Medicinal Chemistry Approaches for the Discovery of Plasmodium Falciparum Dihydroorotate Dehydrogenase Inhibitors as Antimalarial Agents

References

• Winzeler EA . Malaria research in the post-genomic era. Nature455(7214), 751–756 (2008).
   PubMed Web of Science ®Google Scholar
• Vyas VK , BhatiS, PatelS, GhateM. Structure- and ligand-based drug design methods for the modeling of antimalarial agents: a review of updates from 2012 onwards. J. Biomol. Struct. Dyn.40(20), 10481–10506 (2021).
   PubMed Web of Science ®Google Scholar
• Pink R , HudsonA, MourièsM-A, BendigM. Opportunities and challenges in antiparasitic drug discovery. Nat. Rev. Drug Discov.4(9), 727–740 (2005).
   PubMed Web of Science ®Google Scholar
• Wangdi K , PasaribuAP, ClementsACA. Addressing hard-to-reach populations for achieving malaria elimination in the Asia Pacific Malaria Elimination Network countries. Asia Pac. Policy Stud.8(2), 176–188 (2021).
   Web of Science ®Google Scholar
• Tangpukdee N , DuangdeeC, WilairatanaP, KrudsoodS. Malaria diagnosis: a brief review. Korean J. Parasitol.47(2), 93–102 (2009).
   PubMed Web of Science ®Google Scholar
• Sato S . Plasmodium – a brief introduction to the parasites causing human malaria and their basic biology. J. Physiol. Anthropol.40(1), 1–13 (2021).
   PubMed Web of Science ®Google Scholar
• Antonelli LR , JunqueiraC, VinetzJM, GolenbockDT, FerreiraMU, GazzinelliRT. The immunology of Plasmodium vivax malaria. Immunol. Rev.293(1), 163–189 (2020).
   PubMed Web of Science ®Google Scholar
• Meibalan E , MartiM. Biology of malaria transmission. Cold Spring Harb. Perspect. Med.7(3), a025452 (2017).
   PubMed Web of Science ®Google Scholar
• Snow RW , GuerraCA, NoorAM, MyintHY, HaySI. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature434(7030), 214–217 (2005).
   PubMed Web of Science ®Google Scholar
• Snow RW . Global malaria eradication and the importance of Plasmodium falciparum epidemiology in Africa. BMC Med.13, 23 (2015).
   PubMed Web of Science ®Google Scholar
• WHO . World Malaria Report 2022. WHO, Geneva, Switzerland (2022).
   Google Scholar
• Kurtovic L , AgiusPA, FengGet al. Induction and decay of functional complement-fixing antibodies by the RTS, S malaria vaccine in children, and a negative impact of malaria exposure. BMC Med.17(1), 1–14 (2019).
   PubMedGoogle Scholar
• Kurtovic L , BoyleMJ, OpiDHet al. Complement in malaria immunity and vaccines. Immunol. Rev.293(1), 38–56 (2020).
   PubMed Web of Science ®Google Scholar
• Calic PPS , MansouriM, McGowanS. Driving antimalarial design through understanding of target mechanism. Biochem. Soc. Trans.48(5), 2067–2078 (2020).
   PubMed Web of Science ®Google Scholar
• Biamonte MA , WannerJ, LeRoch KG. Recent advances in malaria drug discovery. Bioorg. Med. Chem. Lett.23(10), 2829–2843 (2013).
   PubMed Web of Science ®Google Scholar
• Hyde JE . Drug-resistant malaria – an insight. FEBS J.274(18), 4688–4698 (2007).
   PubMed Web of Science ®Google Scholar
• Hyde JE . Drug-resistant malaria. Trends Parasitol.21(11), 494–498 (2005).
   PubMed Web of Science ®Google Scholar
• Conrad MD , RosenthalPJ. Antimalarial drug resistance in Africa: the calm before the storm?Lancet Infect. Dis.19(10), e338–e351 (2019).
   PubMed Web of Science ®Google Scholar
• Cowell AN , IstvanES, LukensAKet al. Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics. Science359(6372), 191–199 (2018).
