Exploration and Biological Evaluation of 1,3-Diamino-7H-pyrrol[3,2-f]quinazoline Derivatives as Dihydrofolate Reductase Inhibitors

Abstract

Dihydrofolate reductase (DHFR), a core enzyme of folate metabolism, plays a crucial role in the biosynthesis of purines and thymidylate for cell proliferation and growth in both prokaryotic and eukaryotic cells. However, the development of new DHFR inhibitors is challenging due to the limited number of scaffolds available for drug development. Hence, we designed and synthesized a new class of DHFR inhibitors with a 1,3-diamino-7H-pyrrol­[3,2-f]­quinazoline derivative (PQD) structure bearing condensed rings. Compound 6r exhibited therapeutic effects on mouse models of systemic infection and thigh infection caused by methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. Moreover, methyl-modified PQD compound 8a showed a strong efficacy in a murine model of breast cancer, which was better than the effects of taxol. The findings showcased in this study highlight the promising capabilities of novel DHFR inhibitors in addressing bacterial infections as well as breast cancer.

Design, Synthesis, and Biological Evaluation of 5-(5-Iodo-2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine (AF-353) Derivatives as Novel DHFR Inhibitors against Staphylococcus aureus

“…The time-kill curve assay is a critically important test that assesses the bactericidal activity of drugs at various concentrations and stages of bacterial development . Bacterial suspensions of S.…”

“…Additionally, classical DHFR inhibitors must be actively taken up into the cell by reduced folate carriers (RFCs), and due to the lack of reduced folate carriers in bacterial cell membranes, classical DHFR inhibitors cannot be used in bacterial infections. , Nonclassical DHFRs ( e.g. , trimethoprim, iclaprim, propargyl-linked antifolates (PLAs), and 1,3-diamino-7 H -pyrrol­[3,2- f ]­quinazoline derivatives (PQDs) , in Figure B) are structurally simpler than classical DHFR inhibitors because they replace the 4-amino benzoic acid and glutamic acid moieties with a lipophilic ring, allowing the inhibitors to enter the cell passively in the absence of folate carriers . The favorable efficacy of these nonclassical DHFR inhibitors against S.…”