111
Views
0
CrossRef citations to date
0
Altmetric
Review

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

& ORCID Icon
Pages 579-596 | Received 26 Jun 2023, Accepted 03 Nov 2023, Published online: 14 Nov 2023

References

  • Vyas VK, Bhati S, Patel S, et al. Structure- and ligand-based drug design methods for the modeling of antimalarial agents: a review of updates from 2012 onwards. J Biomol Struct Dynamics. 2022;40(20):10481–10506. doi: 10.1080/07391102.2021.1932598
  • Weiss DJ, Lucas TCD, Nguyen M, et al. Mapping the global prevalence, incidence, and mortality of Plasmodium falciparum, 2000–17: a spatial and temporal modelling study. Lancet. 2019;394(10195):322–331.
  • Escalante AA, Pacheco MA. Malaria molecular epidemiology: an evolutionary genetics perspective. Microbiol Spectr. 2019;7(4). doi: 10.1128/microbiolspec.AME-0010-2019
  • Lou Y, Han X, Kuglstatter A, et al. Structure-based drug design of RN486, a potent and selective bruton’s tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis. J Med Chem. 2015;58(1):512–516.
  • World malaria report 2022. 2022[ Online].
  • WHO. WHO malaria Policy Advisory Committee (MPAC) 2018; (April):p. 1–18.
  • Howes RE, Battle KE, Mendis KN, et al. Global Epidemiology of Plasmodium vivax. Am J Trop Med Hyg. 2016;95(6 Suppl):15–34.
  • Lee J-H, Yang D-S, Goulbourne CN, et al. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci. 2022;25(6):688–701.
  • Lubis IND, Wijaya H, Lubis M, et al. Contribution of Plasmodium knowlesi to Multispecies human malaria Infections in North Sumatera, Indonesia. J Infect Dis. 2017;215(7):1148–1155.
  • Ng YL, Lee W-C, Lau Y-L, et al. The impact of geographical variation in Plasmodium knowlesi apical membrane protein 1 (PkAMA-1) on Invasion Dynamics of P. knowlesi. Trop Med Infect Dis. 2023;8(1):56.
  • Mace KE, Arguin PM, Tan KR. Malaria surveillance — United States, 2015. MMWR Surveill Summ. 2018;67(7):1–28. doi: 10.15585/mmwr.ss6707a1
  • Khan MI, Qureshi H, Bae SJ, et al. Malaria prevalence in Pakistan: a systematic review and meta-analysis (2006–2021). Heliyon. 2023;9(4):e15373.
  • White NJ, Pukrittayakamee S, Hien TT, et al. Malaria. Lancet. 2014;383(9918):723–735.
  • Naserrudin NA, Yong PPL, Monroe A, et al. Seeing malaria through the eyes of affected communities: using photovoice to document local knowledge on zoonotic malaria causation and prevention practices among rural communities exposed to Plasmodium knowlesi malaria in Northern Borneo Island. Malaria j. 2023;22(1):166.
  • Fornace KM, Topazian HM, Routledge I, et al. No evidence of sustained nonzoonotic Plasmodium knowlesi transmission in Malaysia from modelling malaria case data. Nat Commun. 2023;14(1):2945.
  • Sutherland CJ. Persistent parasitism: the adaptive biology of malariae and ovale malaria. Trends Parasitol. 2016;32(10):808–819. doi: 10.1016/j.pt.2016.07.001
  • Daniels RF, Deme AB, Gomis JF, et al. Evidence of non-Plasmodium falciparum malaria infection in Kédougou, Sénégal. Malaria j. 2017;16(1):9.
  • Conroy AL, Datta D, John CC. What causes severe malaria and its complications in children? Lessons learned over the past 15 years. BMC Med. 2019;17(1):52. doi: 10.1186/s12916-019-1291-z
  • Horak P, Auer H, Wiedermann U, et al. Malaria in Austria: a retrospective analysis of malaria cases diagnosed at a reference center in 2010-2020. Wien Klin Wochenschr. 2023;135:1–8.
  • Ashley EA, Pyae Phyo A, Woodrow CJ. Malaria. Lancet. 2018;391(10130):1608–1621. doi: 10.1016/S0140-6736(18)30324-6
  • Benelli G, Beier JC. Current vector control challenges in the fight against malaria. Acta tropica. 2017;174:91–96. doi: 10.1016/j.actatropica.2017.06.028
  • Lamptey H, Ofori MF, Kusi KA, et al. The prevalence of submicroscopic Plasmodium falciparum gametocyte carriage and multiplicity of infection in children, pregnant women and adults in a low malaria transmission area in Southern Ghana. Malaria j. 2018;17(1):331.
