Modified 2,4-diaminopyrimidine-based dihydrofolate reductase inhibitors as potential drug scaffolds against Bacillus anthracis

Abstract

The current paper describes the synthesis and biological evaluation of dihydrophthalazine-appended 2,4-diaminopyrimidine (DAP) inhibitors (1) oxidized at the methylene bridge linking the DAP ring to the central aromatic ring and (2) modified at the central ring ether groups. Structures 4a-b incorporating an oxidized methylene bridge showed a decrease in activity, while slightly larger alkyl groups (CH2CH3 versus CH3) on the central ring oxygen atoms (R2 and R3) had a minimal impact on the inhibition. Comparison of the potency data for previously reported RAB1 and BN-53 with the most potent of the new derivatives (19b and 20a-b) showed similar values for inhibition of cellular growth and direct enzymatic inhibition (MICs 0.5-2 μg/mL). Compounds 29-34 with larger ester and ether groups containing substituted aromatic rings at R3 exhibited slightly reduced activity (MICs 2-16 μg/mL). One explanation for this attenuated activity could be encroachment of the extended R3 into the neighboring NADPH co-factor. These results indicate that modest additions to the central ring oxygen atoms are well tolerated, while larger modifications have the potential to act as dual-site inhibitors of dihydrofolate reductase (DHFR).

Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs

“…Therefore, 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]. Several classes of compounds have been explored for their potential antifolate activity; among the most outstanding are diaminopyrimidine [13,14], diaminoquinazolin [15], diaminopteridine [16], and also diaminotriazines [17]. Over the last decade, 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].…”

Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs

“…Consequently, targeting DHFR is lethal for rapidly proliferating cells like cancer or bacterial cells. Several classes of compounds have been explored for their potential anti-folate activity, among the most prominent are diaminoquinazoline 20 , diaminopyrimidine 21 , 22 , diaminopteridine 23 and diaminotriazines 24 . DHFR inhibitors that have found widespread application in therapy are methotrexate (used in chemotherapy against cancer cells and rheumatoid arthritis), trimethoprim, (for bacterial DHFR) and pyrimethamine (against Plasmodium falciparum DHFR).…”

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

“…Therefore, 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 variety of fatal disorders e.g., cancer [8,9]. Several classes of compounds have been explored for their potential antifolate activity, among the most outstanding are diaminopyrimidine [10,11], diaminoquinazolin [12], diaminopteridine [13], and also diaminotriazines [14]. Inhibitors of DHFR characterize widespread application in the treatment of cancer and rheumatoid arthritis (methotrexate, MTX), bacterial DHFR enzyme (trimethoprim, TMP), and Plasmodium falciparum (pf)DHFR (pyrimethamine, PYR).…”