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.

Fig. 1

Structures of classical and nonclassical DHFR inhibitors

Fig. 2

Structures of selected antifolates and TMP analogues

Fig. 3

Rashid’s hydroxyl TMP analogues

Fig. 4

Structures of selected TMP analogues containing quinoline ring

Fig. 5

Structures of selected TMP analogues against Toxoplasmosis, Mycobacterium avium, and Pneumocystis carinii DHFR enzyme

Fig. 6

Structures of compounds 49–51

Fig. 7

Structures of propargyl-linked inhibitors—A

Fig. 8

Structures of propargyl-linked inhibitors—B

Fig. 9

Structures of propargyl-linked inhibitors—C

Fig. 10

Structures of TMP analogues directed at new targets