  • Zekar L, Sharman T Plasmodium Falciparum malaria StatPearls 2022[Online] 2022.
  • Meibalan E, Marti M. Biology of malaria transmission. Cold Spring Harb Perspect Med. 2017;7(3):a025452. doi: 10.1101/cshperspect.a025452
  • Milner DA. Malaria Pathogenesis. Cold Spring Harb Perspect Med. 2018;8(1):a025569. doi: 10.1101/cshperspect.a025569
  • Vyas VK, Bhati S, Sharma M, et al. 3D-QSAR-based design, synthesis and biological evaluation of 2,4-disubstituted quinoline derivatives as antimalarial agents. SAR QSAR Environ Res. 2023;34(8):639–659.
  • Pinheiro LCS, Feitosa LM, Silveria FD, et al. Current antimalarial therapies and advances in the development of semi-synthetic artemisinin derivatives. Anais da Academia Brasileira de Ciências. 2018;90(1 suppl 2):1251–1271.
  • Tse EG, Korsik M, Todd MH. The past, present and future of anti-malarial medicines. Malaria j. 2019;18(1):93. doi: 10.1186/s12936-019-2724-z
  • Okombo J, Chibale K. Insights into integrated lead generation and target Identification in malaria and tuberculosis drug discovery. Acc Chem Res. 2017;50(7):1606–1616. doi: 10.1021/acs.accounts.6b00631
  • Consalvi S, Tammaro C, Appetecchia F, et al. Malaria transmission blocking compounds: a patent review. Expert Opin Ther Patents. 2022;32(6):649–666. doi: 10.1080/13543776.2022.2049239
  • Wells TNC, RH van H, WC Van V. Malaria medicines: a glass half full? Nat Rev Drug Discov. 2015;14(6):424–442. doi: 10.1038/nrd4573
  • Fonte M, Tassi N, Gomes P, et al. Acridine-based antimalarials—from the very first synthetic antimalarial to Recent developments. Molecules. 2021;26(3):600.
  • Shalini, Kumar S, Gendrot M, et al. Amide tethered 4-aminoquinoline-naphthalimide hybrids: a new class of possible Dual function antiplasmodials. ACS Med Chem Lett. 2020;11(12):2544–2552.
  • Gao X, Bai Y, Sun P, et al. Combined chemical transformation and biological transformation of artemisinin: a facile approach to diverse artemisinin derivatives. Front Chem. 2022;10:1089290. doi: 10.3389/fchem.2022.1089290
  • Zhan W, Li D, Subramanyaswamy SB, et al. Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance. Cell Chem Biol. 2023;30(5):457–469.e11.
  • Quagliata M, Papini AM, Rovero P. Malaria vaccines. Expert Opinion on Therapeutic Patents. Expert Opin Ther Patents. 2023;33(3):169–178. doi: 10.1080/13543776.2023.2190884
  • Bhanot A, Sundriyal S. Physicochemical Profiling and comparison of research Antiplasmodials and advanced stage antimalarials with oral drugs. ACS Omega. 2021;6(9):6424–6437. doi: 10.1021/acsomega.1c00104
  • Boor SVD, Alkema M, Gemert G-JV, et al. Whole sporozoite immunization with Plasmodium falciparum strain NF135 in a randomized trial. BMC Med. 2023;21(1):137.
  • Walker IS, Rogerson SJ. Pathogenicity and virulence of malaria: sticky problems and tricky solutions. Virulence. 2023;14(1):2150456. doi: 10.1080/21505594.2022.2150456
  • Trager W, Jensen JB. Human Malaria Parasites in Continuous Culture. Science. 1976;193(4254):673–675. doi: 10.1126/science.781840
  • Foquet L, Schafer C, Minkah NK, et al. Plasmodium falciparum liver stage infection and transition to stable blood stage infection in liver-humanized and blood-humanized FRGN KO mice enables testing of blood stage inhibitory antibodies (reticulocyte-binding protein homolog 5) in vivo. Front Immunol. 2018;9: doi: 10.3389/fimmu.2018.00524
  • Mo AX, McGugan G. Understanding the liver-stage biology of malaria parasites: insights to enable and accelerate the development of a highly efficacious vaccine. Am J Trop Med Hyg. 2018;99(4):827–832. doi: 10.4269/ajtmh.17-0895
  • Dorjsuren D, Eastman RT, Wicht KJ, et al. Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites. Sci Rep. 2021;11(1):2121.
