Abstract
A new series of trimethoprim (TMP) analogs containing amide bonds (1–6) 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.
Highlights
Folate metabolism has long been recognized as an important and attractive target for the development of therapeutic agents against bacterial, parasitic infections [1], and cancer therapy [2,3].Dihydrofolate reductase (DHFR) is an essential enzyme, which catalyzes the reduction of dihydrofolate acid (7,8-dihydrofolate, DHF) to tetrahydrofolic acid (5,6,7,8-THF) using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Scheme 1) [4,5,6]
Inhibition of folate-metabolizing enzymes leads to an imbalance in the pathways involved in active synthesizing thymidylate, disrupts DNA replication, and eventually causes cell death [10]
dihydrofolate reductase (DHFR) is a very good example of a well-established molecular target of new active compounds, which could be approved as antibacterial drugs and therapeutic agents against a variety of fatal disorders e.g., cancer [11,12]
Summary
Folate metabolism has long been recognized as an important and attractive target for the development of therapeutic agents against bacterial, parasitic infections [1], and cancer therapy [2,3].Dihydrofolate reductase (DHFR) is an essential enzyme, which catalyzes the reduction of dihydrofolate acid (7,8-dihydrofolate, DHF) to tetrahydrofolic acid (5,6,7,8-THF) using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Scheme 1) [4,5,6]. Folate metabolism has long been recognized as an important and attractive target for the development of therapeutic agents against bacterial, parasitic infections [1], and cancer therapy [2,3]. Inhibition of folate-metabolizing enzymes leads to an imbalance in the pathways involved in active synthesizing thymidylate, disrupts DNA replication, and eventually causes cell death [10]. DHFR is a very good example of a well-established molecular target of new active compounds, which could be approved as antibacterial drugs and therapeutic agents against a variety of fatal disorders e.g., cancer [11,12]. A lot of research projects have focused on the search for new compounds active against this enzyme, most often derivatives of methotrexate (MTX), which is confirmed to be an effective inhibitor by extensive literature in this field [18,19]
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