   PubMed Web of Science ®Google Scholar
• Dondorp AM , NostenF, YiPet al. Artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med.361(5), 455–467 (2009).
   PubMed Web of Science ®Google Scholar
• Shibeshi MA , KifleZD, AtnafieSA. Antimalarial drug resistance and novel targets for antimalarial drug discovery. Infect. Drug Resist.13, 4047–4060 (2020).
   PubMed Web of Science ®Google Scholar
• Shang X-F , YangC-J, Morris-NatschkeSLet al. Biologically active isoquinoline alkaloids covering 2014–2018. Med. Res. Rev.40(6), 2212–2289 (2020).
   PubMed Web of Science ®Google Scholar
• Çapcı A , HerrmannL, SampathKumar HM, FröhlichT, TsogoevaSB. Artemisinin-derived dimers from a chemical perspective. Med. Res. Rev.41(6), 2927–2970 (2021).
   PubMed Web of Science ®Google Scholar
• Tople MS , PatelNB, PatelPP, PurohitAC, AhmadI, PatelH. An in silico–in vitro antimalarial and antimicrobial investigation of newer 7-chloroquinoline based Schiff-bases. J. Mol. Struct.1271, 134016 (2023).
   Web of Science ®Google Scholar
• Löffler M , FairbanksLD, ZameitatE, MarinakiAM, SimmondsHA. Pyrimidine pathways in health and disease. Trends Mol. Med.11(9), 430–437 (2005).
   PubMed Web of Science ®Google Scholar
• Phillips MA , RathodPK. Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect. Disord. Drug Targets10(3), 226–239 (2012).
   Google Scholar
• Vyas VK , GhateM. Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors. Mini Rev. Med. Chem.11(12), 1039–1055 (2011).
   PubMed Web of Science ®Google Scholar
• Reis RAG , CalilFA, FelicianoPR, PinheiroMP, NonatoMC. The dihydroorotate dehydrogenases: past and present. Arch. Biochem. Biophys.632, 175–191 (2017).
   PubMed Web of Science ®Google Scholar
• Haldar K , BhattacharjeeS, SafeukuiI. Drug resistance in Plasmodium. Nat. Rev. Microbiol.16(3), 156–170 (2018).
   PubMed Web of Science ®Google Scholar
• Ridley RG . Medical need, scientific opportunity and the drive for antimalarial drugs. Nature415(6872), 686–693 (2002).
   PubMed Web of Science ®Google Scholar
• Boschi D , PippioneAC, SainasS, LolliML. Dihydroorotate dehydrogenase inhibitors in anti-infective drug research. Eur. J. Med. Chem.183, 111681 (2019).
   PubMed Web of Science ®Google Scholar
• Singh A , MaqboolM, MobashirM, HodaN. Dihydroorotate dehydrogenase: a drug target for the development of antimalarials. Eur. J. Med. Chem.125, 640–651 (2017).
   PubMed Web of Science ®Google Scholar
• Cohen A , DumètreA, AzasN. A decade of Plasmodium falciparum metabolic pathways of therapeutic interest to develop new selective antimalarial drugs. Mini Rev. Med. Chem.13(9), 1340–1347 (2013).
   PubMed Web of Science ®Google Scholar
• Reyes P , RathodPK, SanchezDJ, MremaJE, RieckmannKH, HeidrichH-G. Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum. Mol. Biochem. Parasitol.5(5), 275–290 (1982).
   PubMed Web of Science ®Google Scholar
• Rathod PK , ReyesP. Orotidylate-metabolizing enzymes of the human malarial parasite, Plasmodium falciparum, differ from host cell enzymes. J. Biol. Chem.258(5), 2852–2855 (1983).
   PubMed Web of Science ®Google Scholar
• Zeng T , ZuoZ, LuoY, ZhaoY, YuY, ChenQ. A novel series of human dihydroorotate dehydrogenase inhibitors discovered by in vitro screening: inhibition activity and crystallographic binding mode. FEBS Open Bio.9(8), 1348–1354 (2019).
