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Eighteen previously undescribed trimethoprim (TMP) analogs containing amide bonds ( 1–18 ) were synthesized and compared with TMP, methotrexate (MTX), and netropsin (NT). These compounds were designed as potential minor groove binding agents (MGBAs) and inhibitors of human dihydrofolate reductase ( h DHFR). The all-new derivatives were obtained via solid phase synthesis using 4-nitrophenyl Wang resin. Data from the ethidium displacement test confirmed their DNA-binding capacity. Compounds  13–14  (49.89% and 43.85%) and  17–18  (41.68% and 42.99%) showed a higher binding affinity to pBR322 plasmid than NT. The possibility of binding in a minor groove as well as determination of association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT) 2 , and poly (dG-dC) 2 . With the exception of compounds  9  (IC50 = 56.05 µM) and  11  (IC50 = 55.32 µM), all of the compounds showed better inhibitory properties against  h DHFR than standard, which confirms that the addition of the amide bond into the TMP structures increases affinity towards  h DHFR. Derivatives  2 ,  6 ,  13 ,  14 , and  16  were found to be the most potent  h DHFR inhibitors. This molecular modelling study shows that they interact strongly with a catalytically important residue Glu-30.

international journal of molecular sciences

Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents