Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation

Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation

<b>Background/Objectives:</b> In connection with previous work on V-shaped polycyclic thiazolo[5,4-<i>f</i>]quinazolin-9-one and [5,4-<i>f</i>]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-...

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Main Authors: Nathan Broudic, Alexandra Pacheco-Benichou, Cécile Corbière, Blandine Baratte, Thomas Robert, Stéphane Bach, Hélène Solhi, Rémy Le Guével, Corinne Fruit, Thierry Besson
Format: Article
Language:English
Published: MDPI AG 2024-10-01
Series:Pharmaceuticals
Subjects:
thiazoloquinazolinones
thiazoloquinazolines
4,5-dichloro-1,2,3-dithiazolium chloride
microwave-assisted chemistry
cytotoxicity
kinase inhibition
Online Access:https://www.mdpi.com/1424-8247/17/11/1452
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Summary:<b>Background/Objectives:</b> In connection with previous work on V-shaped polycyclic thiazolo[5,4-<i>f</i>]quinazolin-9-one and [5,4-<i>f</i>]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-<i>g</i>] or [5,4-<i>g</i>]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. <b>Methods:</b> An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5-<i>h</i>] and [5,4-<i>h</i>]quinazolin-8-one derivatives was also explored with the aim of comparing biological results. The compounds obtained were tested against a representative panel of eight mammalian protein kinases of human origin: CDK9/CyclinT, Haspin, Pim-1, GSK-3β, CK-1ε, JAK3, CLK1 and DYRK1A. <b>Results and Conclusions:</b> The results obtained show that the novel linear thiazoloquinazolines are not kinase inhibitors. The cytotoxicity of these newly synthesized compounds was assessed against seven representative tumor cell lines (human cancers: Huh7-D12, Caco-2, HCT-116, MCF-7, MDA-MB-231, MDA-MB-468 and PC-3). The majority of these novel molecules proved capable of inhibiting the growth of the tested cells. The 7-Benzyl-8-oxo-7,8-dihydrothiazolo[5,4-<i>g</i>]quinazolinones <b>5b</b> and <b>6b</b> are the most potent, with IC<sub>50</sub> values in the micromolar range. None of these compounds showed toxicity against normal cells. A larger program of investigations will be launched to investigate the real potential interest of such compounds in anticancer applications.
ISSN:1424-8247

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