- Synthesis, biological activity and preliminary in silico ADMET screening of polyamine conjugates with bicyclic systems
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Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC-3, DU-145 and MCF-7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds-DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs.
- Szumilak, Marta,Galdyszynska, Malgorzata,Dominska, Kamila,Bak-Sypien, Irena I.,Merecz-Sadowska, Anna,Stanczak, Andrzej,Karwowski, Boleslaw T.,Piastowska-Ciesielska, Agnieszka W.
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Read Online
- Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3 H)-one
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In the face of the clinical challenge posed by resistant bacteria, the present needs for novel classes of antibiotics are genuine. In silico docking and screening, followed by chemical synthesis of a library of quinazolinones, led to the discovery of (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. We document that the antibiotic also inhibits PBP1 of S. aureus, indicating a broad targeting of structurally similar PBPs by this antibiotic. This class of antibiotics holds promise in fighting MRSA infections.
- Bouley, Renee,Kumarasiri, Malika,Peng, Zhihong,Otero, Lisandro H.,Song, Wei,Suckow, Mark A.,Schroeder, Valerie A.,Wolter, William R.,Lastochkin, Elena,Antunes, Nuno T.,Pi, Hualiang,Vakulenko, Sergei,Hermoso, Juan A.,Chang, Mayland,Mobashery, Shahriar
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Read Online
- Pd-Catalyzed Carbonylative Synthesis of 4H-Benzo[d][1,3]Oxazin-4-Ones Using Benzene-1,3,5-Triyl Triformate as the CO Source
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A facile synthesis of 4H-benzo[d][1,3]oxazin-4-one derivatives by Pd-catalyzed carbonylative cross-coupling between N-(ortho-bromoaryl)amides and benzene-1,3,5-triyl triformate (TFBen) was developed. This procedure does not require the toxic and flammable gas CO as the carbonyl source and tolerates a wide scope of functional groups. Remarkably, 4H-benzo[d][1,3]oxazin-4-ones incorporated to natural products and drugs can be constructed by this method.
- Zheng, Yan,Dong, Mengke,Qu, Erdong,Bai, Jin,Wu, Xiao-Feng,Li, Wanfang
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p. 16219 - 16224
(2021/10/06)
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- Recyclable palladium-catalyzed carbonylative annulation of 2-iodoanilines with acid anhydrides: A practical synthesis of 2-alkylbenzoxazinones
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A highly efficient heterogeneous palladium-catalyzed carbonylative annulation of 2-iodoanilines and acid anhydrides has been developed. The reaction proceeds effectively in toluene using N,N-diisopropylethylamine (DiPEA) as the base at 100 °C under 2 bar of CO and provides a novel, general, and practical method for the assembly of a wide variety of 2-alkylbenzoxazinones with high functional group tolerance and good to excellent yields. This supported palladium complex can be readily separated from the product and recovered by a simple filtration of the reaction solution and reused up to seven times with almost consistent catalytic efficiency.
- Zhou, Zebiao,Huang, Bin,Cai, Mingzhong
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p. 3150 - 3163
(2021/08/30)
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- Novel quinolinone–pyrazoline hybrids: synthesis and evaluation of antioxidant and lipoxygenase inhibitory activity
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Abstract: The present project deals with the investigation of structure–activity relationship of several quinolinone–chalcone and quinolinone–pyrazoline hybrids, in an effort to discover promising antioxidant and anti-inflammatory agents. In order to accomplish this goal, four bioactive hybrid quinolinone–chalcone compounds (8a–8d) were synthesized via an aldol condensation reaction, which were then chemically modified, forming fifteen new pyrazoline analogues (9a–9o). All the synthesized analogues were in vitro evaluated in terms of their antioxidant and soybean lipoxygenase (LOX) inhibitory activity. Among all the pyrazoline derivatives, compounds 9b and 9m were found to possess the best combined activity, whereas 9b analogue exhibited the most potent LOX inhibitory activity, with IC50 value 10?μM. The in silico docking results revealed that the synthetic pyrazoline analogue 9b showed high AutoDock Vina score (? 10.3?kcal/mol), while all the tested derivatives presented allosteric interactions with the enzyme. Graphic Abstract: [Figure not available: see fulltext.]
- Kostopoulou, Ioanna,Diassakou, Antonia,Kavetsou, Eleni,Kritsi, Eftichia,Zoumpoulakis, Panagiotis,Pontiki, Eleni,Hadjipavlou-Litina, Dimitra,Detsi, Anastasia
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p. 723 - 740
(2020/02/25)
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- Design, Synthesis, and Structure-Activity Relationship of Quinazolinone Derivatives as Potential Fungicides
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Plant diseases caused by phytopathogenic fungi reduce the yield and quality of crops. To develop novel antifungal agents, we designed and synthesized eight series of quinazolinone derivatives and evaluated their anti-phytopathogenic fungal activity. The bioassay results revealed that compounds KZL-15, KZL-22, 5b, 6b, 6c, 8e, and 8f exhibited remarkable antifungal activity in vitro. Especially, compound 6c displayed the highest bioactivity against Sclerotinia sclerotiorum, Pellicularia sasakii, Fusarium graminearum, and Fusarium oxysporum, displaying appreciable IC50 values (50% inhibitory concentration) of 2.46, 2.94, 6.03, and 11.9 μg/mL, respectively. A further mechanism interrogation revealed abnormal mycelia, damaged organelles, and changed permeability of cell membranes in S. sclerotiorum treated with compound 6c. In addition, the in vivo bioassay indicated that compound 6c possessed comparable curative and protective effects (87.3 and 90.7%, respectively) to the positive control azoxystrobin (89.5 and 91.2%, respectively) at 100 μg/mL concentration against S. sclerotiorum. This work validated the potential of compound 6c as a new and promising fungicide candidate, contributing to the exploration of potent antifungal agents.
