Exploring Novel Tetrahydropyrimidine and Fused Pyrimidine-Based Compounds as DHFR Inhibitors and Antimicrobial Agents: Synthesis, In Vitro, In Vivo, and In Silico Studies
Abstract
New series of 2‐imino/oxo‐tetrahydropyrimidines (4a‐4j), and fused pyrimidines (5a‐5i and 6a‐6h) were designed and synthesized as attractive scaffolds to be investigated in vitro and in vivo for antimicrobial activity against gram‐positive Staphylococcus aureus, gram‐negative Escherichia coli and Klebsiella pneumoniae, and fungus Candida albicans. In the in vitro antimicrobial screening using agar diffusion method, compounds 4 d, 4 f, 6a and 6 d showed broad‐spectrum antimicrobial activity against all the tested strains when compared to levofloxacin as a reference drug. Moreover, compound 4 f showed higher antibacterial activity against all the tested microorganisms with MIC = 22–45 µM compared with levofloxacin with MIC = 50‐ > 708 µM. Compound 5 g exhibited lower IC50 than that of reference trimethoprim (TMP) towards the DHFR enzyme inhibition. Additionally, compounds 4 d, 4 f, 4 g, 6 d and 6 f had kept the superiority over the reference drug with IC50 ranging from 4.10 to 4.77 µM. Compounds 4 f and 6a were subjected to in vivo evaluation for their antibacterial activity. They caused a significant reduction in abscess volume and area in the skin of mice inoculated with S. aureus. Moreover, compound 4 f had reduced the immune‐expression of interleukin‐1β in the isolated tissues of the infected skin. Molecular docking results were in a good agreement with the DHFR enzyme assay results and justified the binding profiles and affinities profile of all tested compounds.…
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