Synthesis, In Silico Prediction and In Vitro Evaluation of Antitumor Activities of Novel Pyrido[2,3-d]pyrimidine, Xanthine and Lumazine Derivatives

Abstract

Ethyl 5-arylpyridopyrimidine-6-carboxylates <b>3a</b>-<b>d</b> were prepared as a one pot three component reaction via the condensation of different aromatic aldehydes and ethyl acetoacetate with 6-amino-1-benzyluracil <b>1a</b> under reflux condition in ethanol. Additionally, condensation of ethyl 2-(2-hydroxybenzylidene) acetoacetate with 6-amino-1-benzyluracil in DMF afforded 6-acetylpyridopyrimidine-7-one <b>3e</b>; a facile, operationally, simple and efficient one-pot synthesis of 8-arylxanthines <b>6a</b>-<b>f</b> is reported by refluxing 5,6-diaminouracil <b>4</b> with aromatic aldehydes in DMF. Moreover, 6-aryllumazines <b>7a</b>-<b>d</b> was obtained via the reaction of 5,6-diaminouracil with the appropriate aromatic aldehydes in triethyl orthoformate under reflux condition. The synthesized compounds were characterized by spectral (¹H-NMR, ¹³C-NMR, IR and mass spectra) and elemental analyses. The newly synthesized compounds were screened for their anticancer activity against lung cancer A549 cell line. Furthermore, a molecular-docking study was employed to determine the possible mode of action of the synthesized compounds against a group of proteins highly implicated in cancer progression, especially lung cancer. Docking results showed that compounds <b>3b</b>, <b>6c</b>, <b>6d</b>, <b>6e</b>, <b>7c</b> and <b>7d</b> were the best potential docked compounds against most of the tested proteins, especially CDK2, Jak2, and DHFR proteins. These results are in agreement with cytotoxicity results, which shed a light on the promising activity of these novel six heterocyclic derivatives for further investigation as potential chemotherapeutics.