DihydrofolateReductase (DHFR) Inhibitors: A Comprehensive Review

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Dihydrofolate reductase (DHFR) is essential for cellular biosynthesis in prokaryotes and eukaryotes.
• DHFR is a validated target for treating diverse diseases including cancer, infections (bacterial, malaria, tuberculosis), and inflammatory conditions.
• A need exists for novel DHFR inhibitors, particularly against drug-resistant pathogens.

Purpose of the Study:

• To review recent advancements in DHFR inhibitors over the past two decades.
• To highlight promising DHFR inhibitors, their structures, and mechanisms of action.
• To explore the pharmacological applications, in-silico studies, and patents related to DHFR inhibitors for future drug design.

Main Methods:

• Literature review focusing on the last 20 years of DHFR inhibitor research.
• Analysis of structural features, mechanisms of action, and pharmacological data of reported inhibitors.
• Examination of in-silico studies and recent patents concerning DHFR inhibitors.

Main Results:

• Recent DHFR inhibitors, both synthetic and natural, frequently incorporate heterocyclic structures.
• Substituted 2,4-diaminopyrimidine motifs are common in effective non-classical antifolates like trimethoprim and pyrimethamine.
• In-silico studies and patent literature reveal ongoing efforts in DHFR inhibitor development.

Conclusions:

• DHFR remains a highly promising target for developing novel therapeutics.
• Heterocyclic compounds and modified diaminopyrimidine structures are key features of effective DHFR inhibitors.
• Further research into DHFR inhibitors holds significant potential for addressing unmet medical needs and combating drug resistance.