Dihydroorotate dehydrogenase inhibitors in anti-infective drug research

Abstract

Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.

Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro

“…Inhibitors of de novo pyrimidine biosynthesis have broad-spectrum antiviral activity [25][26][27][28][29]. Dihydroorotate dehydrogenase (DHODH) is a key enzyme involved in de novo pyrimidine biosynthesis, converting dihydroorotate (DHO) into orotate, and DHODH has been validated as one of the targets of pyrimidine biosynthesis inhibitors exhibiting antiviral activity [30]. We investigated the antiviral activity of a series of novel DHODH inhibitors (i.e., Compound (Cmp) 1, Cmp 2, Cmp 3, Cmp 4, and Cmp 5) against diverse mammarenaviruses.…”

Microwave‐assisted synthesis of 2‐styrylquinoline‐4‐carboxylic acid derivatives to improve the toxic effect against Leishmania (Leishmania) amazonensis

“…As a possible candidate affected by 2‐arylvinyl‐4‐quinolinecarboxylic acid derivatives, the flavoenzyme dihydroorotate dehydrogenase (DHODH) is a validated target for the inhibitory effect against Leishmania spp., as well as an antiparasite drug in the research field of new drug discovery. [ 40 ] DHODHs catalyze the stereoselective oxidation of ( S )‐dihydroorotate (DHO) to orotate (ORO) in the fourth reaction of the de novo pyrimidine biosynthetic pathway, been divided into Class 1 and Class 2 according to sequence similarity, subcellular location, and preference for the substrate. [ 41 ] Class 1 DHODHs are cytosolic enzymes, present in Leishmania genus and T. cruzi , with a few examples of specific inhibitors being mentioned in the literature.…”

Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

“…Blocking of DHODH results in pyrimidine depletion which is very effective against rotavirus (responsible for dehydrating diarrhea). For that reason, LF anti-microbial activity was investigated against other organisms such as Helicobacter pylori , Plasmodium falciparum , and Schistosoma mansoni [89] .…”