- Peng, Jing-Wen,Yin, Xiao-Dan,Li, Hu,Ma, Kun-Yuan,Zhang, Zhi-Jun,Zhou, Rui,Wang, Yu-Ling,Hu, Guan-Fang,Liu, Ying-Qian
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p. 4604 - 4614
(2021/05/06)
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- Cytotoxicity and Antibacterial Evaluation of O-Alkylated/Acylated Quinazolin-4-one Schiff Bases
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A series of quinazolin-4-one Schiff bases were synthesized and tested in vitro for their cytotoxicity against two cancerous cell lines (MCF-7, Caco-2) and a human embryonic cell line (HEK-293) including their antibacterial evaluation against two Gram-positive and four Gram-negative bacterial strains. Most of the quinazoline-Schiff bases exhibited potent cytotoxicity against Caco-2. 3-[(Z)-({4-[(But-2-yn-1-yl)oxy]phenyl}methylidene)amino]-2-methylquinazolin-4(3H)-one (6f) with the O-butyne functional group displayed three-fold higher cytotoxic activity (IC50=376.8 μM) as compared to 5-fluorouracil (5-FU; IC50=1086.1 μM). However, all compounds were found to be toxic to HEK-293, except for 3-[(Z)-({4-[(2,4-difluorophenyl)methoxy]phenyl}methylidene)amino]-2-methylquinazolin-4(3H)-one (6h) that showed ~three-fold lower toxicity and higher selectivity index than 5-FU. Structure–activity relationship (SAR) analysis revealed that O-alkylation generally increased the anticancer activity and selectivity of quinazoline-4-one Schiff bases toward Caco-2 cells. The fluorinated Schiff-base generally exhibited even more significant cytotoxic activity compared to their chlorine analogs. Surprisingly, none of the quinazoline-4-one Schiff bases displayed encouraging antibacterial activity against the bacterial strains investigated. Most of the compounds were predicted to show compliance with the Lipinski parameters and ADMET profiles, indicating their drug-like properties.
- Manhas, Neha,Singh, Parvesh,Mocktar, Chunderika,Singh, Moganavelli,Koorbanally, Neil
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- Recyclable Heterogeneous Palladium-Catalyzed Cyclocarbonylation of 2-Iodoanilines with Acyl Chlorides in the Biomass-Derived Solvent 2-Methyltetrahydrofuran
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A highly efficient, green palladium-catalyzed cyclocarbonylation of 2-iodoanilines with acyl chlorides has been developed that proceeds smoothly in a biomass-derived solvent 2-methyltetrahydrofuran with N,N-diisopropylethylamine as base at 100 °C under 20 bar of carbon monoxide using an 2-aminoethylamino-modified MCM-41-anchored palladium acetate complex [2N-MCM-41-Pd(OAc)2] as a heterogeneous catalyst, yielding a wide variety of 2-substituted 4H-3,1-benzoxazin-4-one derivatives in good to excellent yields. This supported palladium catalyst could be facilely obtained by a two-step procedure from easily available starting materials and readily recovered via a simple filtration process and recycled at least 8 times without any apparent decrease in catalytic efficiency. The developed methodology not only avoids the use of toxic solvents such as tetrahydrofuran and dimethylformamide but also solves the basic problem of expensive palladium catalyst recovery and reuse and prevents effectively palladium contamination of the desired product.
- Hao, Wenyan,Xu, Zhaotao,Zhou, Zebiao,Cai, Mingzhong
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p. 8522 - 8532
(2020/07/16)
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- Activity-directed expansion of a series of antibacterial agents
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The feasibility of using activity-directed synthesis to drive antibacterial discovery was investigated. An array of 220 Pd-catalysed microscale reactions was executed, and the crude product mixtures were evaluated for activity against Staphylococcus aureus. Scale-up of the hit reactions, purification and evaluation, enabled expansion of a class of antibacterial quinazolinones. The novel antibacterials had MICs from 0.016 μg mL-1 (i.e. 38 nM) to 2-4 μg mL-1 against S. aureus ATCC29213. This journal is
- Chow, Shiao,Clarke, Justin E.,Leggott, Abbie,Nelson, Adam,O'Neill, Alex J.,Warriner, Stuart L.
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supporting information
p. 8047 - 8050
(2020/08/03)
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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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- 4H-Benzo[d][1,3]oxazin-4-ones and Dihydro analogs from substituted anthranilic acids and orthoesters
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A one-pot route to 2-alkyl and 2-aryl-4H-benzo[d][1,3]oxazin-4-ones (also known as 4H-3,1-benzoxazin-4-ones) has been developed and studied. The method involves the reaction of aryl-substitutedanthranilic acidswithorthoesters inethanol catalyzedby acetic acid. Additionally,wehave also investigated the reaction under microwave conditions. Not all of the substrates were successful in yielding the target heterocycles as some of the reactions failed to undergo the final elimination. This process led to the isolation of (±)-2-alkyl/aryl-2-ethoxy-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-ones. The formation of the dihydro analogs correlated with the electron density on the aromatic ring: Electron-donating groups favored the 4H- benzo[d][1,3]oxazin-4-ones, while electron-withdrawing groups tended to favor the dihydro product. Substituting a pyridine ring for the benzene ring in the substrate acid suppressed the reaction.
- Annor-Gyamfi, Joel K.,Bunce, Richard A.
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- Design, synthesis, in-silico studies and biological screening of quinazolinone analogues as potential antibacterial agents against MRSA
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Type or The emergence of resistance to antibiotic has developed a complicated situation in the treatment of bacterial infections. Considering the antimicrobial resistance phenomenon as one of the greatest challenge of medicinal chemists for search of better anti-bacterial agents, which have potential narrow spectrum activity with low development of resistance potential and low toxicity to host. Cross-linking of peptidoglycan is a key step catalyze by Penicillin binding protein (PBP) to maintain integrity of cell wall in bacterial cell. However, these Penicillin binding protein (PBP) has developed resistance in methicillin-resistant Staphylococcus aureus (MRSA) due to acquisition of additional PBP2a. Various Quinazolinone analogues are reported in literature as potential anti-bacterial agents against MRSA. In present study new quinazolinone analogues has been designed, guided by molecular docking, In-silico and MM-GBSA study. Newly designed molecules have been synthesized by medicinal chemistry route and their characterization was done by using IR, NMR, & HR-MS techniques. Biological evaluation of synthesized compounds has been done on wild type Gram-negative (Escherichia coli), Gram-positive (Staphylococcus aureus) and resistant MRSA bacterial strains using Streptomycin, Kanamycin and Linezolid as standard drugs respectively. The in vitro evaluation results have shown that compound 5f is active with MIC value 15.625 μg/mL against S. aureus and with MIC value 31.25 μg/mL against MRSA.