   PubMed Web of Science ®Google Scholar
• Rowland P , NøragerS, JensenKF, LarsenS. Structure of dihydroorotate dehydrogenase B: electron transfer between two flavin groups bridged by an iron–sulphur cluster. Structure8(12), 1227–1238 (2000).
   PubMed Web of Science ®Google Scholar
• Sousa FM , RefojoPN, PereiraMM. Investigating the amino acid sequences of membrane bound dihydroorotate:quinone oxidoreductases (DHOQOs): structural and functional implications. Biochim. Biophys. Acta Bioenerg.1862(1), 148321 (2021).
   PubMed Web of Science ®Google Scholar
• Rawls J , KnechtW, DiekertK, LillR, LöfflerM. Requirements for the mitochondrial import and localization of dihydroorotate dehydrogenase. Eur. J. Biochem.267(7), 2079–2087 (2000).
   PubMedGoogle Scholar
• Knecht W , HenselingJ, LöfflerM. Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem. Biol. Interact.124(1), 61–76 (2000).
   PubMed Web of Science ®Google Scholar
• Cheleski J , RochaJR, PinheiroMPet al. Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery. Eur. J. Med. Chem.45(12), 5899–5909 (2010).
   PubMed Web of Science ®Google Scholar
• Argyrou A , WashabaughMW, PickartCM. Dihydroorotate dehydrogenase from Clostridium oroticum is a class 1B enzyme and utilizes a concerted mechansim of catalysis. Biochemistry39(34), 10373–10384 (2000).
   PubMed Web of Science ®Google Scholar
• Hurt DE , WidomJ, ClardyJ. Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. Acta Crystallogr. D Biol. Crystallogr.62(3), 312–323 (2006).
   PubMedGoogle Scholar
• Deng X , GujjarR, ElMazouni Fet al. Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J. Biol. Chem.284(39), 26999–27009 (2009).
   PubMed Web of Science ®Google Scholar
• Booker ML , BastosCM, KramerMLet al. Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J. Biol. Chem.285(43), 33054–33064 (2010).
   PubMed Web of Science ®Google Scholar
• Coteron JM , MarcoM, EsquiviasJet al. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J. Med. Chem.54(15), 5540–5561 (2011).
   PubMed Web of Science ®Google Scholar
• Ross LS , GamoFJ, Lafuente-MonasterioMJet al. In vitro resistance selections for Plasmodium falciparum dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the drug-binding site and altered growth. J. Biol. Chem.289(26), 17980–17995 (2014).
   PubMed Web of Science ®Google Scholar
• Deng X , KokkondaS, ElMazouni Fet al. Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. J. Med. Chem.57(12), 5381–5394 (2014).
   PubMed Web of Science ®Google Scholar
• Deng X , MatthewsD, RathodPK, PhillipsMA. The x-ray structure of Plasmodium falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions. Acta Crystallogr. F Struct. Biol. Commun.71, 553–559 (2015).
   PubMed Web of Science ®Google Scholar
• Phillips MA , LothariusJ, MarshKet al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci. Transl. Med.7(296), 296ra11 (2015).
   Web of Science ®Google Scholar
• Kokkonda S , DengX, WhiteKLet al. Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidines targeting Plasmodium falciparum dihydroorotate dehydrogenase display potent and selective antimalarial activity. J. Med. Chem.59(11), 5416–5431 (2016).
   PubMed Web of Science ®Google Scholar
• Phillips MA , WhiteKL, KokkondaSet al. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. ACS Infect. Dis.2(12), 945–957 (2016).
   PubMed Web of Science ®Google Scholar
• White J , DhingraSK, DengXet 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.5(1), 90–101 (2019).
   PubMed Web of Science ®Google Scholar
• Kokkonda S , ElMazouni F, WhiteKLet al. Isoxazolopyrimidine-based inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity. ACS Omega3(8), 9227–9240 (2018).
