Dihydrofolate reductase inhibitors: patent landscape and phases of clinical development (2001–2021)

ABSTRACT

Introduction

Dihydrofolate reductase (DHFR) plays an important role in the biosynthesis of amino acid and folic acid. It participates by reducing dihydrofolate to tetrahydrofolate, in the presence of nicotinamide dinucleotide phosphate cofactor, and has been verified by various clinical studies to use DHFR as a target for the treatment of cancer and various bacterial infections.

Area covered

In this review, we have disclosed patents of synthetics and natural DHFR inhibitors with diaminopyrimidine and quinazoline nucleus from 2001. Additionally, this review highlights the clinical progression of numerous DHFR inhibitors received from the last five years.

Expert Opinion

From 2001 to 2021, numerous active chemical scaffolds have been introduced and are exposed as lead candidates that have entered clinical trials as potent DHFR inhibitors. Moreover, researchers have paid considerable attention to the development of a new class of DHFR inhibitors with higher selectivity and potency. This development includes synthesis of synthetic as well as natural compounds that are potent DHFR inhibitors. On the basis of literature review, we can anticipate that there are a huge number of novel active molecules available for the future that could possess superior abilities to target this enzyme with a profound pharmacological profile.

KEYWORDS:

• Dihydrofolate reductase enzyme
• bacterial infections
• cancer
• patent review
• clinical development
• dihydrofolate reductase inhibitors

Article highlights

• Summary of DHF-THF cycle

• Detailed mechanism of conversion of dihydrofolate to tetrahydrofolate reductase enzyme and its crystal structure with its binding domain has been demonstrated

• Numerous DHFR inhibitors patented from 2001 have been reported

• Several DHFR inhibitors screened in clinical trial study over the last few years have been presented

• Multiple synthetic as well natural DHFR inhibitors published during the last few years have also been revealed

• Most active compounds that exhibited higher DHFR inhibitory activity against different strains were also exemplified

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

The data is carefully assessed and gathered from different bibliographic sources from https://www.sciencedirect.com, https://patents.google.com, https://www.rcsb.org and https://clinicaltrials.gov and the link for any specific study is available from the corresponding author upon reasonable request.

Additional information

Funding

Authors are grateful to the Women Scientists Scheme-A (WOS A) under Department of Science and Technology: Project No. (SR/WOS-A/CS-62/2018) and University Grants Commission under Council of Scientific and Industrial Research (CSIR).