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.

五十多年来，病原体之间的新抗性机制的发展，导致抗生素不敏感性的基因的发生和传播以及癌症疾病一直是世界范围内的严重临床问题。因此，非常重要的是寻找可用作新药的新的领先结构和活性物质，特别是针对对所有可用疗法产生抗药性的菌株。二氢叶酸还原酶（DHFR）作为细菌耐药性的分子靶标已引起了数十年的关注，从而产生了许多有用的药物。甲氧苄啶（TMP）（2,4-二氨基-5-（3'，4'，5'-三甲氧基苄基）嘧啶）是众所周知的二氢叶酸还原酶抑制剂，是尿路感染（UTI）中使用的标准抗生素之一。这篇综述着重介绍了TMP作为DHFR抑制剂在结构修饰方面的设计，合成和生物学评估方面的进展。此外，本报告还介绍了人类和病原体DHFR活性位点的差异。此外，对DHFR抑制作用及其与抗菌药物和寄生虫化学疗法的相关性进行了详尽的综述。