   PubMed Web of Science ®Google Scholar
• Pippione AC , SainasS, GoyalPet al. Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: synthesis, biological evaluation and x-ray structural studies. Eur. J. Med. Chem.163, 266–280 (2019).
   PubMed Web of Science ®Google Scholar
• Palmer MJ , DengX, WattsSet al. Potent antimalarials with development potential identified by structure-guided computational optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series. J. Med. Chem.64(9), 6085–6136 (2021).
   PubMed Web of Science ®Google Scholar
• Liu S , NeidhardtEA, GrossmanTH, OcainT, ClardyJ. Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure8(1), 25–33 (2000).
   PubMed Web of Science ®Google Scholar
• Malmquist NA , GujjarR, RathodPK, PhillipsMA. Analysis of flavin oxidation and electron-transfer inhibition in Plasmodium falciparum dihydroorotate dehydrogenase. Biochemistry47(8), 2466–2475 (2008).
   PubMed Web of Science ®Google Scholar
• Batt DG . Inhibitors of dihydroorotate dehydrogenase. Expert Opin. Ther. Pat.9(1), 41–54 (1999).
   Web of Science ®Google Scholar
• Cassera MB , ZhangY, HazletonKZ, SchrammVL. Purine and pyrimidine pathways as targets in Plasmodium falciparum. Curr. Top. Med. Chem.11(16), 2103–2115 (2011).
   PubMed Web of Science ®Google Scholar
• Schrader FC , BarhoM, SteinerI, OrtmannR, SchlitzerM. The antimalarial pipeline – an update. Int. J. Med. Microbiol.302(4–5), 165–171 (2012).
   PubMed Web of Science ®Google Scholar
• Munier-Lehmann H , VidalainP-O, TangyF, JaninYL. On dihydroorotate dehydrogenases and their inhibitors and uses. J. Med. Chem.56(8), 3148–3167 (2013).
   PubMed Web of Science ®Google Scholar
• NixonGL , PidathalaC, ShoneAE et al. Targeting the mitochondrial electron transport chain of Plasmodium falciparum: new strategies towards the development of improved antimalarials for the elimination era. Future Med. Chem.5(13), 1573–1591 (2013).
   PubMed Web of Science ®Google Scholar
• Okombo J , ChibaleK. Insights into integrated lead generation and target identification in malaria and tuberculosis drug discovery. Acc. Chem. Res.50, 1606–1616 (2017).
   PubMed Web of Science ®Google Scholar
• Kumar S , NarasimhanB. Therapeutic potential of heterocyclic pyrimidine scaffolds. Chem. Cent. J.12(1), 1–29 (2018).
   PubMedGoogle Scholar
• Hoelz LV , CalilFA, NonatoMC, PinheiroLC, BoechatN. Plasmodium falciparum dihydroorotate dehydrogenase: a drug target against malaria. Future Med. Chem.10(15), 1853–1874 (2018).
   PubMed Web of Science ®Google Scholar
• Pinheiro LCS , FeitosaLM, GandiMO, SilveiraFF, BoechatN. The development of novel compounds against malaria: quinolines, triazolpyridines, pyrazolopyridines and pyrazolopyrimidines. Molecules24(22), 1–20 (2019).
   Web of Science ®Google Scholar
• Hines V , JohnstonM. Analysis of the kinetic mechanism of the bovine liver mitochondrial dihydroorotate dehydrogenase. Biochemistry28(3), 1222–1226 (1989).
   PubMed Web of Science ®Google Scholar
• Knecht W , LöfflerM. Redoxal as a new lead structure for dihydroorotate dehydrogenase inhibitors: a kinetic study of the inhibition mechanism. FEBS Lett.467(1), 27–30 (2000).
   PubMed Web of Science ®Google Scholar
• Balagué C , PontM, PratsN, GodessartN. Profiling of dihydroorotate dehydrogenase, p38 and JAK inhibitors in the rat adjuvant-induced arthritis model: a translational study. Br. J. Pharmacol.166(4), 1320–1332 (2012).
