Functionalization of Quinazolin‐4‐ones Part 3: Synthesis, Structures Elucidation, DNA‐PK, PI3K, and Cytotoxicity of Novel 8‐Aryl‐2‐morpholino‐quinazolin‐4‐ones

Abstract

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.

Unlocking the Antiviral Arsenal: Multiparametric Optimization of Small-Molecule Inhibitors against RSV and hCoV-229E

“…To combine them with 1-(3-(chloromethyl)-4methoxyphenyl)ethan-1-one in an O-alkylation reaction we optimized our published procedure 35 in terms of the yield (data not shown) resulting in GPB-1. Additionally, we performed late-stage modifications, such as methylation (a), nucleophilic aromatic substitution (b), cyanation 40 (c), sulfonylation 41 (d), and Suzuki reaction 42,43 (e) following common and literature-known protocols. (Scheme 1) As previously mentioned, we conducted linker modifications as part of our study.…”

“…Some combi-derivatives and alkylations as well as arylations were performed according to Scheme 3 by late-stage modifications applying Suzuki reactions according to literature-known conditions. 42,43…”

“…General procedure E (GP E): Suzuki reaction as latestage modification. For this reaction, commonly known conditions 42 were adapted. The brominated starting material, boronic acid (1.2 5.0 equiv) and K2CO3 (2.5 equiv) were weighed into a c. v., flushed with nitrogen and mixed with degassed solvents, 1,4-dioxane (0.05 M) and water (0.3 M).…”