52353-35-2Relevant academic research and scientific papers
Synthesized 2-trifluoromethylquinazolines and quinazolinones protect bv2 and n2a cells against lps-and h2 o2-induced cytotoxicity
Nallathamby, Neeranjini,Phan, Chia-Wei,Sova, Matej,Saso, Luciano,Sabaratnam, Vikineswary
, p. 623 - 629 (2021/04/02)
Background: Microglia are associated with neuroinflammation, which play a key role in the pathogenesis of neurodegenerative diseases. It has been reported that some quinazolines and quinazolinones possess anti-inflammatory properties. However, the pharmacological properties of certain quinazoline derivatives are still unknown. Objective: The antioxidant, cytotoxic, and protective effects of a series of synthesized 2-trifluoromethylquinazolines (2, 4, and 5) and quinazolinones (6-8) in lipopolysaccharide (LPS)-murine microglia (BV2) and hydrogen peroxide (H2 O2 )-mouse neuroblastoma-2a (N2a) cells were investigated. Method: The antioxidant activity of synthesized compounds was evaluated with ABTS and DPPH assays. The cytotoxic activities were determined by MTS assay in BV2 and N2a cells. The production of nitric oxide (NO) in LPS-induced BV2 microglia cells was quantified. Results: The highest ABTS and DPPH scavenging activities were observed for compound 8 with 87.7% of ABTS scavenge percentage and 54.2% DPPH inhibition. All compounds were non-cytotoxic in BV2 and N2a cells at 5 and 50 μg/mL. The compounds which showed the highest protective effects in LPS-induced BV2 and H2 O2-induced N2a cells were 5 and 7. All tested com-pounds, except 4, also reduced NO production at concentrations of 50 μg/mL. The quinazolinone series 6-8 exhibited the highest percentage of NO reduction, ranging from 38 to 60%. Compounds 5 and 8 possess balanced antioxidant and protective properties against LPS-and H2 O2-induced cell death, thus showing great potential to be developed into anti-inflammatory and neuroprotective agents. Conclusion: Compounds 5 and 7 were able to protect the BV2 and N2a cells against LPS and H2 O2 toxicity, respectively, at a low concentration (5 μg/mL). Compounds 6-8 showed potent reduction of NO production in BV2 cells.
Selective Toll-like receptor 7 agonists with novel chromeno[3,4-d]imidazol-4(1H)-one and 2-(trifluoromethyl)quinoline/ quinazoline-4-amine scaffolds
Dol?ak, Ana,?vajger, Urban,Le?nik, Samo,Konc, Janez,Gobec, Stanislav,Sova, Matej
, p. 109 - 122 (2019/06/27)
Toll-like receptors (TLRs) are promising targets for treatment of viral infections, autoimmune diseases, and cancers. Here, two new series of selective small-molecule TLR7 agonists with novel scaffolds and good selectivity over TLR8 are described, some with potencies in the low micromolar range. 8-Hydroxy-1-isobutylchromeno[3,4-d]imidazol-4(1H)-one (26) from the first series was designed and synthesized on the basis of previously described TLR7 antagonist 2, and is shown to be a selective TLR7 agonist (EC50, 1.8 μM). The second series was based on 2-(trifluoromethyl)quinolin-4-amine and 2-(trifluoromethyl)quinazolin-4-amine scaffolds, which were defined according to our in-house ligand-based virtual screening protocol. Further synthesis of a focused library of analogs, biological evaluation, and docking studies provided systematic exploration of the structure?activity relationships, which indicate that a secondary or tertiary amine with smaller flexible alkyl substituents up to three carbon atoms in length, or bulkier rigid aliphatic rings is required at position 4 on 2-(trifluoromethyl)quinoline/quinazoline scaffold for potent TLR7 agonist activity. The influence of selected TLR7 agonists on cytokine production is also reported showing that N-cyclopropyl-2-(trifluoromethyl)quinazolin-4-amine (46) is able to induce increased levels of IL-6 and IL-8. These data demonstrate successful in-silico definition of novel TLR7 versus TLR8-selective compounds as promising chemical probes for further development of potent small-molecule immunomodulators.
One-Pot Synthesis of Trifluoromethylated Quinazolin-4(3 H)-ones with Trifluoroacetic Acid as CF3 Source
Almeida, Sofia,Marti, Roger,Vanoli, Ennio,Abele, Stefan,Tortoioli, Simone
, p. 5104 - 5113 (2018/05/22)
A novel and convenient one-pot sequential cascade method for the preparation of 2-trifluoromethylquinazolin-4(3H)-ones is described. Trifluoroacetic acid (TFA) was employed as inexpensive and readily available CF3 source, which in the presence
X-ray crystallography and computational docking for the detection and development of protein-ligand interactions
Kershaw,Wright,Sharma,Antonyuk,Strange,Berry,O'Neill,Hasnain
, p. 569 - 575 (2013/07/28)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective dysfunction and death of the upper and lower motor neurons. Median survival rates are between 3 and 5 years after diagnosis. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been linked to a subset of familial forms of ALS (fALS). Herein, we describe a fragment- based drug discovery (FBDD) approach for the investigation of small molecule binding sites in SOD1. X-ray crystallography has been used as the primary screening method and has been shown to directly detect protein-ligand interactions which cannot be unambiguously identified using other biophysical methods. The structural requirements for effective binding at Trp32 are detailed for a series of quinazoline-containing compounds. The investigation of an additional site that binds a range of catecholamines and the use of computational modelling to assist fragment evolution is discussed. This study also highlights the importance of ligand solubility for successful Xray crystallographic campaigns in lead compound design.