  • Valenciano AL, Gomez-Lorenzo MG, Vega-Rodríguez J, et al. In vitro models for human malaria: targeting the liver stage. Trends Parasitol. 2022;38(9):758–774.
  • Posfai D, Maher SP, Roesch C, et al. Plasmodium vivax liver and blood stages recruit the druggable host membrane channel aquaporin-3. Cell Chem Biol. 2020;27(6):719–727.e5.
  • Goswami D, Minkah NK, Kappe SHI. Malaria parasite liver stages. J Hepatol. 2022;76(3):735–737. doi: 10.1016/j.jhep.2021.05.034
  • Phillips MA, Lotharius J, Marsh K, et al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci, trans med. 2015;7(296). doi: 10.1126/scitranslmed.aaa6645
  • Lee RS, Waters AP, Brewer JM. A cryptic cycle in haematopoietic niches promotes initiation of malaria transmission and evasion of chemotherapy. Nat Commun. 2018;9(1):1689. doi: 10.1038/s41467-018-04108-9
  • Erbland M. Chronic obstructive pulmonary disease and carbohydrate feedings. Ann internal med. 1986;104(6):889–890. doi: 10.7326/0003-4819-104-6-889_2
  • Colomina MT, Peris-Sampedro F. Aluminum and Alzheimer’s disease. Advan in Neurobi. 2017;18:183–197.
  • Kumar S, Bhardwaj TR, Prasad DN, et al. Drug targets for resistant malaria: Historic to future perspectives. Biomed Pharmacother. 2018;104:8–27. doi: 10.1016/j.biopha.2018.05.009
  • Pinheiro L CS, Feitosa L M, Gandi M O, et al. The development of novel compounds against malaria: quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines. Molecules. 2019;24(22):4095.
  • Lopes EA, Santos MMM, Mori M. Antimalarial drugs: what’s new in the patents? Expert opinion on therapeutic patents. 2023;33(3):151–168. doi: 10.1080/13543776.2023.2203814
  • Adigun RA, Malan FP, Balogun MO, et al. Design, synthesis, and in silico-in vitro antimalarial evaluation of 1,2,3-triazole-linked dihydropyrimidinone quinoline hybrids. Struct Chem. 2023. doi: 10.1007/s11224-023-02142-y
  • Madu UL, Ogundeji AO, Pohl CH, et al. Primaquine, an antimalarial drug that controls the growth of cryptococcal cells. Journal de mycologie medicale. 2023;33(2):101361.
  • Zorc B, Perković I, Pavić K, et al. Primaquine derivatives: modifications of the terminal amino group. Eur J Med Chem. 2019;182:111640. doi: 10.1016/j.ejmech.2019.111640
  • Antony H, Parija S. Antimalarial drug resistance: An overview. Trop Parasitol. 2016;6(1):30. doi: 10.4103/2229-5070.175081
  • Singh S, Singh A, Singh M, et al. Modern advancement in the area of antimalarial drug development. Indian J Heterocycl Chem. 2018;28(2):185–194.
  • Yadav MK, Tripathi MK, Yadav S. Discovery of novel inhibitors targeting Plasmodium knowlesi dihydrofolate reductase using molecular docking and molecular dynamics simulation. Microbial Pathogenesis. 2021;161(Pt A):105214. doi: 10.1016/j.micpath.2021.105214
  • Adeel AA, Elnour FAA, Elmardi KA, et al. High efficacy of artemether-lumefantrine and declining efficacy of artesunate + sulfadoxine-pyrimethamine against Plasmodium falciparum in Sudan (2010-2015): evidence from in vivo and molecular marker studies. Malaria j. 2016;15(1):285.
  • Yang J, He Y, Li Y, et al. Advances in the research on the targets of anti-malaria actions of artemisinin. Pharmacol Ther. 2020;216:107697. doi: 10.1016/j.pharmthera.2020.107697
  • Mbengue A, Bhattacharjee S, Pandharkar T, et al. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature. 2015;520(7549):683–687.
