Recent advances on patents of Plasmodium falciparum dihydroorotate dehydrogenase ( Pf DHODH) inhibitors as antimalarial agents

ABSTRACTIntroduction Pyrimidine nucleotides are essential for the parasite's growth and replication. Parasites have only a de novo pathway for the biosynthesis of pyrimidine nucleotides. Dihydroorotate dehydrogenase (DHODH) enzyme is involved in the rate-limiting step of the pyrimidine biosynthesis pathway. DHODH is a biochemical target for the discovery of new antimalarial agents.Area covered This review discussed the development of patented PfDHODH inhibitors published between 2007 and 2023 along with their chemical structures and activities.Expert opinion PfDHODH enzyme is involved in the rate-limiting 4th step of the pyrimidine biosynthesis pathway. Thus, inhibition of PfDHODH using species-selective inhibitors has drawn much attention for treating malaria, because they inhibit parasite growth without affecting normal human functions. Looking at the current scenario of antimalarial drug resistance with most of the available antimalarial drugs, there is a huge need for targeted newer agents. Newer agents with unique mechanisms of action may be devoid of drug toxicity, adverse effects and the ability of parasites to quickly gain resistance, and PfDHODH inhibitors can be those newer agents. Many PfDHODH inhibitors were patented in the past, and the dependency of Plasmodium on de novo pyrimidine provided a new approach for the development of novel antimalarial agents.KEYWORDS: Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH)PfDHODH inhibitorsde novo Pyrimidine pathwayMalariaantimalarial agentsDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsThis review provides an overview of the PfDHODH enzyme as a druggable target for the treatment of malaria.Information regarding antimalarial drugs and their role in the malaria life cycle is also included in the review.This review summarises the role of the PfDHODH enzyme in the de novo pyrimidine biosynthesis pathway.The review covers a detailed description of PfDHODH inhibitors patented between 2007 and 2023.The chemical structures and antimalarial activities of PfDHODH inhibitors, along with their general synthetic schemes, are covered in this review.The discovery of species-selective PfDHODH inhibitors can be a useful approach for eliminating antimalarial drug resistance and adverse and toxic effects.Declaration of interestsP Gehlot is supported by the grant from INSPIRE of Department of Science & Technology (DST INSPIRE/IF210107). The authors have no other 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 apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contribution statementV. K. Vyas designed and conceptualized this idea. P. Gehlot gathered all the literature and patent-related information. The manuscript was written and revised by P. Gehlot. V. K. Vyas supervised, edited, and finalised the framework of the article. V. K. Vyas and P. Gehlot have approved the final version of this manuscript.AcknowledgmentsThe authors are thankful to Nirma University, Ahmedabad, India for this work, which is a part of the Doctor of Philosophy (PhD) research work of Pinky Gehlot, to be submitted to Nirma University, Ahmedabad, IndiaAdditional informationFundingThis paper was funded by DST INSPIRE-Department of Science and Technology, India for financial assistance under Project number DST INSPIRE/[IF210107].