Novel palladium-free synthesis of a key quinazolinap precursor
Milhau, Ludovic,Guiry, Patrick J.
, p. 383 - 385 (2011/04/22)
A novel, short synthetic route has been successfully developed for a key precursor of Quinazolinap ligands. The key step is a Friedel-Crafts-type reaction between 2-naphthol and 4-chloroquinazoline, with moderate to quantitative yields recorded. A variation of this reaction allows for the introduction of an amine group on the naphthalene unit. Georg Thieme Verlag Stuttgart New York.
Convenient and practical one-pot synthesis of 4-chloropyrimidines via a novel chloroimidate annulation
Storz, Thomas,Heid, Richard,Zeldis, Joseph,Hoagland, Steven M.,Rapisardi, Vito,Hollywood, Susan,Morton, George
experimental part, p. 918 - 924 (2012/07/14)
Reaction of aromatic or heteroaromatic 2-acyl(amino)nitriles with phosphorus pentachloride triggers a novel chloroimidate cyclization, leading directly to the corresponding annullated 4-chloropyrimidines in good to excellent yields. The reaction lends itself to the telescoped one-pot construction of 4-functionalized pyrimidines from the corresponding (hetero)aromatic 2-aminonitriles. For a pyrazolopyrimidine development intermediate, this reaction was scaled up to multikilogram scale with excellent results. A total of 10 examples with different substrates are provided. This one-pot reaction provides an attractive and sustainable alternative to the commonly used multistep methodology for this transformation.
Synthesis leading to novel 2,4,6-trisubstituted quinazoline derivatives, their antibacterial and cytotoxic activity against thp-1, hl-60 and a375 cell lines
Chandrika, P Mani,Yakaiah,Narsaiah,Sridhar,Venugopal,Rao, J Venkateshwara,Kumar, K Pranay,Murthy,Rao, A Raghu Ram
experimental part, p. 840 - 847 (2009/12/24)
A series of novel 2,4,6-trisubstituted quinazoline derivatives 6 have been synthesized from anthranilic acids 1 in five steps via benzoxazinones 2, N-benzoyl benzamides 3, quinazol-4-ones 4, 4-chloroquinazolines 5. Products 6 have been screened for antibacterial and cytotoxic activity, promising compounds have been identified.
Discovery of potent LPA2 (EDG4) antagonists as potential anticancer agents
Beck, Hilary P.,Kohn, Todd,Rubenstein, Steven,Hedberg, Christine,Schwandner, Ralf,Hasslinger, Kerstin,Dai, Kang,Li, Cong,Liang, Lingming,Wesche, Holger,Frank, Brendon,An, Songhzu,Wickramasinghe, Dineli,Jaen, Juan,Medina, Julio,Hungate, Randall,Shen, Wang
, p. 1037 - 1041 (2008/12/20)
The LPA2 protein is overexpressed in many tumor cells. We report the optimization of a series of LPA2 antagonists using calcium mobilization assay (aequorin assay) that led to the discovery of the first reported inhibitors selective for LPA2. Key compounds were evaluated in vitro for inhibition of LPA2 mediated Erk activation and proliferation of HCT-116 cells. These compounds could be used to evaluate the benefits of LPA2 inhibition both in vitro and in vivo.
ANTIPROLIFERATIVE PYRIMIDYL, FUSED PYRIMIDYL AND PYRIMIDYL HYDRAZONES
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Page/Page column 32-33, (2010/11/27)
The present invention is related to a novel series of pyrimidyl or fused pyrimidyl hydrazones. Compounds of Formula (I) wherein A is selected from the group consisting of Formulas (A1), (A2), (A3), (A4), (A5) are useful for the treatment and/or prevention of a proliferative disease.
COMPOUNDS USEFUL AS CHEMOKINE RECEPTOR ANTAGONISTS
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Page/Page column 133, (2008/06/13)
The present invention relates to compounds useful as Chemokine Receptor antagonists. Compounds of general formula (I) are provided or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compounds and compositions for the inhibition of Chemokine Receptors and also for the treatment of various diseases, conditions, or disorders, including acute or chronic inflammatory disease, cancer, and osteolytic bone disorders.