   PubMed Web of Science ®Google Scholar
• Vyas VK , VariyaB, GhateMD. Design, synthesis and pharmacological evaluation of novel substituted quinoline-2-carboxamide derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents. Eur. J. Med. Chem.82, 385–393 (2014).
   PubMed Web of Science ®Google Scholar
• Knecht W , LöfflerM. Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives. Biochem. Pharmacol.56(9), 1259–1264 (1998).
   PubMed Web of Science ®Google Scholar
• Caballero I , LafuenteMJ, GamoFJ, CidC. A high-throughput fluorescence-based assay for Plasmodium dihydroorotate dehydrogenase inhibitor screening. Anal. Biochem.506, 13–21 (2016).
   PubMed Web of Science ®Google Scholar
• Yin S , KabashimaT, ZhuQ, ShibataT, KaiM. Fluorescence assay of dihydroorotate dehydrogenase that may become a cancer biomarker. Sci. Rep.7, 40670 (2017).
   PubMed Web of Science ®Google Scholar
• Sullivan O . Radioassay for dihydroorotate dehydrogenase. Anal. Biochem.103, 93–103 (1978).
   Google Scholar
• Dileepan KN , KennedyJ. Rapid conversion of newly-synthesized orotate to uridine-5-monophosphate by rat liver cytosolic enzymes. FEBS Lett.153(1), 1–5 (1983).
   PubMed Web of Science ®Google Scholar
• Pádua RAP , TomaleriGP, ReisRAGet al. ThermoFMN – a thermofluor assay developed for ligand-screening as an alternative strategy for drug discovery. J. Braz. Chem. Soc.25(10), 1864–1871 (2014).
   Web of Science ®Google Scholar
• Krungkrai J , CeramiA, HendersonGB. Purification and characterization of dihydroorotate dehydrogenase from the rodent malaria parasite Plasmodium berghei. Biochemistry30(7), 1934–1939 (1991).
   PubMed Web of Science ®Google Scholar
• Krungkrai J . Purification, characterization and localization of mitochondrial dihydroorotate dehydrogenase in Plasmodium falciparum, human malaria parasite. Biochim. Biophys. Acta1243(3), 351–360 (1995).
   PubMed Web of Science ®Google Scholar
• Krungkrai J , KrungkraiSR, PhakanontK. Antimalarial activity of orotate analogs that inhibit dihydroorotase and dihydroorotate dehydrogenase. Biochem. Pharmacol.43(6), 1295–1301 (1992).
   PubMed Web of Science ®Google Scholar
• Baldwin J , FarajallahAM, MalmquistNA, RathodPK, PhillipsMA. Malarial dihydroorotate dehydrogenase: substrate and inhibitor specificity. J. Biol. Chem.277(44), 41827–41834 (2002).
   PubMed Web of Science ®Google Scholar
• Baldwin J , MichnoffCH, MalmquistNAet al. High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J. Biol. Chem.280(23), 21847–21853 (2005).
   PubMed Web of Science ®Google Scholar
• Malmquist NA , BaldwinJ, PhillipsMA. Detergent-dependent kinetics of truncated Plasmodium falciparum dihydroorotate dehydrogenase. J. Biol. Chem.282(17), 12678–12686 (2007).
   PubMed Web of Science ®Google Scholar
• Patel V , BookerM, KramerMet al. Identification and characterization of small molecule inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J. Biol. Chem.283(50), 35078–35085 (2008).
   PubMed Web of Science ®Google Scholar
• Dickerman BK , ElsworthB, CobboldSAet al. Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum. Sci. Rep.6, 37502 (2016).
   PubMed Web of Science ®Google Scholar
• Llanos-Cuentas A , CasapiaM, ChuquiyauriRet 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.18(8), 874–883 (2018).
   PubMed Web of Science ®Google Scholar
• ClinicalTrials.gov . DSM265 phase IIa investigation treating Plasmodium falciparum or vivax (2016). https://clinicaltrials.gov/ct2/show/NCT02123290
   Google Scholar
• McCarthy JS , LothariusJ, RückleTet 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.17(6), 626–635 (2017).
