An Insight into Synthetic Strategies and Recent Developments of Dihydrofolate Reductase Inhibitors

Abstract

The dihydrofolate reductase (DHFR) is a significant target in cancer, microbial infection, fungal infection, malaria, leishmaniasis, and tuberculosis, among other diseases. The DHFR gene was discovered in prokaryotes and eukaryotes in the late 1950s and is found in all dividing cells. DHFR inhibitors are used for a variety of medicinal purposes. Increased resistance to therapeutic agents such as anticancer, antibiotic, anti‐tuberculosis, and antifungal sparked interest in the development of potent, broad‐spectrum medicines to address the issues. DHFR is a critical target in the development of innovative solutions to address the issues. Methotrexate, trimethoprim, sulfonamides, pyrimethamine, aminopterin, methotrexate, edatrexate, and pralatrexate are only a few of the medications that target DHFR. These medications are known as DHFR inhibitors. These inhibitors block the enzyme dihydrofolate reductase, resulting in a folic acid synthesis pathway that is compromised. The DHFR is involved in the conversion of dihydrofolate to tetrahydrofolate. Purine, pyrazole, pyrimidine, triazole, oxadiazole, and other heterocyclic motifs have shown to have a potential effect on the DHFR. In the medicinal chemistry community, a better understanding of the so‐called enzyme and biochemical underpinnings responsible for enzyme selectivity has led to the development of improved, unique, and new treatments. Several researchers are working on DHFR inhibitors intensely, using a variety of synthetic techniques, molecular modelling, mechanistic studies, in‐vitro and in‐vivo biological evaluations, and structure‐activity relationships (SAR). This review, compiles the findings of several research groups during the last five years. The molecular biology of DHFR, its biosynthetic pathway, and the powerful structure of DFHR inhibitors discovered during the search are all included in this review. The study also includes the latest developments in synthetic methods, molecular docking, and structure‐activity relationships.

Nitrogen‐Containing Heterocyclic Scaffolds as EGFR Inhibitors: Design Approaches, Molecular Docking, and Structure‐Activity Relationships

“…Some of the N‐heterocyclic containing EGFR inhibitor approved by the US FDA are shown in Figure 5 [44,59] . Moreover, N‐heterocyclic compounds exhibit different biological properties such as anti‐HIV, antidiabetic, herbicidal activity, anticancer activity, insecticidal agents, anti‐inflammatory, [60] antibacterial, [41b] antioxidant, [44,61] anticonvulsant, [58b,62] antiallergic, and enzyme inhibitors. These N‐heterocyclic rings also meet the fundamental pharmacophore which is a prerequisite requirement for any molecule to be an EGFR inhibitor.…”

Unveiling the Efficacy of Sesquiterpenes from Marine Sponge Dactylospongia elegans in Inhibiting Dihydrofolate Reductase Using Docking and Molecular Dynamic Studies

“…Owing to the growing drug resistance to some of the available DHFR inhibitors, research for the discovery of new and selective DHFR inhibitors has been intensely increased, using molecular modeling, synthetic techniques, in vivo and in vitro biological investigation, mechanistic studies, and structure-activity relationships [ 10 , 11 , 12 ].…”

Interaction of Pteridophytic Bioactive Compounds With Fungal Dihydrofolate Reductase Enzyme as Inhibitor

“…DHFR is an important target in cancer, microbial infections, malaria, tuberculosis, fungal infections etc. [5]. DHFR is involved in the folate synthetic pathway responsible for DNA synthesis which is initiated by the cellular uptake of folic acid through a specialized mechanism followed by the reduction of dihydrofolate to tetrahydrofolate (THF) in the presence of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) [3].…”