- Qureshi, Shahnawaz I.,Chaudhari, Hemchandra K.
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supporting information
p. 2676 - 2688
(2019/05/17)
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- 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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p. 404 - 410
(2019/03/28)
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- Synthesis, Characterization, and Biological Evaluation of Novel 3-(4-Chlorophenyl)-2-(substituted)quinazolin-4(3H)-one Derivatives as Multi-target Anti-inflammatory Agents
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A novel class of 3-(4-chlorophenyl)-2-(substituted)quinazolin-4(3H)-one derivatives were synthesized, and the structure of synthesized compounds was characterized by IR, 1H NMR, and mass spectroscopy. The newly synthesized compounds (4a–g and 6a–g) were tested for their in vitro cyclooxygenase (COX) inhibition activity. The compounds have inhibitory profile against both COX-1 and COX-2, and some of the compounds are found to be selective against COX-2. The compound 6g showed distinct inhibitory activity on COXs. The synthesized compounds were evaluated for their potential anti-inflammatory activity as inhibitors of the proinflammatory cytokines IL-6. Compounds 4d–g showed the highest level of inhibition among all the tested compounds. Thus, our data suggested that these compounds may represent a new class of potent anti-inflammatory agents.
- Raghu,Pradeep Kumar,Yogesh Kumar,Prashanth,Jayanna
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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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- Synthesis and evaluation of new quinazolin-4(3H)-one derivatives as potent antibacterial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis
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Staphylococcus aureus and Mycobacterium tuberculosis are major causative agents responsible for serious nosocomial and community-acquired infections impacting healthcare systems globally. Over several decades, these pathogens have developed resistance to multiple antibiotics significantly affecting morbidity and mortality. Thus, these recalcitrant pathogens are amongst the most formidable microbial pathogens for which international healthcare agencies have mandated active identification and development of new antibacterial agents for chemotherapeutic intervention. In our present work, a series of new quinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP pathogens and pathogenic mycobacteria. The experiments revealed that 4'c, 4'e, 4'f and 4'h displayed selective and potent inhibitory activity against Staphylococcus aureus with MIC values ranging from 0.03-0.25 μg/mL. Furthermore, compounds 4'c and 4'e were found to be benign to Vero cells (CC50 = >5 μg/mL) and displayed promising selectivity index (SI) > 167 and > 83.4 respectively. Additionally, 4'c and 4'e demonstrated equipotent MIC against multiple drug-resistant strains of S. aureus including VRSA, concentration dependent bactericidal activity against S. aureus and synergized with FDA approved drugs. Moreover, compound 4′c exhibited more potent activity in reducing the biofilm and exhibited a PAE of ~2 h at 10X MIC which is comparable to levofloxacin and vancomycin. In vivo efficacy of 4'c in murine neutropenic thigh infection model revealed that 4'c caused a similar reduction in cfu as vancomycin. Gratifyingly, compounds 4d, 4e, 9a, 9b, 14a, 4'e and 4'f also exhibited anti-mycobacterial activity with MIC values in the range of 2-16 μg/mL. In addition, the compounds were found to be less toxic to Vero cells (CC50 = 12.5->100 μg/mL), thus displaying a favourable selectivity index. The interesting results obtained here suggest the potential utilization of these new quinazolin-4(3H)-one derivatives as promising antibacterial agents for treating MDR-Staphylococcal and mycobacterial infections.
- Gatadi, Srikanth,Gour, Jitendra,Shukla, Manjulika,Kaul, Grace,Dasgupta, Arunava,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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p. 287 - 308
(2019/05/15)
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- Synthesis and evaluation of anticancer, antiphospholipases, antiproteases, and antimetabolic syndrome activities of some 3H-quinazolin-4-one derivatives
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Some new 3H-quinazolin-4-one derivatives were synthesised and screened for anticancer, antiphospholipases, antiproteases, and antimetabolic syndrome activities. Compound 15d was more potent in reducing the cell viabilities of HT-29 and SW620 cells lines to 38%, 36.7%, compared to 5-FU which demonstrated cell viabilities of 65.9 and 42.7% respectively. The IC50 values of 15d were ~20?μg/ml. Assessment of apoptotic activity revealed that 15d decreased the cell viability by down regulating Bcl2 and BclxL. Moreover, compounds, 8j, 8d/15a/15e, 5b, and 8f displayed lowered IC50 values than oleanolic acid against proinflammatory isoforms of hGV, hG-X, NmPLA2, and AmPLA2. In addition, 8d, 8h, 8j, 15a, 15b, 15e, and 15f showed better anti-α-amylase than quercetin, whereas 8g, 8h, and 8i showed higher anti-α-glucosidase activity than allopurinol. Thus, these compounds can be considered as potential antidiabetic agents. Finally, none of the compounds showed higher antiproteases or xanthine oxidase activities than the used reference drugs.
- El-Sayed, Nahed N. E.,Almaneai, Norah M.,Ben Bacha, Abir,Al-Obeed, Omar,Ahmad, Rehan,Abdulla, Maha,Alafeefy, Ahmed M.
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p. 672 - 683
(2019/04/02)
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- Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
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The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC50 values, 0.10–0.16 μm) were found to be approximately 30-fold more cytotoxic than SAHA (IC50 values of 3.29–3.67 μm). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC50 values of 0.21–0.38 μm) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.
