| Summary: | The present work describes the design and development of seventeen pyrimidine-clubbed benzimidazole derivatives as potential dihydrofolate reductase (DHFR) inhibitors. These compounds were filtered by using ADMET, drug-likeness characteristics calculations, and molecular docking experiments. Compounds <b>27</b>, <b>29</b>, <b>30</b>, <b>33</b>, <b>37</b>, <b>38</b>, and <b>41</b> were chosen for the synthesis based on the results of the in silico screening. Each of the synthesized compounds was tested for its in vitro antibacterial and antifungal activities using a variety of strains. All the compounds showed antibacterial properties against Gram-positive bacteria (<i>Staphylococcus aureus</i> and <i>Staphylococcus pyogenes</i>) as well as Gram-negative bacteria (<i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i>). Most of the compounds either had a higher potency than chloramphenicol or an equivalent potency to ciprofloxacin. Compounds <b>29</b> and <b>33</b> were effective against all the bacterial and fungal strains. Finally, the 1,2,3,4-tetrahydropyrimidine-2-thiol derivatives with a 6-chloro-2-(chloromethyl)-1<i>H</i>-benzo[<i>d</i>]imidazole moiety are potent enough to be considered a promising lead for the discovery of an effective antibacterial agent.
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