  • Suresh N, Haldar K. Mechanisms of artemisinin resistance in Plasmodium falciparum malaria. Curr Opin Pharmacol. 2018;42:46–54. doi: 10.1016/j.coph.2018.06.003
  • Wang J, Huang Y, Zhao Y, et al. Introduction of F446I mutation in the K13 propeller gene leads to increased ring survival rates in Plasmodium falciparum isolates. Malaria j. 2018;17(1):248.
  • Intharabut B, Kingston HW, Srinamon K, et al. Artemisinin resistance and stage dependency of parasite clearance in falciparum malaria. J Infect Dis. 2019;219(9):1483–1489.
  • Bhattacharjee S, Coppens I, Mbengue A, et al. Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance. Blood. 2018;131(11):1234–1247.
  • Dogovski C, Xie SC, Burgio G, et al. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biol. 2015;13(4):e1002132.
  • Tilley L, Straimer J, Gnädig NF, et al. Artemisinin Action and Resistance in Plasmodium falciparum. Trends Parasitol. 2016;32(9):682–696.
  • Rocamora F, Zhu L, Liong KY, et al. Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites. PLOS Pathogens. 2018;14(3):e1006930.
  • Mok S, Ashley EA, Ferreira PE, et al. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science. 2015;347(6220):431–435.
  • Hanboonkunupakarn B, Tarning J, Pukrittayakamee S, et al. Artemisinin resistance and malaria elimination: where are we now? Front Pharmacol. 2022;13: doi: 10.3389/fphar.2022.876282
  • Baker DA, Drought LG, Flueck C, et al. Cyclic nucleotide signalling in malaria parasites. Open Biol. 2017;7(12):170213.
  • Goodman CD, Buchanan HD, McFadden GI. Is the mitochondrion a good malaria drug target? Trends Parasitol. 2017;33(3):185–193. doi: 10.1016/j.pt.2016.10.002
  • Blanshard A, Hine P. Atovaquone-proguanil for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2021;2021(2). doi: 10.1002/14651858.CD004529.pub3
  • Komatsuya K, Sakura T, Shiomi K, et al. Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III. Pharmaceuticals. 2022;15(7). doi: 10.3390/ph15070903
  • Baragaña B, Hallyburton I, Lee MCS, et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature. 2015;522(7556):315–320.
  • Hochegger P, Faist J, Seebacher W, et al. New derivatives of quinoline-4-carboxylic acid with antiplasmodial activity. Bioorg Med Chem. 2017;25(7):2251–2259.
  • Ross LS, Fidock DA. Elucidating Mechanisms of Drug-Resistant Plasmodium falciparum. Cell Host Microbe. 2019;26(1):35–47. doi: 10.1016/j.chom.2019.06.001
  • Siqueira-Neto JL, Wicht KJ, Chibale K, et al. Antimalarial drug discovery: progress and approaches. Nat Rev Drug Discov. 2023;22(10):807–826.
  • Aroonsri A, Akinola O, Posayapisit N, et al. Identifying antimalarial compounds targeting dihydrofolate reductase-thymidylate synthase (DHFR-TS) by chemogenomic profiling. Int J Parasitol. 2016;46(8):527–535.
  • Ittarat W, Pornthanakasem W, Mungthin M, et al. Characterization of Plasmodium knowlesi dihydrofolate reductase-thymidylate synthase and sensitivity to antifolates. Parasitol Int. 2018;67(6):787–792.
  • Chaianantakul N, Sungkapong T, Supatip J, et al. Antimalarial effect of cell penetrating peptides derived from the junctional region of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase. Peptides. 2020;131:170372. doi: 10.1016/j.peptides.2020.170372
  • Cowell AN, Istvan ES, Lukens AK, et al. Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science. 2018;359(6372):191–199.
  • Shibeshi MA, Kifle ZD, Atnafie SA. Antimalarial drug resistance and novel targets for antimalarial drug discovery. Infect Drug Resist. 2020;13:4047–4060. doi: 10.2147/IDR.S279433
  • Shang X, Yang C, Morris‐Natschke SL, et al. Biologically active isoquinoline alkaloids covering 2014–2018. Med Res Rev. 2020;40(6):2212–2289.
  • Çapcı A, Herrmann L, Sampath Kumar HM, et al. Artemisinin‐derived dimers from a chemical perspective. Med Res Rev. 2021;41(6):2927–2970.