- Hieu, Doan Thanh,Anh, Duong Tien,Hai, Pham-The,Thuan, Nguyen Thi,Huong, Le-Thi-Thu,Park, Eun Jae,Young Ji,Soon Kang, Jong,Phuong Dung, Phan Thi,Han, Sang-Bae,Nam, Nguyen-Hai
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- Novel N-Hydroxybenzamides or N-Hydroxypropenamides Incorporating Quinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Anticancer Composition Comprising the Same
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The present invention relates to novel N-hydroxy benzamides or N-hydroxy propenamides based on quinazoline-4(3H)-ones as histone deacetylase (HDAC) inhibitors and a use thereof. More specifically, a compound according to the present invention has a strong HDAC inhibitory activity, thereby being able to be used as proliferation inhibitors for various cancer cells. Therefore, the compound according to the invention is expected to be able to be developed as an active component of strong anti-cancer drugs.COPYRIGHT KIPO 2019
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Paragraph 0155; 0156
(2019/05/15)
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- Quinazolinone compounds and application in preparing drug for preventing agricultural plant diseases
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The invention discloses application of quinazolinone compounds KZL-01-KZL-34 in preventing or resisting agricultural plant fungal diseases. Antimicrobial activity testing results show that the compounds have inhibition activity on the plant fungal diseases caused by sclerotinia sclerotiorum, rhizoctonia solani, fusarium graminearum Sehw. and botrytis cinerea, and especially have higher inhibitionactivity on the rhizoctonia solani, the inhibition activity of part of the compounds on the germs is higher than that of azoxystrobin, and the quinazolinone compounds can be used as lead compounds ofan agricultural fungicide to be developed.
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Paragraph 0020; 0023
(2019/11/25)
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- Novel Hydroxamic Acid Incorporating Quinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Anticancer Composition Comprising the Same
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The compound according HDAC(histone deacetylase) to the present -4(3H)- won invention can, be used as an active. ingredient of, a potent anticancer agent, HDAC since the compound according, to the present invention can be used. as, an active ingredient of a potent anticancer agent, since the compound. according to the present invention can be used as an active ingredient of a potent anticancer agent. (by machine translation)
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Paragraph 0103; 0144-0145
(2020/03/03)
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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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- Synthesis, photochemical and luminescent properties of ortho-hydroxystyrylquinazolinone-linked benzocrown ethers
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Photoinduced transformations of (E)-2-(2-hydroxystyryl)quinazolinone-linked benzo[15(18)]crown-5(6) ethers in solutions have been studied by using UV–vis absorption and NMR spectroscopy. These crown ethers were found to have dual emission at 520 and 650 nm, associated with proton-transfer tautomer emission (ESIPT-luminescence) as a rare case of excited-state proton-transfer reaction in the non-pseudocyclic chromophoric systems. It was established also, that the organic bases affect the luminescence intensity of solutions of these compounds in the 550–650-nm wavelength range. An X-ray crystallography analysis of molecular structures of crown ethers and their complexes in crystals has been carried out. The fact of reversible photo/thermal E-Z isomerization in DMF and Et3N for these macroheterocyclic compounds has been confirmed. An opportunity to control the photochemical isomerization rate of quinazolinone 2-(hydroxyphenyl)ethenyl derivatives by changing pH of the medium has been demonstrated.
- Ovchinnikova, Irina G.,Kim, Grigory A.,Matochkina, Eugene G.,Kodess, Mikhail I.,Slepukhin, Pavel A.,Kovalev, Igor S.,Nosova, Emilia V.,Rusinov, Gennady L.,Charushin, Valery N.
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- Electron-Transfer-Induced Intramolecular Heck Carbonylation Reactions Leading to Benzolactones and Benzolactams
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A metal-catalyst-free intramolecular Heck carbonylation reaction of benzyl alcohols and benzyl amines with carbon monoxide under heating at 250 °C affords the corresponding benzolactones and benzolactams in good to excellent yields. A hybrid radical/ionic chain mechanism, involving electron transfer from radical anions generated by nucleophilic attack of alcohols or amines on intermediate acyl radicals, is proposed.
- Fukuyama, Takahide,Bando, Takanobu,Ryu, Ilhyong
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supporting information
p. 3015 - 3021
(2018/06/08)
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- Conjugate addition from the excited state
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Conjugate addition occurs efficiently from excited hydrazide based acrylanilides under both UV and metal free visible light irradiations. The reaction proceeds via an excited state encounter complex that bifurcates either via an electron or energy transfer pathway. The generality of excited state conjugate addition is demonstrated using chloromethylation and by thiol addition.
- Iyer, Akila,Ahuja, Sapna,Jockusch, Steffen,Ugrinov, Angel,Sivaguru, Jayaraman
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supporting information
p. 11021 - 11024
(2018/10/08)
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- Benzoxazin-4-ones as novel, easily accessible inhibitors for rhomboid proteases
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Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms.
- Yang, Jian,Barniol-Xicota, Marta,Nguyen, Minh T.N.,Ticha, Anezka,Strisovsky, Kvido,Verhelst, Steven H.L.
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supporting information
p. 1423 - 1427
(2018/03/06)
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- Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors
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Rhomboids are intramembrane serine proteases with diverse physiological functions in organisms ranging from archaea to humans. Crystal structure analysis has provided a detailed understanding of the catalytic mechanism, and rhomboids have been implicated in various disease contexts. Unfortunately, the design of specific rhomboid inhibitors has lagged behind, and previously described small molecule inhibitors displayed insufficient potency and/or selectivity. Using a computer-aided approach, we focused on the discovery of novel scaffolds with reduced liabilities and the possibility for broad structural variations. Docking studies with the E. coli rhomboid GlpG indicated that 2-styryl substituted benzoxazinones might comprise novel rhomboid inhibitors. Protease in vitro assays confirmed activity of 2-styryl substituted benzoxazinones against GlpG but not against the soluble serine protease α-chymotrypsin. Furthermore, mass spectrometry analysis demonstrated covalent modification of the catalytic residue Ser201, corroborating the predicted mechanism of inhibition and the formation of an acyl enzyme intermediate. In conclusion, 2-styryl substituted benzoxazinones are a novel rhomboid inhibitor scaffold with ample opportunity for optimization.