   PubMed Web of Science ®Google Scholar
• Sulyok M , RückleT, RothAet al. DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect. Dis.17(6), 636–644 (2017).
   PubMed Web of Science ®Google Scholar
• Phillips MA , GujjarR, MalmquistNAet al. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum. J. Med. Chem.51(12), 3649–3653 (2008).
   PubMed Web of Science ®Google Scholar
• Gujjar R , MarwahaA, ElMazouni Fet al. Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J. Med. Chem.52(7), 1864–1872 (2009).
   PubMed Web of Science ®Google Scholar
• Gujjar R , ElMazouni F, WhiteKLet al. Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice. J. Med. Chem.54(11), 3935–3949 (2011).
   PubMed Web of Science ®Google Scholar
• Marwaha A , WhiteJ, ElMazouni Fet al. Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase. J. Med. Chem.55(17), 7425–7436 (2012).
   PubMed Web of Science ®Google Scholar
• Silveira FF , de SouzaJO, HoelzLVBet al. Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors. Eur. J. Med. Chem.209, 112941 (2021).
   PubMed Web of Science ®Google Scholar
• Kokkonda S , DengX, WhiteKLet al. Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria. J. Med. Chem.63(9), 4929–4956 (2020).
   PubMed Web of Science ®Google Scholar
• Skerlj RT , BastosCM, BookerMLet al. Optimization of potent inhibitors of P. falciparum dihydroorotate dehydrogenase for the treatment of malaria. ACS Med. Chem. Lett.2(9), 708–713 (2011).
   PubMed Web of Science ®Google Scholar
• Azeredo LFSP , CoutinhoJP, JaborVAPet al. Evaluation of 7-arylaminopyrazolo[1,5-a]pyrimidines as anti-Plasmodium falciparum, antimalarial, and Pf-dihydroorotate dehydrogenase inhibitors. Eur. J. Med. Chem.126, 72–83 (2017).
   PubMed Web of Science ®Google Scholar
• Vah L , MedvedT, GrošeljUet al. Regioselective synthesis of 5- and 3-hydroxy-N-aryl-1H-pyrazole-4-carboxylates and their evaluation as inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Molecules27(15), 1–18 (2022).
   Web of Science ®Google Scholar
• Chowdhary S , MosnierJ, FontaIet al. Synthesis, anti-plasmodial activities, and mechanistic insights of 4-aminoquinoline–triazolopyrimidine hybrids. ACS Med. Chem. Lett.13, 1068–1076 (2022).
   PubMedGoogle Scholar
• Bedingfield PTP , CowenD, AcklamPet al. Factors influencing the specificity of inhibitor binding to the human and malaria parasite dihydroorotate dehydrogenases. J. Med. Chem.55(12), 5841–5850 (2012).
   PubMed Web of Science ®Google Scholar
• Heikkilä T , ThirumalairajanS, DaviesMet al. The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg. Med. Chem. Lett.16(1), 88–92 (2006).
   PubMed Web of Science ®Google Scholar
• Heikkilä T , RamseyC, DaviesMet al. Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J. Med. Chem.50(2), 186–191 (2007).
   PubMed Web of Science ®Google Scholar
• Davies M , HeikkiläT, McConkeyGA, FishwickCWG, ParsonsMR, JohnsonAP. Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases. J. Med. Chem.52(9), 2683–2693 (2009).
   PubMed Web of Science ®Google Scholar
• McConkey GA , BedingfieldPTP, BurrellDRet al. Interconvertible geometric isomers of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors exhibit multiple binding modes. Bioorg. Med. Chem. Lett.27(16), 3878–3882 (2017).
   PubMed Web of Science ®Google Scholar
• Maetani M , KatoN, JaborVAPet al. Discovery of antimalarial azetidine-2-carbonitriles that inhibit P. falciparum dihydroorotate dehydrogenase. ACS Med. Chem. Lett.8(4), 438–442 (2017).
