- Semi-synthesis and structural elucidation of brevicanines A–D, four new C19-diterpenoid alkaloids with rotameric phenomenon from Aconitum brevicalcaratum
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Four new C19-diterpenoid alkaloids brevicanines A–D (1–4) with rotameric phenomenon were isolated from Aconitum brevicalcaratum. They all possessed an unusual axial chiral phenyl-quinazoline side chain and their structures were elucidated by extensive spectroscopic analysis and chemical methods. Meanwhile, brevicanines A and B were semi-synthesized from their parent compound scaconine to further confirm their structures. Variable-temperature NMR spectroscopy was also used to investigate the atropisomers of brevicanine A, in which two sets of signals in 1H NMR spectra were observed at room temperature and coalesced over 140 °C. It's the first time to determine the atropisomeric preference of diterpenoid alkaloids.
- Wang, Zhong-Sheng,Chen, Wei,Jiang, Hai-Yue,Gao, Feng,Zhou, Xian-Li
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- Exploration of the Structural Space in 4(3 H)-Quinazolinone Antibacterials
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We report herein the syntheses of 79 derivatives of the 4(3H)-quinazolinones and their structure-activity relationship (SAR) against methicillin-resistant Staphylococcus aureus (MRSA). Twenty one analogs were further evaluated in in vitro assays. Subsequent investigation of the pharmacokinetic properties singled out compound 73 ((E)-3-(5-carboxy-2-fluorophenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one) for further study. The compound synergized with piperacillin-tazobactam (TZP) both in vitro and in vivo in a clinically relevant mouse model of MRSA infection. The TZP combination lacks activity against MRSA, yet it synergized with compound 73 to kill MRSA in a bactericidal manner. The synergy is rationalized by the ability of the quinazolinones to bind to the allosteric site of penicillin-binding protein (PBP)2a, resulting in opening of the active site, whereby the β-lactam antibiotic now is enabled to bind to the active site in its mechanism of action. The combination effectively treats MRSA infection, for which many antibiotics (including TZP) have faced clinical obsolescence.
- Qian, Yuanyuan,Allegretta, Giuseppe,Janardhanan, Jeshina,Peng, Zhihong,Mahasenan, Kiran V.,Lastochkin, Elena,Gozun, Melissa Malia N.,Tejera, Sara,Schroeder, Valerie A.,Wolter, William R.,Feltzer, Rhona,Mobashery, Shahriar,Chang, Mayland
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p. 5287 - 5296
(2020/06/10)
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- Synthesis and evaluation of new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives as potent antibacterial agents effective against multidrug resistant Staphylococcus aureus
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Treatment of nosocomial and community acquired Staphylococcus aureus infections has become more challenging due to the egression of multi-drug resistance. This has spurred the need for rapid development of new therapeutic agents which can effectively negate the resistance mechanisms. In our current work, several new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives were synthesized and examined for their antimicrobial activity against ESKAP pathogen panel and pathogenic mycobacteria. In the primary screening, compounds 4a, 4b, 6′a, 6′b, 6′h, 6′i and 6′j were found to demonstrate selective and potent inhibitory activity against Staphylococcus aureus (MICs = 0.25–0.5 μg/mL). When tested against Vero cells, all the compounds were found to be non toxic possessing favourable selectivity index (SI > 10), which encouraged us for carrying out further studies. Compound 6′a (SI > 40) was tested against a number of multiple clinical strains of multi-drug resistant S. aureus and was found to exhibit potent activity, irrespective of the resistant status of the strain. Besides, compound 6′a also exhibited concentration dependent bactericidal activity and synergized with the FDA approved drugs tested. The interesting results obtained suggest the potential utility of the newly synthesized compounds for treatment of multidrug resistant S. aureus infections.