- Goel, Parul,Jumpertz, Thorsten,Tichá, Ane?ka,Ogorek, Isabella,Mikles, David C.,Hubalek, Martin,Pietrzik, Claus U.,Strisovsky, Kvido,Schmidt, Boris,Weggen, Sascha
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supporting information
p. 1417 - 1422
(2018/02/21)
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- Design, graph theoretical analysis, density functionality theories, Insilico modeling, synthesis, characterization and biological activities of novel thiazole fused quinazolinone derivatives
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(Table presented.). A series of 2-(2-substituted benzylidenehydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolo din-3-yl]phenyl)quinazolin-4(3H)-one 7a-7l were synthesized and characterized by IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analyses. In this present study, the density functionality theory was performed to identify drug stability. Further we introduced graph theoretical analysis by utilised Kyoto Encyclopedia of Genes and Genomes (KEGG) database and Cytoscape software to identify drug target. Based on the observed drug target insilico modeling was executed to know effective drug. The antiepileptic effects of title compounds were evaluated by using MES and subcutaneous pentylenetetrazole (scPTZ) test. Acute neurological toxicity of title compounds was studied by using standardized rotorod test. After 0.5 hr of period many of the compounds showed anticonvulsant activity at MES or scPTZ test. Comparison of the biological activity of test compounds with its chemical structures indicates that, compounds possessing electron donating group exhibited superior activity than the analogs having electron withdrawing moieties. Among the electron donating group tested, amino derivative exhibited good activity than rest of derivatives. From the study it was concluded that, the compound 7j was established as very potent compared with rest of the compounds and standard drugs subjected to biological studies. Thus the compound 2-(2-[4-aminobenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl) quinazolin-4(3H)-one (7j) came out as pilot derivative without any neurotoxicity with a wide spectrum of antiepileptic activity. Highlights: The performed work is having great significance in terms of Graph theoretical analysis used to identify drug target In silico modeling used to identify designed drug interaction with identify target Density functionality studies used to identify synthesized compound energy band gap which is correlate with enhancement of its biological activity Antiepileptic effects of entire synthesized quinazolinone scaffolds were evaluated by MES and scPTZ test 2-(2-[4-aminobenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl) quinazolin-4(3H)-one (7j) was established as very potent compared to the rest of the compounds and standard drugs which were subjected to biological studies.
- Saravanan, Govindaraj,Panneerselvam, Theivendren,Alagarsamy, Veerachamy,Kunjiappan, Selvaraj,Parasuraman, Pavadai,Murugan, Indhumathy,Dinesh Kumar, Pandurangan
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p. 260 - 274
(2018/09/27)
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- Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial agents effective against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA)
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Occurrence of infections due to the drug resistant Staphylococcus aureus is on rise necessitating the need for rapid development of new antibacterial agents. In our present work, a series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A. baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125–8 μg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC50 = >10–>100 μg/mL) and exhibited favourable selectivity index (SI = 40–>200). The compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus including VRSA. The promising results obtained indicated the potential use of the above series of compounds as promising antibacterial agents for the treatment of multidrug resistant Staphylococcus aureus infections.
- Gatadi, Srikanth,Gour, Jitendra,Kaul, Grace,Shukla, Manjulika,Dasgupta, Arunava,Akunuri, Ravikumar,Tripathi, Richa,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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p. 175 - 183
(2018/08/23)
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- Synthesis of 1,2,3-triazole linked 4(3H)-Quinazolinones as potent antibacterial agents against multidrug-resistant Staphylococcus aureus
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Methicillin and vancomycin resistant Staphylococcus aureus infections are an emerging global health concern leading to increasing morbidity and mortality. Continuous increase in drug resistance has underlined the need for discovery and development of new antibacterial agents acting via novel mechanisms to overcome this pressing issue. In this context, a number of 1,2,3-triazole linked 4(3H)-quinazolinone derivatives were designed and synthesized as potent antibacterial agents. When evaluated against ESKAP pathogen panel, compounds 7a, 7b, 7c, 7e, 7f, 7g, 7h, 7i, 9a, 9c, 9d and 9e exhibited significantly selective inhibitory activities towards Staphylococcus aureus (MIC = 0.5–4 μg/mL). To understand and confirm the specificity of these compounds, the compounds 7a and 9a were tested against E. coli and A. baumannii in combination with sub-lethal concentrations of Polymyxin B nonapeptide (PMBN) and were found to be inactive. This clearly indicated that these compounds possess specific and potent activity towards S. aureus and are inactive against gram-negative pathogens. Encouragingly, the compounds were also found to be non toxic to Vero cells and displayed favourable selectivity index (SI = 40 to 80). Furthermore, 7a and 9a were found to possess potent inhibitory activity when tested against multidrug resistant S. aureus including strains resistant to vancomycin (MIC values 0.5–32 μg/mL), indicating that the compounds are able to escape current drug-resistance mechanisms. With the potent anti-bacterial activity exhibited the new series of 1,2,3-triazole linked 4(3H)-quinazolinones have emerged as promising candidates for treating multidrug resistant Staphylococcus aureus infections.
- Gatadi, Srikanth,Gour, Jitendra,Shukla, Manjulika,Kaul, Grace,Das, Swetarka,Dasgupta, Arunava,Malasala, Satyaveni,Borra, Ramya Sri,Madhavi,Chopra, Sidharth,Nanduri, Srinivas
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p. 1056 - 1067
(2018/10/16)
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- Styryl quinazolinones as potential inducers of myeloid differentiation via upregulation of C/EBPα
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The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure–activity relationship (SAR) of these small molecules in inducing C/EBPα expression—thereby prompting the leukemic cells to differentiate. We observed that compound 78 causes differentiation at 3 μM concentration, while 1 induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with 78. Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with 78. These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML.
- Sridhar, Radhakrishnan,Takei, Hisashi,Syed, Riyaz,Kobayashi, Ikei S.,Hui, Liu Bee,Kamal, Ahmed,Tenen, Daniel G.,Kobayashi, Susumu S.
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- Oxidative Recyclization of 1H-Indoles for Synthesis of 2-Indolylbenzoxazinones via Cleavage of the C2-C3 Bond with AIBN under Air
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A novel and concise method for the oxidation of unprotected indole derivatives to synthesize 2-indolylbenzoxazinones in the presence of AIBN under open air has been successfully demonstrated. This metal-free reaction is both atom- and step-efficient and is applicable to a broad scope of substrates. This new methodology provides a facile pathway for oxidative C2-C3 bond cleavage and recyclization of 1H-indoles.
