Synthetic approaches for novel fused pyrimidine derivatives: Design, structural characterization, antiviral, antitumor, and molecular docking evaluation

The goal of this work was to synthesize new compounds for anticancer evaluation as a trial to obtain new antitumor agents with higher activity and fewer side effects. Therefore, the precursor 2,2'-(1,4-phenylenebis (thiazole-4,2-diyl))bis (3-(dimethylamino)acrylonitrile) <b>(4)</b> was used to synthesize various azolopyrimidine derivatives connected to the thiazole moiety. Compounds <b>5</b>-<b>11</b>, including pyrazolopyrimidine, triazolopyrimidine, and others, were produced by reacting enaminonitrile <b>4</b> with different <i>N</i>-nucleophiles. Additionally, compounds <b>12</b>-<b>15</b>, such as isoxazole and pyrimidinethione derivatives, were obtained by reacting compound <b>4</b> with guanidine, hydrazine hydrate, hydroxylamine hydrochloride, and thiourea. Enaminonitrile <b>4</b> was also treated with barbituric acid, isoxazolone, and pyrazolone to yield pyranopyrimidine derivatives <b>18</b>-<b>20</b>. Moreover, enaminonitrile <b>4</b> reacts with <i>C</i>-nucleophiles namely ''acetylacetone, dimedone, 2-cyanomethylbenzothiazole, and 2-cyanomethylbenzimidazole'' to give pyrano derivatives <b>21</b>, <b>22</b> and fused pyridone derivatives <b>23</b> and <b>24</b>, respectively. The cytotoxic activity of <b>20</b> novel compounds against HSV-1, HIV-1, and various cancer cell lines was assessed, with compounds <b>5</b>, <b>7</b>, and <b>9</b> showing the strongest effects. Molecular docking studies further evaluated the binding affinity of these derivatives, with docking scores ranging from -7.8679 to -8.3013 kcal/mol. Several new azolopyrimidine derivatives linked to the thiazole moiety were effectively synthesized and assessed in the study, and they showed notable cytotoxic activity against HSV-1, HIV-1, and several cancer cell lines.