  • Tople MS, Patel NB, Patel PP, et al. An in silico-in vitro antimalarial and antimicrobial investigation of newer 7-chloroquinoline based Schiff-bases. J Mol Struct. 2023;1271:134016. doi: 10.1016/j.molstruc.2022.134016
  • Reis RAG, Calil FA, Feliciano PR, et al. The dihydroorotate dehydrogenases: Past and present. Arch Biochem Biophys. 2017;632:175–191. doi: 10.1016/j.abb.2017.06.019
  • Haldar K, Bhattacharjee S, Safeukui I. Drug resistance in Plasmodium. Nature Rev Microbiol. 2018;16(3):156–170. doi: 10.1038/nrmicro.2017.161
  • White J, Dhingra SK, Deng X, et al. Identification and mechanistic understanding of dihydroorotate dehydrogenase point mutations in Plasmodium falciparum that confer in vitro resistance to the clinical candidate DSM265. ACS Infect Dis. 2019;5(1):90–101.
  • Llanos-Cuentas A, Casapia M, Chuquiyauri R, et al. Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study. Lancet Infect Dis. 2018;18(8):874–883.
  • McCarthy JS, Lotharius J, Rückle T, et al. Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. Lancet Infect Dis. 2017;17(6):626–635.
  • Sulyok M, Rückle T, Roth A, et al. DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect Dis. 2017;17(6):636–644.
  • Phillips MA, White KL, Kokkonda S, et al. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. ACS Infect Dis. 2016;2(12):945–957.
  • Phillips M A, Rathod P K. Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord. 2010;10(3):226–239. doi: 10.2174/187152610791163336
  • Vyas K, Ghate M V. Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors. Mini-Rev Med Chem. 2011;11(12):1039–1055. doi: 10.2174/138955711797247707
  • Vyas VK, Parikh H, Ghate M. 3D QSAR studies on 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as P. falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. Med Chem Res. 2013;22(5):2235–2243. doi: 10.1007/s00044-012-0216-6
  • Gehlot P, Vyas VK. A patent review of human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents and their other therapeutic applications (1999-2022). Recent Patents Anti-Cancer Drug Disc. 2023;19(3):280–297. doi: 10.2174/1574892818666230417094939
  • Munier-Lehmann H, Vidalain P-O, Tangy F, et al. On dihydroorotate dehydrogenases and their inhibitors and uses. J Med Chem. 2013;56(8):3148–3167.
  • Azeredo LFSP, Coutinho JP, Jabor VAP, et al. Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors. Eur J Med Chem. 2017;126:72–83. doi: 10.1016/j.ejmech.2016.09.073
  • Boschi D, Pippione AC, Sainas S, et al. Dihydroorotate dehydrogenase inhibitors in anti-infective drug research. Eur J Med Chem. 2019;183:111681. doi: 10.1016/j.ejmech.2019.111681
  • Hoelz LV, Calil FA, Nonato MC, et al. Plasmodium falciparum dihydroorotate dehydrogenase: a drug target against malaria. Future Med Chem. 2018;10(15):1853–1874.
  • Vyas VK, Shukla T, Tulsian K, et al. Integrated structure-guided computational design of novel substituted quinolizin-4-ones as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. Comput Biol Chem. 2022;101:107787. doi: 10.1016/j.compbiolchem.2022.107787
  • Baldwin J, Farajallah AM, Malmquist NA, et al. Malarial Dihydroorotate Dehydrogenase. J Biol Chem. 2002;277(44):41827–41834.
  • Belen Cassera M, Zhang Y, Hazleton K Z, et al. Purine and Pyrimidine Pathways as Targets in Plasmodium falciparum. Curr Top Med Chem. 2011;11(16):2103–2115.
  • Krungkrai SR, Krungkrai J. Insights into the pyrimidine biosynthetic pathway of human malaria parasite Plasmodium falciparum as chemotherapeutic target. Asian Pac J Trop Med. 2016;9(6):525–534. doi: 10.1016/j.apjtm.2016.04.012
  • Roth A, Maher SP, Conway AJ, et al. A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum. Nat Commun. 2018;9(1):1837.