- Liu, Xing-Xing,Luo, Xin-Liang,Wu, Zhao-Yang,Cui, Xin-Feng,Zhou, Xiao-Qiang,He, Yong-Qin,Huang, Guo-Sheng
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p. 2107 - 2113
(2017/02/26)
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- Diversity of Secondary Structure in Catalytic Peptides with β-Turn-Biased Sequences
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X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical β-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3J-values, and 1H-1H-NOESY contacts. hese findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. These findings implicate the advantages of low-barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions.
- Metrano, Anthony J.,Abascal, Nadia C.,Mercado, Brandon Q.,Paulson, Eric K.,Hurtley, Anna E.,Miller, Scott J.
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supporting information
p. 492 - 516
(2017/02/23)
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- Synthesis and Evaluation of Novel [1,2,4]Triazolo[1,5-c]quinazoline Derivatives as Antibacterial Agents
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A series of new 2-aryl-5-methyl-[1,2,4]triazolo[1,5-c]quinazoline derivatives (5a–5g) have been synthesized by the reaction of 3-amino-2-methylquinazolin-4-(3H)-one (3) with aromatic nitriles in potassium tert-butoxide under reflux conditions. 3-Amino-2-methylquinazolin-4-(3H)-one (3) was synthesized by the reaction 2-methyl-4H-benzo[d][1,3]oxazin-4-one (2) with hydrazine hydrate. The chemical structure of products was confirmed by IR, 1H, 13C NMR and elemental analysis. These compounds were screened for antibacterial [Staphylococcus aureus (ATCC 25923), Bacillus cereus (ATCC 11778), Micrococcus luteus (ATCC 9341), Escherichia coli (ATCC 25922), and Pseudomonas aeruginosa (ATCC 27853)] activities, using the zone inhibition method.
- Zeydi, Masoud Mohammadi,Montazeri, Naser,Fouladi, Mahdi
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p. 3549 - 3553
(2017/11/21)
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- Expeditious synthesis and spectroscopic characterization of 2-methyl-3-substituted-quinazolin-4(3H)-one derivatives
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Quinazoline and quinazolinone derivatives are well-known bioactive heterocycles owing to their therapeutic diversity and extensive medicinal application in drug design and pharmaceutics. A series of 2-methyl-3-substituted quinazolin-4(3H)-one derivatives 8a-q was herein synthesized from synthetic conversion of anthranilic acid to 2-methyl-4H-3,1-benzoxazi-4-one, 7 which was subsequently transformed to the targeted 2,3-disubstituted quinazolin-4(3H)-one derivatives 8a-q by reacting with some notable amino-containing moieties via an ameliorable pathway. The catalyst-free synthesis was successful achieved by careful reaction optimization study using solvent choice and reaction temperature variability as key parameters. The chemical structures of the synthesized compounds were confirmed by IR, UV, 1H-NMR, 13C-NMR and DEPT-135 as well as analytical data.
- Ajani, Olayinka O.,Audu, Oluwatosin Y.,Germann, Markus W.,Bello, Babatunde L.
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p. 562 - 574
(2017/05/26)
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- Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of quinazolin-4(3H)-one derivatives as potential PPARγ and SUR agonists
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Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a, 19d, 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40.43, 46.42, 41.23 and 42.50 %, respectively. The most active ten compounds were further evaluated in vitro for their PPARγ binding affinities and insulin-secreting abilities. Compounds 19b, 19d, 19f, 25f and 25g exhibited the highest affinities against PPARγ with IC50 values of 0.371, 0.350, 0.369, 0.408 and 0.353 μM, respectively. In addition, compounds 19d, 19f, and 25d showed the highest insulin-secreting activities with EC50 values of 0.97, 1.01 and 1.15 μM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARγ and SUR, respectively. Also, two QSAR models were generated to explore the structural requirements controlling the different biological activities of the synthesized compounds against PPARγ and SUR.
- Ibrahim, Mohamed K.,Eissa, Ibrahim H.,Alesawy, Mohamed S.,Metwaly, Ahmed M.,Radwan, Mohamed M.,ElSohly, Mahmoud A.
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p. 4723 - 4744
(2017/10/05)
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- Visible Light Photocatalytic Aerobic Oxygenation of Indoles and pH as a Chemoselective Switch
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An efficient chemodivergent strategy for visible light photocatalysis is developed. In the presence of a dicyanopyrazine-derived chromophore (DPZ) photocatalyst, aerobic photooxygenation of indoles could produce either isatins or formylformanilides in satisfactory yields by judiciously selecting inorganic salts or modulating the reaction pH. The current chemodivergent method is also effective with 2-substituted indoles, opening straightforward synthetic routes to valuable 2,2-disubstituted 3-oxindoles, formylformanilide derivatives, and benzoxazinones. Mechanistic investigations involving cyclic voltammetry studies further confirm that reaction pH influences the electrochemical properties of DPZ, thus affecting the oxidative pathway by which indoles are being transformed.
- Zhang, Chenhao,Li, Sanliang,Bure?, Filip,Lee, Richmond,Ye, Xinyi,Jiang, Zhiyong
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p. 6853 - 6860
(2016/10/18)
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- Selective Oxidative Decarbonylative Cleavage of Unstrained C(sp3)-C(sp2) Bond: Synthesis of Substituted Benzoxazinones
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A transition metal (TM)-free practical synthesis of biologically relevant benzoxazinones has been established via a selective oxidative decarbonylative cleavage of an unstrained C(sp3)-C(sp2) bond employing iodine, sodium bicarbonate, and tbutyl hydroperoxide in DMSO at 95 °C. Control experiments and Density Functional Theory (DFT) calculations suggest that the reaction involves a [1,5]H shift and extrusion of CO gas as the key steps. The extrusion of CO has also been established using PMA-PdCl2.
