16431-29-1

Usage

Uses

Used in Pharmaceutical Industry:
(4-Hydroxy-quinazolin-2-ylsulfanyl)-acetic acid is used as a reactant for the development and preparation of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors. Tankyrase inhibitors have shown promise in the treatment of various diseases, including cancer, by modulating the Wnt signaling pathway and affecting cellular processes such as cell proliferation, migration, and survival. The development of these inhibitors can lead to the creation of new therapeutic options for patients suffering from these conditions.

InChI:InChI=1/C10H8N2O3S/c13-8(14)5-16-10-11-7-4-2-1-3-6(7)9(15)12-10/h1-4H,5H2,(H,13,14)(H,11,12,15)

Upstream product

• 13906-09-7 2-thioxo-2,3-dihydro-1H-quinazolin-4-one 
• 79-11-8 chloroacetic acid 
• 333-20-0 potassium thioacyanate 
• 6307-66-0 2-(Chloracetylamino)benzoesaeure-ethylester 
• 13906-09-7 2-mercapto-3H-quinazolin-4-one 
• 118-92-3 anthranilic acid 
• 79-08-3 bromoacetic acid 
• 561024-76-8 tert-butyl 2-((4-oxo-3,4-dihydroquinazolin-2-yl)thio)acetate 
• 87-25-2 2-ethoxycarbonylaniline 

Relevant academic research and scientific papers

SYNTHESIS OF 2-ALKYLTHIOQUINAZOL-4-ONES

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.

2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

Mycobacterium tuberculosis (MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.

QUINAZOLINONE COMPOUNDS AND DERIVATIVES THEREOF

Compounds of Formula I are useful inhibitors of tankyrase. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.

Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors

Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.

Synthesis of novel 2-(4-oxo-3,4-dihydroquinazolin-2-ylsulfinylmethyl)-3H- quinazolin-4-one

Condensation of 2-mercapto-3H-quinazolin-4-one (1) with chloroacetic acid gave 4-oxo-3,4-dihydroquinazoline-2-yl-sulfanyl)-acetic acid (2) that with anthranilamide (3) gave 2-(4-oxo-3,4-dihydroquinazolin-2-ylsulfanylmethyl)-3H- quinazolin-4-one (4). Oxidation of 4 with sodium hypochlorite in alkaline medium gave the novel product, 2-(4-oxo-3,4-dihydroquinazolin-2-ylsulfinyl methyl)-3H-quinazolin-4-one) (5). The entire sequences of reactions in this work have been carried out using eco-friendly solvents and green conditions. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

New syntheses of 2-alkylthio-4-oxo-3,4-dihydroquinazolines, 2-alkylthioquinazolines, as well as their hetero analogues

N-Chloroacetylanthranilic acid ethyl ester reacts with potassium thiocyanate in the presence of alcohol to give the (4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)acetic acid ester (3a). In the presence of water or amines the acetic acid derivative (3b) or the acetamide derivatives (3c,d) are obtained. 2-Amino-4-oxo-3,4-dihydroquinazolines (4) arise if vigorous reaction conditions are employed. Analogously, N-chloroacetyl derivatives of 5-membered heterocycles with enaminocarbonyl structure (5, 7, 9, 11, 13, 20, 23) react with potassium thiocyanate to yield thieno[2,3-d]-, thieno[3,2-d]-, imidazo[4,5-d]-, pyrrolo[3,2-d]-, and thiazolo[4,5-d]pyrimidines (6, 8, 10, 12, 14, 21, 24). Quinazolines (18, 19) are formed from the reaction of 2-chloroacetylaminoacetophenone (16a) and 2-chloroacetylaminobenzophenone (16b) with potassium thiocyanate and subsequent treatment of the intermediates with amines.