33017-85-5Relevant academic research and scientific papers
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation, DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
Heppell, Jacob T.,Islam, Md. Amirul,McAlpine, Shelli R.,Al-Rawi, Jasim M. A.
, p. 124 - 141 (2019)
A series of novel 8-aryl-2-morpholino quinazolines (11a–n, 12a–d, 14a–f, and 15) were synthesized from the precursor 2-thioxo quinazolin-4-ones 8. The 8-aryl-2-morpholino quinazolines compounds were assayed for DNA-PK and PI3K. All compounds showed low DNA-PK % inhibition activity at 10?μM compound concertation, and the most active was 8-(dibenzo[b,d]thiophen-4-yl) 12d with 38% inhibition. Similar pattern of PI3K α, β, γ, and δ isoforms inhibition activity at 10?μM were observed. The most active isoform was PI3K δ of 41% inhibition for 8-(dibenzo[b,d]furan-4-yl) compound 11. Most compounds were less active than expected in spite of the strong structural resemblance to known inhibitors (NU7441, 3, 4, and 6). Loss of activity could be attributed to the tautomerization to the aromatic enol (4-OH), which could specify that the important functional group for the activity is the 4-carbonyl (C=O) group. Alternatively, the aromatization of the pyrimidine heterocyclic ring could alter the conformation, and thus binding site, of the 2-morpholine ring, which could reduce the compound-receptor hydrogen bonding to the morpholine 4-oxygen. Selected compounds displayed appreciable cytotoxicity with 6-chloro-8-(dibenzo[b,d]thiophen-4-yl)-2-morpholinoquinazolin-4(1H)-one 11j exhibiting the greatest activity with an IC50 of 9.95?μM. Therefore, the mechanism of the cytotoxicity of compound 11j were not through DNA-PK or PI3K inhibition activity.
Original 2-alkylamino-6-halogenoquinazolin-4(3H)-ones and KATP channel activity
Somers,Ouedraogo,Antoine,De Tullio,Becker,Fontaine,Damas,Dupont,Rigo,Delarge,Lebrun,Pirotte
, p. 2575 - 2585 (2001)
A series of 6-substituted 2-alkylaminoquinazolin-4(3H)-ones structurally related to 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested as putative KATP channel openers on isolated pancreatic endocrine tissu
2-((3,5-Dinitrobenzyl)thio)quinazolinones: Potent Antimycobacterial Agents Activated by Deazaflavin (F420)-Dependent Nitroreductase (Ddn)
Jian, Yanlin,Forbes, He Eun,Hulpia, Fabian,Risseeuw, Martijn D. P.,Caljon, Guy,Munier-Lehmann, Hélène,Boshoff, Helena I. M.,Van Calenbergh, Serge
, p. 440 - 457 (2021/01/14)
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.
A facile and convenient method to the one-pot synthesis of 2-mercapto-4(3H)-quinazolinones
Nikpour, Farzad,Mozafari, Roya,Paibast, Touraj
experimental part, p. 1569 - 1571 (2009/12/24)
A facile and convenient method to the one-pot synthesis of 2-mercapto-4(3H)-quinazolinones is described from the reaction of anthranilic acid derivatives with thiourea in PEG.
Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach
Smits, Rogier A.,De Esch, Iwan J. P.,Zuiderveld, Obbe P.,Broeker, Joachim,Sansuk, Kamonchanok,Guaita, Elena,Coruzzi, Gabriella,Adami, Maristella,Haaksma, Eric,Leurs, Rob
scheme or table, p. 7855 - 7865 (2009/12/07)
From a series of small fragments that was designed to probe the histamine H4 receptor (H4R), we previously described quinoxaline-containing fragments that were grown into high affinity H 4R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silico models, we now report the identification and optimization of a series of quinazoline-containing H4R compounds. This approach led to the discovery of 6-chloro-N-(furan-3-ylmethyl)2-(4-methylpiperazin-1-yl)quinazolin-4-amine (VUF10499, 54) and 6-chloro-2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl) quinazolin-4-amine (VUF10497, 55) as potent human H4R inverse agonists (pKi ) 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H 1 receptor (H1R) and therefore represent a novel class of dual action H1R/H4R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H4R and were found to possess anti-inflammatory properties in vivo in the rat.