- Gatadi, Srikanth,Gour, Jitendra,Shukla, Manjulika,Kaul, Grace,das, Swetarka,Dasgupta, Arunava,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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p. 569 - 579
(2018/11/25)
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- Screening of natural deep eutectic solvents for green synthesis of 2-methyl-3-substituted quinazolinones and microwave-assisted synthesis of 3-aryl quinazolinones in ethanol
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In this study, two fast and efficient protocols for green synthesis of 3-substituted quinazolinones were perfomed. A synthesis of 2-methyl-3-substituted quinazolinones was performed in natural deep eutectic solvents, while 3-aryl quinazolinones were obtained by using microwave assisted synthesis. Benzoxazinone, which was used as an intermediate in the synthesis of 2-methyl-3-substituted quinazolinones, was prepared conventionally from anthranilic acid and acetic anhydride. In order to find the most appropriate synthetic path, twenty natural deep eutectic solvents were applied as a solvent in these syntheses. Choline chloride:urea (1: 2) was found to be the most efficient solvent and was further used in the synthesis of 2-methyl quinazolinone derivatives (2–12). 3-Aryl quinazolinones (13–17), on the other hand, were synthesized in one-pot microwave-assisted reaction of anthranilic acid, different amines and trimethyl orthoformate. All compounds were synthesized in good to excellent yields, characterized by LC-MS/MS spectrometry and 1H- and 13C-NMR spectroscopy.
- Komar, Mario,Konjarevi?, Anastazija,Molnar, Maja
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- Formation of tryptanthrin compounds upon Oxone-induced dimerization of indole-3-carbaldehydes
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Tryptanthrin is a natural product with numerous important pharmacological properties. Tryptanthrin and its analogs are commonly prepared by condensation of isatoic anhydride and isatin. In this Letter we investigate the formation of tryptanthrin derivatives upon Oxone-induced oxidative dimerization of indole-3-carbaldehydes.
- Nelson, Amber C.,Kalinowski, Emily S.,Jacobson, Taylor L.,Grundt, Peter
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p. 6804 - 6806
(2013/11/19)
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- Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists
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We describe a new class of subunit-selective antagonists of N-methyl d-aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is noncompetitive and voltage-independent, suggesting that this family of compounds does not exert action on the agonist binding site of the receptor or block the channel pore. The compounds described here resemble CP-465,022 ((S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl] -6-fluoro-3H-quinazolin-4-one), a noncompetitive antagonist of AMPA-selective glutamate receptors. However, modification of ring substituents resulted in analogues with greater than 100-fold selectivity for recombinant NMDA receptors over AMPA and kainate receptors. Furthermore, within this series of compounds, analogues were identified with 50-fold selectivity for recombinant NR2C/D-containing receptors over NR2A/B containing receptors. These compounds represent a new class of noncompetitive subunit-selective NMDA receptor antagonists.
- Mosley, Cara A.,Acker, Timothy M.,Hansen, Kasper B.,Mullasseril, Praseeda,Andersen, Karen T.,Le, Phuong,Vellano, Kimberly M.,Br?uner-Osborne, Hans,Liotta, Dennis C.,Traynelis, Stephen F.
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supporting information; experimental part
p. 5476 - 5490
(2010/11/16)
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- New development of Meyers' methodology: Stereoselective preparation of an axially chiral 5,7-fused bicyclic lactam related to circumdatins/benzomalvins and asperlicins
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The stereoselective preparation of a new Meyers' bicyclic lactam-bridged biaryl 1, highly structurally related to circumdatins, benzomalvins and asperlicins, is reported. Using the popular Meyers' diastereoselective lactamization, under dehydrating conditions (CH2Cl 2/reflux/MgSO4), trans-(aS,R,S)-1 was obtained in a rather modest yield of 25% and an excellent diastereoselectivity >95%. An alternative procedure making use of the activating agents of carboxylic acid (Mukaiyama reagent and FEP) allowed the lactamization process to take place under milder conditions (CH2Cl2/20°C) affording trans-(aS,R,S)-1 in fairly good yields (50%-85%) and in up to 65% de.
- Penhoat, Mael,Bohn, Pierre,Dupas, Georges,Papamicael, Cyril,Marsais, Francis,Levacher, Vincent
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p. 281 - 286
(2007/10/03)
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- Synthesis and biological activity of quinoquinazolinones
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10-Substituted 6-arylaminomethyl-12H-quinoquinazoline-5(6H),12-diones (III) and 5,6-dihydro-5-substituted-12H-quinoquinazoline-5,12(6H)-diones (IV) have been synthesized from 10-substituted-12H-quinoquinazoline-5(6H),12-diones (II) wh
- Saxena, Sushma,Verma, M,Saxena, A K,Gupta, G P,Shanker, K
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p. 453 - 456
(2007/10/02)
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