1. Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs
- Author
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Danuta Drozdowska, Dawid Maliszewski, Maciej Baradyn, and Agnieszka Wróbel
- Subjects
Molecular model ,Pharmaceutical Science ,urologic and male genital diseases ,01 natural sciences ,Trimethoprim ,Analytical Chemistry ,chemistry.chemical_compound ,dihydrofolate reductase ,Drug Discovery ,Dihydrofolate reductase ,Bacteriophage T4 ,heterocyclic compounds ,chemistry.chemical_classification ,0303 health sciences ,biology ,Chemistry ,trimethoprim analogs ,Biological activity ,female genital diseases and pregnancy complications ,Anti-Bacterial Agents ,Molecular Docking Simulation ,Chemistry (miscellaneous) ,Molecular Medicine ,medicine.symptom ,medicine.drug ,Stereochemistry ,DNA-binding agents ,Article ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,medicine ,Physical and Theoretical Chemistry ,Antibacterial drug ,030304 developmental biology ,010405 organic chemistry ,Organic Chemistry ,DNA ,molecular docking ,bacterial infections and mycoses ,0104 chemical sciences ,Tetrahydrofolate Dehydrogenase ,Enzyme ,Mechanism of action ,DNA, Viral ,biology.protein ,Folic Acid Antagonists ,human activities - Abstract
A new series of trimethoprim (TMP) analogs containing amide bonds (1&ndash, 6) have been synthesized. Molecular docking, as well as dihydrofolate reductase (DHFR) inhibition assay were used to confirm their affinity to bind dihydrofolate reductase enzyme. Data from the ethidium displacement test showed their DNA-binding capacity. Tests confirming the possibility of DNA binding in a minor groove as well as determination of the association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT)2 and poly (dG-dC)2. Additionally, the mechanism of action of the new compounds was studied. In conclusion, some of our new analogs inhibited DHFR activity more strongly than TMP did, which confirms, that the addition of amide bonds into the analogs of TMP increases their affinity towards DHFR.
- Published
- 2019