- 2-((3,5-Dinitrobenzyl)thio)quinazolinones: Potent Antimycobacterial Agents Activated by Deazaflavin (F420)-Dependent Nitroreductase (Ddn)
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Swapping the substituents in positions 2 and 4 of the previously synthesized but yet undisclosed 5-cyano-4-(methylthio)-2-arylpyrimidin-6-ones 4, ring closure, and further optimization led to the identification of the potent antitubercular 2-thio-substituted quinazolinone 26. Structure-activity relationship (SAR) studies indicated a crucial role for both meta-nitro substituents for antitubercular activity, while the introduction of polar substituents on the quinazolinone core allowed reduction of bovine serum albumin (BSA) binding (63c, 63d). While most of the tested quinazolinones exhibited no cytotoxicity against MRC-5, the most potent compound 26 was found to be mutagenic via the Ames test. This analogue exhibited moderate inhibitory potency against Mycobacterium tuberculosis thymidylate kinase, the target of the 3-cyanopyridones that lies at the basis of the current analogues, indicating that the whole-cell antimycobacterial activity of the present S-substituted thioquinazolinones is likely due to modulation of alternative or additional targets. Diminished antimycobacterial activity was observed against mutants affected in cofactor F420 biosynthesis (fbiC), cofactor reduction (fgd), or deazaflavin-dependent nitroreductase activity (rv3547), indicating that reductive activation of the 3,5-dinitrobenzyl analogues is key to antimycobacterial activity.
- Jian, Yanlin,Forbes, He Eun,Hulpia, Fabian,Risseeuw, Martijn D. P.,Caljon, Guy,Munier-Lehmann, Hélène,Boshoff, Helena I. M.,Van Calenbergh, Serge
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p. 440 - 457
(2021/01/14)
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- Synthesis and evaluation of 2-substituted 4(3H)-quinazolinone thioether derivatives as monoamine oxidase inhibitors
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In the present study, a series of fourteen 2-mercapto-4(3H)-quinazolinone derivatives was synthesised and evaluated as potential inhibitors of the human monoamine oxidase (MAO) enzymes. Quinazolinone is the oxidised form of quinazoline, and although this class has not yet been extensively explored as MAO inhibitors, it has been shown to possess a wide variety of biological activities. Among the quinazolinone derivatives investigated, seven compounds (IC50 50 value of 0.142 μM. Further investigation showed that this inhibitor is a reversible and competitive inhibitor of MAO-B with a Ki value of 0.068 μM. None of the test compounds were MAO-A inhibitors. Analysis of the structure-activity relationships (SARs) for MAO-B inhibition shows that substitution on the C2 position of quinazolinone with a benzylthio moiety bearing a Cl, Br or I on the meta position yields the most potent inhibitors of the series. In contrast, substitution with the unsubstituted benzylthio moiety (IC50 = 3.03 μM) resulted in significantly weaker inhibition activity towards MAO-B. This study suggests that quinazolinones are promising leads for the development of selective MAO-B inhibitors which may be used for the treatment of neurodegenerative disorders such as Parkinson's disease.
- Qhobosheane, Malikotsi A.,Petzer, Anél,Petzer, Jacobus P.,Legoabe, Lesetja J.
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p. 5531 - 5537
(2018/10/05)
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- Conversion of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones to N(3)-unsubstituted 2-(het)arylquinazolin-4(3H)-ones by copper-mediated Pd-catalysed cross-coupling reactions
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With the purpose of searching for new heterocyclic building blocks, a new method to access N(3)-unsubstituted 2-(het)arylquinazolin-4(3H)-ones from 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives was developed. The synthetic protocol was based on the copper-mediated palladium-catalysed cross-coupling reactions of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones with (het)arylstannanes or their S-benzylated derivatives with (het)arylboronic acids, using CuBr·Me2S and CuMeSal as promoters, respectively. A similar transformation was applied for the preparation of 2-aryl[1]benzothieno[3,2-d]pyrimidin-4(3H)-ones.
- Kri??iūnien?, Vilija,Matulevi?iūt?, Gita,Paliulis, Osvaldas,Rollin, Patrick,?a?kus, Algirdas
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p. 150 - 163
(2017/03/11)
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- Synthesis and evaluation of quinazoline derivatives as phosphodiesterase 7 inhibitors
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The latest scientific findings concerning PDE7 and PDE4 inhibition suggest that selective small-molecule inhibitors of both enzymes could provide a novel approach to treat a variety of immunological diseases. In this context, we describe a new series of quinazoline derivatives from quinazolin-4-thiones which include a substituted biphenyl fragment. Some of these compounds show inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7.
- Sánchez, Ana I.,Martínez-Barrasa, Valentín,Burgos, Carolina,Vaquero, Juan J.,Alvarez-Builla, Julio,Terricabras, Emma,Segarra, Víctor
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p. 2370 - 2378
(2013/05/09)
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- A green and facile synthesis of 2-alkylsulfanyl-3H-quinazolin-4-one
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Reaction of 2-thioquinazolinone (1) with various alkylating agents like dimethyl sulphate, diethyl sulphate and benzyl chloride in the presence of K2CO3 as a mild base, by a simple physical grinding, microwave irradiation and PEG-600 under solvent-free conditions for 10-15 min at room temperature, followed by processing, gave respectively 2-methylsulfanyl-3H-quinazolin-4-one (2a, i.e., R = CH3), 2-ethylsulfanyl-3H-quinazolin-4-one (2b, i.e., R = C2H5) and 2-benzyl sulfanyl-3H-quinazolin-4-one (2c, i.e., R = PhCH2Cl). It appears from this study that green syntheses such as solid phase synthesis (physical grinding) and microwave irradiation gives better yields, quality and in less reaction time the products over conventional methods involving green solvents like ethanol, PEG-600 etc. The entire sequences of reactions have been carried out using eco-friendly solvents and green conditions.
- Reddy, B. Srinivasa,Naidu,Dubey
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p. 2644 - 2646
(2013/05/09)
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- Regioselective sulfonylation and N- to O-sulfonyl migration of quinazolin-4(3H)-ones and analogous thienopyrimidin-4(3H)-ones
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The sulfonylation of quinazolin-4(3H)-ones and related tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones with mesyl, tosyl, and p-cyanobenzenesulfonyl chloride was studied. A hydrogen substituent at 2-position directed the sulfonyl group to the N-3 position, while alkylsulfanyl or amino substituents led to sulfonylation of the carbonyl oxygen. The latter effect was attributed to steric influence and the positive mesomeric effect of the 2-substituent. An access to N-sulfonylated 2-substituted regioisomers was established. An unexpected 1,3-sulfonyl migration was observed and further analyzed. This process occurred as an intramolecular N- to O-shift as verified by kinetic and crossover experiments.
- Mertens, Matthias D.,Pietsch, Markus,Schnakenburg, Gregor,Guetschow, Michael
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p. 8966 - 8979
(2013/10/08)
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- Design, synthesis and biological activity evaluation of 2-mercapto-4(3H)-quinazolinone derivatives as novel inhibitors of protein tyrosine phosphatase 1B
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A series of novel 2-mercapto-4(3H)-quinazolinone derivatives have been synthesized and their inhibitory effects on PTP1B and TCPTP are evaluated for the first time. Most of these derivatives showed good inhibitory activity on PTP1B and reasonable selectivity for PTP1B over TCPTP, among them 32 was the most potent PTP1B inhibitor (IC50 = 1.50 μ ;g/mL), and 27 possessed the best selectivity of 3.0-fold.
- Li, Hui,Wang, Jin-Ping,Yang, Fan,Liu, Ting,Qiu, Wen-Wei,Li, Jing-Ya,Li, Jia,Tang, Jie
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p. 1897 - 1911
(2012/09/07)
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- SYNTHESIS OF 2-ALKYLTHIOQUINAZOL-4-ONES
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Alkylation of 2-thioxoquinazol-4-one by different alkylating agents was studied, and it was found that the reaction proceeds at the exocyclic sulfur atom with the formation of 2-alkylthioquinazol-4-ones.
- Yun, L. M.,Yangibaev, S.,Shakhidoyatov, Kh. M.,Alekseeva, V. Ya.,V'yunov, K. A.
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p. 214 - 216
(2007/10/02)
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