  • Alzain AA, Ahmed ZAM, Mahadi MA, et al. Identification of novel Plasmodium falciparum dihydroorotate dehydrogenase inhibitors for malaria using in silico studies. Scientific African. 2022;16:e01214. doi: 10.1016/j.sciaf.2022.e01214
  • Batt DG. Inhibitors of dihydroorotate dehydrogenase. Expert Opin Ther Patents. 1999;9(1):41–54. doi: 10.1517/13543776.9.1.41
  • Kumar S, Narasimhan B. Therapeutic potential of heterocyclic pyrimidine scaffolds. Chem Cent J. 2018;12(1):38. doi: 10.1186/s13065-018-0406-5
  • Loffler M, Fairbanks L, Zameitat E, et al. Pyrimidine pathways in health and disease. Trends Mol Med. 2005;11(9):430–437. doi: 10.1016/j.molmed.2005.07.003
  • Sørensen P, Dandanell G. A new type of dihydroorotate dehydrogenase, type 1S, from the thermoacidophilic archaeon sulfolobus solfataricus Jun. Extremophiles. 2002;6(3):245–251. doi: 10.1007/s00792-001-0249-0
  • Lane AN, Fan T-M. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 2015;43(4):2466–2485. doi: 10.1093/nar/gkv047
  • Wang X, Yang K, Wu Q, et al. Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells. Sci, trans med. 2019;11(504). doi: 10.1126/scitranslmed.aau4972
  • Phillips M, Rathod PK, Baldwin JG. Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activityp. WO2007149211A1. 2007.
  • Phillips M, Rathod PK, Baldwin JG. Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activityp. US20080027079A1. 2008.
  • Phillips M, Rathod PK, Gujjar R, et al. Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activityp. WO2009082691A1. 2009.
  • Phillips M, Rathod PK, Gujjar R, et al. Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activityp. US20090209557A1. 2009.
  • Phillips M, Rathod PK, Gujjar R, et al. Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activityp. US9216983B2. 2015.
  • Phillips M, Rathod PK, Charman SA, et al. Antimalarial agents that are inhibitors of dihydroorotate dehyrogenasep. WO2011041304A2. 2011.
  • Rathod PK, Floyd D, Burrows J, et al. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. EP2483274B1. 2009.
  • Rathod PK, Floyd D, Burrows J, et al. Antimalarial agents that are inhibitors of dihydroorotate dehydrogenasep. US20120302586A1. 2012.
  • Rathod PK, Floyd D, Burrows J, et al. Antimalarial agents that are inhibitors of dihydroorotate dehyrogenasep. US9238653B2. 2016.
  • Phillips M, Charman SA, Rathod PK, et al. New substituted triazolopyrimidines as anti-malarial agents. EP3072894A1. 2016.
  • Phillips M, Charman SA, Rathod PK, et al. New substituted triazolopyrimidines as anti-malarial agentsp. WO2016151521A1. 2016.
  • Phillips M, Charman SA, Rathod PK, et al. New substituted triazolopyrimidines as anti-malarial agentsp. US20180065968A1. 2018.
  • Booker ML, Celatka CC, Clardy JC, et al. Small molecule inhibitors of plasmodium falciparum dihydroorotate dehyrogenase. WO2009137081A2. 2009; Cambridge (MA): Genzyme Corporation.
  • Bastos C, Booker ML, Celatka CA, et al. Small molecule inhibitors of plasmodium falciparum dihydroorotate dehyrogenase. US8703811B2. 2014.
  • Bastos C, Booker ML, Celatka CA, et al. Small molecule inhibitors of plasmodium falciparum dihydroorotate dehydrogenasep. US20110130381A1. 2011.
  • Phillips M, Palmer M, Charman SA, et al. Anti-malarial agents. EP3842100A1. 2021.
  • Phillips M, Palmer M, Charman SA, et al. Anti-malarial agentsp. WO2021123266A1. 2021.
  • Phillips M, Palmer M, Charman SA, et al. Anti-malarial agents. US20230056202A1. 2023.
  • Singh A, Maqbool M, Mobashir M, et al. Dihydroorotate dehydrogenase: a drug target for the development of antimalarials. Eur J Med Chem. 2017;125:640–651. doi: 10.1016/j.ejmech.2016.09.085
  • Barnett DS, Guy RK. Antimalarials in Development in 2014. Chem Rev. 2014;114(22):11221–11241. doi: 10.1021/cr500543f
  • Schrader FC, Barho M, Steiner I, et al. The antimalarial pipeline – An update. Int J Med Microbiol. 2012;302(4–5):165–171.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.