts
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The transoximation reaction enables the transfer of an oxime to a carbonyl compound and is catalyzed by transoximase in the pupae of the silkworm. Inspired by this bio-synthetic pathway, we achieved the transoximation of oximes to aldehydes and ketones catalyzed by a Br?nsted acid under mild conditions. Hydroxylamine salt, which necessitates a stoichiometric amount of base, was not required. NMR analysis clarified that this reaction proceeded through hydroxylamines generated by the successive hydrolysis of the oxime in situ. In addition, an environmentally benign method for catalytic transoximation was demonstrated in aqueous medium on a one hundred gram scale and the reaction filtrate containing the catalyst was recovered and reused over 10 times.
- Hyodo, Kengo,Togashi, Kosuke,Oishi, Naoki,Hasegawa, Genna,Uchida, Kingo
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supporting information
p. 5788 - 5793
(2016/11/06)
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- Oxime carbamates as potential insecticidal agents: Design, synthesis and biological evaluation
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A series of oxime carbamates derivatives were designed and synthesized as a part of our ongoing search for novel high potential agrochemicals. Their structures were confirmed by 1H NMR, 13C NMR and elemental analysis. The bioassays results indicated that some of the obtained compounds exhibited good insecticidal activity against Heliothis armigera and Plutella xylostella.
- Ke, Shaoyong,Yang, Ziwen,Shi, Liqiao,Liu, Manli,Liang, Ying,Wang, Kaimei,Long, Tong,Jiang, Aibing,Zhang, Zhigang
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p. 771 - 777
(2015/10/05)
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- Efficient solvent-free synthesis of bis(indolyl)methanes on SiO2 solid support under microwave irradiation
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An efficient synthesis of bis(indolyl)methanes was developed. Bis(indolyl)methanes were synthesized starting from various aromatic aldehydes with indole under microwave irradiation and solvent-free conditions (85-98 %). Solid support SiO2 was found to possess favorable catalytic and dispersancy parameters for the condensation reaction. Moreover, novel bis(indolyl)methanes containing an isoxazole ring were synthesized via this method in excellent yields (> 94 %) using 3-substituted isoxazole-5-carbaldehydes and indole.
- Zhang, Da-Wei,Zhang, Yu-Min,Zhang, Yi-Liang,Zhao, Tian-Qi,Liu, Hong-Wei,Gan, Yuan-Ming,Gu, Qiang
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p. 470 - 478
(2015/01/30)
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- Synthesis and biological evaluation of novel Δ2-isoxazoline fused cyclopentane derivatives as potential antimicrobial and anticancer agents
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As a part of our endeavour toward the synthesis of new heterocyclic bioactive agents, three series of Δ2-isoxazoline fused cyclopentane derivatives (27 compounds) were synthesized and characterized by IR, 1H NMR, 13C NMR and MS analysis. The newly synthesized target compounds were evaluated for their preliminary in vitro antimicrobial and anticancer activities. The results indicated that compounds 4b, 4h, 4i, 5d and 5g displayed remarkable anti-microbial activity with respect to their standard drugs Ampicillin, Gentamycin and Amphotericin B. In preliminary MTT cytotoxicity studies, compound 4i was found to be equipotent to the standard drug Etoposide against MCF-7. The influence of the most active cytotoxic compound 4i on the cell cycle distribution was evaluated in the MCF-7 cell line, which displayed a cell cycle arrest at the S phase. Moreover, acridine orange/ethidium bromide staining, annexin V binding assay and mitochondrial membrane potential revealed that compound 4i can induce cell apoptosis in MCF-7 cells. Compounds 4b and 4h are potential leads as antimicrobials owing to no significant cell toxicity observed in the present study. Docking studies revealed that compound 4i binds to Phe1145, Glh698, Met696, Cys1191, Met1169 and Ile1167 on DNA methyltransferase (DNMT1) protein and inhibition of DNMT1 could be the possible mechanism of action for these compounds.
- Prajapti, Santosh Kumar,Shrivastava, Shweta,Bihade, Umesh,Gupta, Ajay Kumar,Naidu,Banerjee, Uttam Chand,Babu, Bathini Nagendra
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supporting information
p. 839 - 845
(2015/05/27)
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- Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism
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Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4′-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50=12.2±0.2μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. X marks the spot: 39 trisubstituted isoxazoles were designed and synthesized, leading to compounds with pharmacological profiles ranging from agonist to antagonist at the farnesoid X receptor (FXR). By using the most potent antagonist as a probe, the essential molecular basis of FXR antagonism is proposed, and E467 on H12 can be regarded as a hot-spot residue for the future design of nonsteroidal antagonists of FXR.
- Huang, Huang,Si, Pei,Wang, Lei,Xu, Yong,Xu, Xin,Zhu, Jin,Jiang, Hualiang,Li, Weihua,Chen, Lili,Li, Jian
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p. 1184 - 1199
(2015/07/07)
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- Efficient synthesis of bis-isoxazole ethers via 1,3-dipolar cycloaddition catalysed by Zn/Zn2+ and their antifungal activities
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An efficient method was developed for synthesising isoxazoles. A series of novel bis-isoxazole ether compounds VI, VII and VIII were synthesised starting from different substituted aldehydes (I) via a 1,3-dispolar cycloaddition using Zn/Zn2+ as a catalyst; these were characterised by FT-IR, HRMS, 1H NMR and 13C NMR spectroscopy. In addition, the antimicrobial properties of the synthesised products were investigated. The synthesised compounds exhibited significant antifungal activities in comparison with the standard drugs, fluconazole and itraconazole. It was found that Candida albicans was sensitive to 2-substituted phenyl bis-isoxazole ethers bearing pyridyl.
- Zhang, Da-Wei,Lin, Feng,Li, Bo-Chao,Liu, Hong-Wei,Zhao, Tian-Qi,Zhang, Yu-Min,Gu, Qiang
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p. 1500 - 1511
(2015/09/15)
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- Substituted Acyloxyamidines as HCV NS3/4A Inhibitors
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Disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof, in which A, G, R1 and R2 are as defined herein. The compounds and pharmaceutical compositions of the compounds are suitable for the treatment of HCV infection in mammals and are also useful to modulate or inhibit NS3/4 dimerization.
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Paragraph 0150; 0151
(2015/05/26)
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- Copper(ii)-promoted direct conversion of methylarenes into aromatic oximes
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A simple and efficient catalytic system for direct conversion of methylarenes into aromatic oximes has been developed, with Cu(OAc)2 as catalyst, NHPI (N-Hydroxyphthalimide) as additive, TBN (tert-butyl nitrite) as both the nitrogen source and the oxidant. This process proceeds under mild conditions, tolerates a wide range of substrates, affording the targeted aromatic oximes in 63-86% yields.
- Yu, Jiatao,Lu, Ming
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supporting information
p. 7397 - 7401
(2015/07/15)
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