Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel <i>h</i>LDHA Inhibitors
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...
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/7/792 |
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| author | Iván Díaz Sofia Salido Manuel Nogueras Justo Cobo |
| author_facet | Iván Díaz Sofia Salido Manuel Nogueras Justo Cobo |
| author_sort | Iván Díaz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T10:13:20Z |
| format | Article |
| id | doaj.art-53ffc590be2245bc951f32c4e08a141b |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T10:13:20Z |
| publishDate | 2022-06-01 |
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| spelling | doaj.art-53ffc590be2245bc951f32c4e08a141b2023-12-01T22:33:11ZengMDPI AGPharmaceuticals1424-82472022-06-0115779210.3390/ph15070792Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel <i>h</i>LDHA InhibitorsIván Díaz0Sofia Salido1Manuel Nogueras2Justo Cobo3Facultad de Ciencias Experimentales, Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, E-23071 Jaén, SpainFacultad de Ciencias Experimentales, Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, E-23071 Jaén, SpainFacultad de Ciencias Experimentales, Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, E-23071 Jaén, SpainFacultad de Ciencias Experimentales, Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, E-23071 Jaén, SpainA 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.https://www.mdpi.com/1424-8247/15/7/792<i>h</i>LDHA inhibitorsquinolonespyrimidinesfragment-based drug designdocking |
| spellingShingle | Iván Díaz Sofia Salido Manuel Nogueras Justo Cobo Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel <i>h</i>LDHA Inhibitors Pharmaceuticals <i>h</i>LDHA inhibitors quinolones pyrimidines fragment-based drug design docking |
| title | Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel <i>h</i>LDHA Inhibitors |
| title_full | Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel <i>h</i>LDHA Inhibitors |
| title_fullStr | Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel <i>h</i>LDHA Inhibitors |
| title_full_unstemmed | Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel <i>h</i>LDHA Inhibitors |
| title_short | Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel <i>h</i>LDHA Inhibitors |
| title_sort | design and synthesis of new pyrimidine quinolone hybrids as novel i h i ldha inhibitors |
| topic | <i>h</i>LDHA inhibitors quinolones pyrimidines fragment-based drug design docking |
| url | https://www.mdpi.com/1424-8247/15/7/792 |
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