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

Abstract

The development of new mechanisms of resistance among pathogens, the occurrence and transmission of genes responsible for antibiotic insensitivity, as well as cancer diseases have been a serious clinical problem around the world for over 50 years. Therefore, intense searching of new leading structures and active substances, which may be used as new drugs, especially against strain resistant to all available therapeutics, is very important. Dihydrofolate reductase (DHFR) has attracted a lot of attention as a molecular target for bacterial resistance over several decades, resulting in a number of useful agents. Trimethoprim (TMP), (2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine) is the well-known dihydrofolate reductase inhibitor and one of the standard antibiotics used in urinary tract infections (UTIs). This review highlights advances in design, synthesis, and biological evaluations in structural modifications of TMP as DHFR inhibitors. In addition, this report presents the differences in the active site of human and pathogen DHFR. Moreover, an excellent review of DHFR inhibition and their relevance to antimicrobial and parasitic chemotherapy was presented.

Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents

“…TMP is a pyrimidine antifolate drug, which exerts antimicrobial activity by blocking the reduction of dihydrofolate to tetrahydrofolate, the active form of folic acid, by susceptible organisms [ 2 , 24 , 25 ]. One of our reviews presents an extensive range of research literature on the first and most recent achievements in TMP analogs as DHFR inhibitors and underlines new directions in developing and modeling DHFR inhibitors [ 26 ]. This literature analysis confirms that there are only a few reports showing the anticancer activity of TMP analogs.…”

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

“…The mechanism of this inhibition consists in preventing the conversion of DHF to an active form, i.e., THF [3,32]. One of our reviews presents an extensive range of research literature on the first and most recent achievements in TMP analogs as DHFR inhibitors and underlines new directions in developing and modeling DHFR inhibitors [33]. Currently, Pedrola et al [34] showed group of TMP analogs display meaningful structural features of the initial drug together with relevant modifications at several points, keeping antibiotic potency and showing satisfactory antimicrobial profile (good activity levels and reduced growth rates), especially against methicillin-resistant Staphylococcus aureus (Figure 1).…”

Folic acid-sulfonamide conjugates as antibacterial agents: design, synthesis and molecular docking studies

“…Compounds containing pyrimidine, pteridine and azine moieties have already been reported as good DHFR inhibitors. 33,34 The rate of folate metabolism accelerates during microbial infection owing to their particular DNA and for protein synthesis to maintain proper cell replication. Taking advantage of this accelerated rate of metabolism, folic acid antagonists have been used to treat various microbial infections.…”