| Čoahkkáigeassu: | A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A (<i>h</i>LDHA) inhibitors. Structures with different linkers between the pyrimidine and quinolone scaffolds (<b>10</b>-<b>21</b> and <b>24</b>–<b>31</b>) were studied in silico, and those with the 2-aminophenylsulfide (U-shaped) and 4-aminophenylsulfide linkers (<b>24</b>–<b>31</b>) were finally selected. These new pyrimidine-quinolone hybrids (<b>24</b>–<b>31</b>)(<b>a</b>–<b>c</b>) were easily synthesized in good to excellent yields by a green catalyst-free microwave-assisted aromatic nucleophilic substitution reaction between 3-(((2/4-aminophenyl)thio)methyl)quinolin-2(1<i>H</i>)-ones <b>22/23</b>(<b>a</b>–<b>c</b>) and 4-aryl-2-chloropyrimidines (<b>1</b>–<b>4</b>). The inhibitory activity against <i>h</i>LDHA of the synthesized hybrids was evaluated, resulting IC<sub>50</sub> values of the U-shaped hybrids <b>24</b>–<b>27</b>(<b>a</b>–<b>c</b>) much better than the ones of the 1,4-linked hybrids <b>28</b>–<b>31</b>(<b>a</b>–<b>c</b>). From these results, a preliminary structure–activity relationship (SAR) was established, which enabled the design of novel 1,3-linked pyrimidine-quinolone hybrids (<b>33</b>–<b>36</b>)(<b>a</b>–<b>c</b>). Compounds <b>35</b>(<b>a</b>–<b>c</b>), the most promising ones, were synthesized and evaluated, fitting the experimental results with the predictions from docking analysis. In this way, we obtained novel pyrimidine-quinolone hybrids (<b>25a</b>, <b>25b,</b> and <b>35a</b>) with good IC<sub>50</sub> values (<20 μM) and developed a preliminary SAR.
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