Fluoroorotic Acid, Ultra Pure is an inhibitor of thymidylate synthase and can be used as a selector in yeast molecular genetics [1]. Fluoroorotic Acid has similar antifungal effects to 5-fluorocytosine and a mild antifungal effect on dermatophytes [2]. Fluoroorotic Acid has strong antimalarial activity [3-4].
In vitro, Fluoroorotic Acid (1nM-100μM; 48h) has dose-dependent and effective antimalarial activity against Plasmodium falciparum, with an IC50 of 6nM. Compared to the vulnerability of the malaria parasites, Fluoroorotic Acid (1nM-100μM; 48h) shows lower cytotoxicity in mammalian cells HT-1080 with an IC50 of 10μM [5].
In vivo, Fluoroorotic Acid (0.2-5mg/kg; ip; every 4 hours for 3 days) can significantly inhibit the parasitemia of the P. yoelii mouse model infected with malaria parasites. Without uridine (dose of 5mg/kg), high-dose treatment of Fluoroorotic Acid shows toxicity to mice [6]. 5-Fluoroorotic acid (2.5, 5.0, and 10mg/kg/day for 3 days; p.o.) used alone can dose-dependently inhibit the number of parasites and parasitemia in mice infected with Plasmodium berghei, with inhibition rates ranging from 92% to 100%. At the highest dose, the combination of Fluoroorotic acid-pyrimethamine and Fluoroorotic acid-dapsone-artesunate has a synergistic effect, with a cure rate of 100% [7].
References:
[1] Boeke JD, Trueheart J, Natsoulis G, Fink GR. 5-Fluoroorotic acid as a selective agent in yeast molecular genetics. Methods Enzymol. 1987;154:164-175.
[2] Nikolova K, Maneva L, Karamanov G, Golovinsky E. Studies on the antimycotic activity of 5-fluoroorotic acid. Methods Find Exp Clin Pharmacol. 1987;9(2):85-89.
[3] Santiago T C. Understanding phospholipid biosynthesis in the human malaria parasite Plasmodium falciparum using Saccharomyces cerevisiae as a surrogate system[M]. University of Connecticut, 2005.
[4] Biagini G A, Viriyavejakul P, O'neill P M, et al. Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria[J]. Antimicrobial agents and chemotherapy, 2006, 50(5): 1841-1851.
[5] Rathod PK, Khatri A, Hubbert T, Milhous WK. Selective activity of 5-fluoroorotic acid against Plasmodium falciparum in vitro. Antimicrob Agents Chemother. 1989;33(7):1090-1094.
[6] Gómez ZM, Rathod PK. Antimalarial activity of a combination of 5-fluoroorotate and uridine in mice. Antimicrob Agents Chemother. 1990;34(7):1371-1375.
[7] Muregi FW, Kano S, Kino H, Ishih A. Plasmodium berghei: efficacy of 5-fluoroorotate in combination with commonly used antimalarial drugs in a mouse model. Exp Parasitol. 2009;121(4):376-380.
Fluoroorotic Acid, Ultra Pure是thymidylate synthase的抑制剂，可以作为酵母分子遗传学中的一种选择剂 [1]。Fluoroorotic Acid具有与5-fluorocytosine相近的抗念珠菌的作用，以及温和的抗皮肤癣菌作用 [2]。Fluoroorotic Acid具有较强的抗疟活性 [3-4]。
在体外，Fluoroorotic Acid（1nM-100μM; 48h)对Plasmodium falciparum具有剂量依赖性的有效的抗疟活性，IC50为6nM。相对于疟疾寄生虫的脆弱性，Fluoroorotic Acid（1nM-100μM; 48h)在哺乳动物细胞HT-1080中表现出较低的细胞毒性，IC50为10μM [5]。
在体内，Fluoroorotic Acid（0.2-5mg/kg/d; i.p.; every 4 hours for 3 days）可显著抑制感染P. yoelii小鼠模型中的疟原虫血症。在没有尿苷（剂量为5mg/kg）的情况下，Fluoroorotic Acid高剂量治疗对小鼠表现出毒性 [6]。Fluoroorotic Acid（2.5, 5.0, and 10mg/kg/d for 3 days; p.o.）单独使用能够以剂量依赖性抑制感染Plasmodium berghei后小鼠的寄生虫数量和寄生虫血症，抑制率在92%至100%之间。在最高使用剂量下，Fluoroorotic Acid-pyrimethamine和Fluoroorotic Acid-dapsone-artesunate组合具有协同作用，治愈率为100% [7]。