Human dihydrofolate reductase (
hDHFR) is an essential cellular enzyme, and inhibiting its activity is a promising strategy for cancer therapy. We have chosen the trimethoprim molecule (
TMP) as a model compound in our search for a new class of
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Human dihydrofolate reductase (
hDHFR) is an essential cellular enzyme, and inhibiting its activity is a promising strategy for cancer therapy. We have chosen the trimethoprim molecule (
TMP) as a model compound in our search for a new class of
hDHFR inhibitors. We incorporated an amide bond, a structural element typical of netropsin, a ligand that binds selectively in the minor groove of DNA, into the molecules of
TMP analogs. In this work, we present previously obtained and evaluated eleven benzamides (
JW1–
JW8;
MB1,
MB3-
MB4). Recently, these compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1).
JW8 was most active against AChE, with an inhibitory concentration of AChE IC
50 = 0.056 µM, while the IC
50 for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC
50 value was 9.01 µM compared to that for quercetin, with IC
50 = 4.89 µM. All the benzamides were active against
hDHFR, with IC
50 values ranging from 4.72 to 20.17 µM, and showed activity greater than
TMP (55.26 µM). Quantitative results identified the derivatives
JW2 and
JW8 as the most promising. A molecular modeling study demonstrates that
JW2 interacts strongly with the key residue Gly-117
, while
JW8 interacts strongly with Asn-64 and Arg-70. Furthermore,
JW2 and
JW8 demonstrate the ability to stabilize the
hDHFR enzyme, despite forming fewer hydrogen bonds with the protein compared to reference ligands. It can be concluded that this class of compounds certainly holds great promise for good active leads in medicinal chemistry.
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