Sehrawat Renu, Rathee Priyanka, Khatkar Sarita, Akkol EsraKüpeli, Khayatkashani Maryam, Nabavi Seyed Mohammad, Khatkar Anurag
Gurugram Global College of Pharmacy, Gurugram, Haryana, India.
SBMN Institute of Pharmaceutical Sciences and Research, B.M.U., Rohtak.
Curr Med Chem. 2023 Mar 10. doi: 10.2174/0929867330666230310091510.
Dihydrofolate reductase (DHFR) is an indispensable enzyme required for the survival of most prokaryotic and eukaryotic cells as it is involved in the biosynthesis of essential cellular components. DHFR has attracted a lot of attention as a molecular target for various diseases like cancer, bacterial infection, malaria, tuberculosis, dental caries, trypanosomiasis, leishmaniasis, fungal infection, influenza, Buruli ulcer, and respiratory illness. Various teams of researchers have reported different DHFR inhibitors to explore their therapeutic efficacy. Despite all the progress made, there is a strong need to find more novel leading structures, which may be used as better and safe DHFR inhibitors, especially against the microorganisms which are resistant to the developed drug candidates.
This review aims to pay attention to recent development, particularly made in the past two decades and published in this field, and pay particular attention to promising DHFR inhibitors. Hence, an attempt has been made in this article to highlight the structure of dihydrofolate reductase, the mechanism of action of DHFR inhibitors, most recently reported DHFR inhibitors, diverse pharmacological applications of DHFR inhibitors, reported in-silico study data and recent patents based on DHFR inhibitors to comprehensively portray the current scenery for researchers interested in designing novel DHFR inhibitors.
A critical review of recent studies revealed that most novel DHFR inhibitor compounds either synthetically or naturally derived are characterized by the presence of heterocyclic moieties in their structure. Non-classical antifolates like trimethoprim, pyrimethamine, and proguanil are considered excellent templates to design novel DHFR inhibitors, and most of them have substituted 2,4-diamino pyrimidine motifs. Targeting DHFR has massive potential to be investigated for newer therapeutic possibilities to treat various diseases of clinical importance.
二氢叶酸还原酶（DHFR）是大多数原核细胞和真核细胞生存所必需的一种酶，因为它参与细胞必需成分的生物合成。作为癌症、细菌感染、疟疾、结核病、龋齿、锥虫病、利什曼病、真菌感染、流感、布鲁里溃疡和呼吸道疾病等各种疾病的分子靶点，DHFR引起了广泛关注。多个研究团队报道了不同的DHFR抑制剂，以探索其治疗效果。尽管取得了所有这些进展，但仍迫切需要找到更多新颖的先导结构，这些结构可作为更好、更安全的DHFR抑制剂，尤其是针对对已开发候选药物耐药的微生物。
本综述旨在关注该领域尤其是过去二十年的最新进展，并特别关注有前景的DHFR抑制剂。因此，本文试图突出二氢叶酸还原酶的结构、DHFR抑制剂的作用机制、最近报道的DHFR抑制剂、DHFR抑制剂的多种药理学应用、报道的计算机模拟研究数据以及基于DHFR抑制剂的近期专利，以便全面描绘对设计新型DHFR抑制剂感兴趣的研究人员的当前研究状况。
对近期研究的批判性综述表明，大多数新型DHFR抑制剂化合物无论是合成的还是天然衍生的，其结构中都含有杂环部分。像甲氧苄啶、乙胺嘧啶和氯胍这样的非经典抗叶酸剂被认为是设计新型DHFR抑制剂的优秀模板，并且它们大多数都有取代的2,4-二氨基嘧啶基序。针对DHFR进行研究以探索治疗各种具有临床重要性疾病的新治疗可能性具有巨大潜力。
