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Article

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

1
Department of Organic Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland
2
Department of Physical Chemistry, Institute of Chemistry, University of Bialystok, 15-245 Bialystok, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Paulino Gómez-Puertas
Int. J. Mol. Sci. 2021, 22(7), 3685; https://doi.org/10.3390/ijms22073685
Received: 7 March 2021 / Revised: 27 March 2021 / Accepted: 29 March 2021 / Published: 1 April 2021
(This article belongs to the Special Issue Computational Methods in Drug Design)
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 (hDHFR). 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 hDHFR than standard, which confirms that the addition of the amide bond into the TMP structures increases affinity towards hDHFR. Derivatives 2, 6, 13, 14, and 16 were found to be the most potent hDHFR inhibitors. This molecular modelling study shows that they interact strongly with a catalytically important residue Glu-30. View Full-Text
Keywords: trimethoprim; DHFR inhibitors; netropsin; MGBAs; drug design; molecular dynamics trimethoprim; DHFR inhibitors; netropsin; MGBAs; drug design; molecular dynamics
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MDPI and ACS Style

Wróbel, A.; Baradyn, M.; Ratkiewicz, A.; Drozdowska, D. 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. Int. J. Mol. Sci. 2021, 22, 3685. https://doi.org/10.3390/ijms22073685

AMA Style

Wróbel A, Baradyn M, Ratkiewicz A, Drozdowska D. 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. International Journal of Molecular Sciences. 2021; 22(7):3685. https://doi.org/10.3390/ijms22073685

Chicago/Turabian Style

Wróbel, Agnieszka, Maciej Baradyn, Artur Ratkiewicz, and Danuta Drozdowska. 2021. "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" International Journal of Molecular Sciences 22, no. 7: 3685. https://doi.org/10.3390/ijms22073685

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