- Verma, Ajay,Kumar, Sangit
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supporting information
p. 4388 - 4391
(2016/10/11)
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- Catalytic aza-wittig reaction of acid anhydride for the synthesis of 4H-benzo[d][1,3]oxazin-4-ones and 4-benzylidene-2-aryloxazol-5(4H)-ones
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Compared to the aza-Wittig reaction of aldehydes, ketones, amides, and esters, the aza-Wittig reaction of acid anhydride was always overlooked, which should be an important part of Wittig reactions. Here, the aza-Wittig reaction of anhydride and catalytic aza-Wittig reaction of anhydride were both developed with high yields, which provides an efficient method to synthesize of 4H-benzo[d][1,3]oxazin-4-ones and 4-benzylidene-2-aryloxazol-5(4H)-ones. The strategy of copper-catalyzed reduction of phosphine oxide was used and found effective for this transformation. Additionally, the one-pot catalytic aza-Wittig reaction of carboxylic acids was achieved. Furthermore, NMR experiments and Hammett plot recorded the process of catalytic aza-Wittig reaction of anhydride, which provides direct proof that the copper-catalyzed reduction of waste phosphine oxide is the key step in this transformation.
- Wang, Long,Xie, Yi-Bi,Huang, Nian-Yu,Yan, Jia-Ying,Hu, Wei-Min,Liu, Ming-Guo,Ding, Ming-Wu
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p. 4010 - 4016
(2016/07/06)
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- 2-Amino[1,2,4]triazolo[1,5-c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure–Activity Relationships of Potent Adenosine Receptor Antagonists
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2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A3AR antagonists were discovered, including 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17, Kihuman A3AR 1.16 nm) and 5′-phenyl-1,2-dihydro-3′H-spiro[indole-3,2′-[1,2,4]triazolo[1,5-c]quinazolin]-2-one (20, Kihuman A3AR 6.94 nm). In addition, multitarget antagonists were obtained, such as the dual A1/A3antagonist 2,5-diphenyl[1,2,4]triazolo[1,5-c]quinazoline (13 b, Kihuman A1AR 51.6 nm, human A3AR 11.1 nm), and the balanced pan-AR antagonists 5-(2-thienyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 c, Kihuman A1AR 131 nm, A2AAR 32.7 nm, A2BAR 150 nm, A3AR 47.5 nm) and 9-bromo-5-phenyl[1,2,4]triazolo[1,5-c]quinazolin-2-amine (11 q, Kihuman A1AR 67.7 nm, A2AAR 13.6 nm, A2BAR 75.0 nm, A3AR 703 nm). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species.
- Burbiel, Joachim C.,Ghattas, Wadih,Küppers, Petra,K?se, Meryem,Lacher, Svenja,Herzner, Anna-Maria,Kombu, Rajan Subramanian,Akkinepally, Raghuram Rao,Hockemeyer, J?rg,Müller, Christa E.
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p. 2272 - 2286
(2016/10/25)
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- Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials
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We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity against Staphylococcus aureus. The first structure-activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability and shows efficacy in a mouse neutropenic thigh infection model.
- Bouley, Renee,Ding, Derong,Peng, Zhihong,Bastian, Maria,Lastochkin, Elena,Song, Wei,Suckow, Mark A.,Schroeder, Valerie A.,Wolter, William R.,Mobashery, Shahriar,Chang, Mayland
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p. 5011 - 5021
(2016/06/13)
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- Design, synthesis and in vivo screening of some novel quinazoline analogs as anti-hyperlipidemic and hypoglycemic agents
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A novel series of substituted quinazoline derivatives were designed, synthesized and evaluated for their hypolipidemic activity in cholesterol induced hyperlipidemic rats. In vivo screening concluded that compounds A-4, C-5 and C-6 have shown potent antihyperlipidemic activity by decreasing the plasma level of triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), followed by increase in level of high density lipoprotein (HDL).
- Mokale, Santosh N.,Palkar, Akash D.,Dube, Pritam N.,Sakle, Nikhil S.,Miniyar, Pankaj B.
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supporting information
p. 272 - 276
(2016/01/09)
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- Synthesis and biological evaluation of quinazolin-4(3 H)-one derivatives bearing dithiocarbamate side chain at C2-position as potential antitumor agents
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A series of quinazolin-4(3H)-one derivatives bearing dithiocarbamate side chain at the C2-position were synthesized and evaluated for their antiproliferative activities against A549, MCF-7, HeLa, HT29 and HCT-116 cell lines. Most of the synthesized compounds exhibited broad spectrum antitproliferative activity against five cell lines, of which 5c was the most potent against HT29 cell line with an IC50 value of 5.53 μM, inducing a G2/M phase arrest in HT29 cells. Treatment of HT29 cells with 5c resulted in BubR1 phosphorylation and an increase of mitotic index in a time-dependent manner. Furthermore, 5c promoted tubulin polymerization in vitro. These results demonstrate that quinazolin-4(3H)-one derivatives bearing dithiocarbamate side chain at C2-position may be potentially novel antitumor agents targeting tubulin to activate the spindle assembly checkpoint.
- Ding, Pan-Pan,Gao, Man,Mao, Bei-Bei,Cao, Sheng-Li,Liu, Cui-Huan,Yang, Chao-Rui,Li, Zhong-Feng,Liao, Ji,Zhao, Hongchang,Li, Zheng,Li, Jing,Wang, Hailong,Xu, Xingzhi
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p. 364 - 373
(2016/01/20)
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- Synthesis and antibacterial activity of 6-amino-2-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-3,4-dihydroquinazolin-4-one and its intermediate compounds
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6-Amino-2-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-3,4-dihydroquinazolin-4-one was synthesized in four steps. The synthesized product from each step was purified by washing and recrystallization. Purity testing was performed by examining the melting range and by thin layer chromatography. The molecular mass of the synthesized compound was determined using LC-MS. Structure of synthesized compound was elucidated using UV-visible, FT-IR, 1H NMR, 13C NMR, COSY, HMQC and HMBC. Screening for antibacterial activity was performed against Staphylococcus aureus ATCC 25923, Salmonella typhimurium ATCC 14028 and Escherichia coli ATCC 25922. The results indicated that the titled compound had been successfully synthesized and purified. The structure of desired compound was confirmed based on structural elucidation analysis. The result of testing the titled compound for the antibacterial activity was negative.
- Arrahman,Hayun,Suryadi
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p. 256 - 260
(2016/01/20)
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- Structural studies of β-turn-containing peptide catalysts for atroposelective quinazolinone bromination
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We describe herein a crystallographic and NMR study of the secondary structural attributes of a β-turn-containing tetra-peptide, Boc-Dmaa-d-Pro-Acpc-Leu-NMe2, which was recently reported as a highly effective catalyst in the atroposelective bromination of 3-arylquinazolin-4(3H)-ones. Inquiries pertaining to the functional consequences of residue substitutions led to the discovery of a more selective catalyst, Boc-Dmaa-d-Pro-Acpc-Leu-OMe, the structure of which was also explored. This new lead catalyst was found to exhibit a type I′ β-turn secondary structure both in the solid state and in solution, a structure that was shown to be an accessible conformation of the previously reported catalyst, as well.
- Metrano,Abascal,Mercado,Paulson,Miller
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supporting information
p. 4816 - 4819
(2016/04/09)
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- Synthesis, biological evaluation of 2,3-disubstituted-imidazolyl/benzimidazolyl-quinazolin-4(3H)-one derivatives
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A series of disubstituted-quinazolin-4(3H)-ones derivatives have been synthesized and confirmed through IR, 1H- and 13C-NMR, MS spectroscopy and elemental analysis. Synthesized compounds were screened for in vitro and in vivo anti-inflammatory using human red blood cell membrane stabilization method and carrageenan-induced rat paw edema. The antimicrobial potency was measured by disk diffusion method. The compounds with imidazole (3g) and benzimidazole nucleus (4b and 4f) displayed a significant anti-inflammatory activity by in vitro method. Moreover, the compounds 3d and 4a exhibited a significant anti-inflammatory activity in vivo. The compounds 3d, 3f and 4g were found to be active antimicrobial agents, when compared with reference drug ciprofloxacin and amphotericin B. Thus, these compounds can serve as promising leads for further biological studies.
- Patil, Dilip A.,Surana, Sanjay J.
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p. 1125 - 1139
(2016/07/06)
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- Synthesis, characterization, and screening for analgesic and anti-inflammatory activities of new 1,3,4-oxadiazole derivatives linked to quinazolin-4-one ring
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In the present study, several new 1,3,4-oxadiazole derivatives linked with quinazolin-4-one moiety were synthesized by following steps. 2-methyl -4H-3, 1-benzoxazin-4-one, and 2-phenyl -4H-3, 1-benzoxazin-4-one were synthesized in the first and second step by stirring anthranilic acid in pyridine with benzoyl chloride and with an acetic anhydride for 30 min at room temperature. On treatment with semicarbazide with the above synthesized intermediates, that is, 2-methyl-4H-3,1-benzoxazin-4-one, and 2-phenyl-4H-3,1-benzoxazin-4-one in the third step afforded 2-methyl-4-oxoquinazoline-3(4H)-carbohydrazide and 2-phenyl-4-oxoquinazoline-3(4H)-carbohydrazide. These were introduced in cyclization reaction with different aromatic acids, aromatic aldehydes, and carbon disulfide in the next step, producing the corresponding 3-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-phenyl-quinazolin-4(3H)-one derivatives, 3-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methyl-quinazolin-4(3H)-one derivatives, 3-(5-aryl-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one derivatives and 3-(5-aryl-1,3,4-oxadiazol-2-yl)-2-methylquinazolin-4(3H)-one derivatives. Purity of these synthesized derivatives was confirmed by thin layer chromatography, melting point. Structure of the derivatives was set up by determining infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All the synthesized derivatives were evaluated for their analgesic and anti-inflammatory activities in mice and rats. In animal studies, the derivatives 3-[4-acetyl-5-(2-hydroxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one and 3-[4-acetyl-5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one shown more potent analgesic activity and the derivatives 3-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one and 3-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-methylquinazolin-4(3H)-one shown more potent anti-inflammatory activity as compared to other derivatives. The results of current study indicate that cyclization of carbohydrazide group of intermediate 2-methyl-4-oxoquinazoline-3(4H)-carbohydrazide and 2-phenyl-4-oxoquinazoline-3(4H)-carbohydrazide with different aromatic acids, aromatic aldehydes, and carbon disulfide produces novel quinazolin-4-one linked oxadiazole derivatives with potent analgesic and anti-inflammatory activities.
- Dewangan, Dhansay,Verma, Vinay Sagar,Nakhate, Kartik T.,Tripathi, Dulal Krishna,Kashyap, Pranita,Dhongade, Hemant
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p. 2143 - 2154
(2016/10/25)
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- Concise synthesis of cyclic carbonyl compounds from haloarenes using phenyl formate as the carbonyl source
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Various cyclic carbonyl compounds were concisely synthesized by carbonylative cyclization of haloarenes bearing nucleophilic moieties under Pd catalysis. A broad substrate scope and a feasible large-scale synthesis clearly demonstrate the high applicability of the reaction as a general, user-friendly method for access to cyclic carbonyl compounds.
- Konishi, Hideyuki,Nagase, Hiroki,Manabe, Kei
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p. 1854 - 1857
(2015/01/30)
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- Ruthenium(II) Catalyzed Regiospecific C-H/O-H Annulations of Directing Arenes via Weak Coordination
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Ruthenium(II) catalyzed oxidative C-H/O-H annulations have been demonstrated using two different directing arenes viz. 2-arylquinolinone and 2-arylbenzoxazinone with internal alkynes. Regiospecific annulations have been observed for both directing arenes via the assistance of weaker carbonyl oxygen in the presence of a stronger nitrogen-directing site. In this substrate-controlled convergent protocol the weaker directing group dictates the annulation path.
- Banerjee, Arghya,Santra, Sourav Kumar,Mohanta, Prakash Ranjan,Patel, Bhisma K.
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supporting information
p. 5678 - 5681
(2015/12/01)
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- Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination
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We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using density functional theory calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereodetermining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other atropisomerically defined products of interest. For example, (1) a dehalogenation Suzuki-Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.
- Diener, Matthew E.,Metrano, Anthony J.,Kusano, Shuhei,Miller, Scott J.
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supporting information
p. 12369 - 12377
(2015/10/12)
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