   PubMed Web of Science ®Google Scholar
• Xu M , ZhuJ, DiaoYet al. Novel selective and potent inhibitors of malaria parasite dihydroorotate dehydrogenase: discovery and optimization of dihydrothiophenone derivatives. J. Med. Chem.56(20), 7911–7924 (2013).
   PubMed Web of Science ®Google Scholar
• Strašek N , LavrenčičL, OštrekAet al. Tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylates as inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg. Chem.89, 102982 (2019).
   PubMed Web of Science ®Google Scholar
• Hartuti ED , SakuraT, TagodMSOet al. Identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives as novel selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Int. J. Mol. Sci.22(13), 7236 (2021).
   PubMed Web of Science ®Google Scholar
• Fritzson I , BedingfieldPTP, SundinAP, McConkeyG, NilssonUJ. N-substituted salicylamides as selective malaria parasite dihydroorotate dehydrogenase inhibitors. Medchemcomm2(9), 895–898 (2011).
   Web of Science ®Google Scholar
• Cowen D , BedingfieldP, McConkeyGA, FishwickCWG, JohnsonAP. A study of the effects of substituents on the selectivity of the binding of N-arylaminomethylene malonate inhibitors to DHODH. Bioorg. Med. Chem. Lett.20(3), 1284–1287 (2010).
   PubMed Web of Science ®Google Scholar
• Ittarat I , WebsterHK, YuthavongY. High-performance liquid chromatographic determination of dihydroorotate dehydrogenase of Plasmodium falciparum and effects of antimalarials on enzyme activity. J. Chromatogr.582(1–2), 57–64 (1992).
   PubMed Web of Science ®Google Scholar
• Ittarat I , AsawamahasakdaW, MeshnickSR. The effects of antimalarials on the Plasmodium falciparum dihydroorotate dehydrogenase. Exp. Parasitol.79(1), 50–56 (1994).
   PubMed Web of Science ®Google Scholar
• Boa AN , CanavanSP, HirstPR, RamseyC, SteadAMW, McConkeyGA. Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase. Bioorg. Med. Chem.13(6), 1945–1967 (2005).
   PubMed Web of Science ®Google Scholar
• Xu L , LiW, DiaoYet al. Synthesis, design, and structure–activity relationship of the pyrimidone derivatives as novel selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Molecules23(6), 1254 (2018).
   PubMed Web of Science ®Google Scholar
• Lukens AK , RossLS, HeidebrechtRet al. Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance. Proc. Natl Acad. Sci. U. S. A.111(2), 799–804 (2014).
   PubMed Web of Science ®Google Scholar
• Ross LS , Lafuente-MonasterioMJ, Sakata-KatoTet al. Identification of collateral sensitivity to dihydroorotate dehydrogenase inhibitors in Plasmodium falciparum. ACS Infect. Dis.4(4), 508–515 (2018).
   PubMed Web of Science ®Google Scholar
• Painter HJ , MorriseyJM, MatherMWet al. Atypical molecular basis for drug resistance to mitochondrial function inhibitors in Plasmodium falciparum. Antimicrob. Agents Chemother.65(3), e02143-20 (2021).
   PubMed Web of Science ®Google Scholar
• Ojha PK , RoyK. Chemometric modeling, docking and in silico design of triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors as antimalarials. Eur. J. Med. Chem.45(10), 4645–4656 (2010).
   PubMed Web of Science ®Google Scholar
• Ojha PK , MitraI, KarS, DasRN, RoyK. Lead hopping for PfDHODH inhibitors as antimalarials based on pharmacophore mapping, molecular docking and comparative binding energy analysis (COMBINE): a three-layered virtual screening approach. Mol. Inform.31(10), 711–718 (2012).
   PubMed Web of Science ®Google Scholar
• Shah P , KumarS, TiwariS, SiddiqiMI. 3D-QSAR studies of triazolopyrimidine derivatives of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors using a combination of molecular dynamics, docking, and genetic algorithm-based methods. J. Chem. Biol.5(3), 91–103 (2012).
   PubMedGoogle Scholar
• Ibrahim ZY , UzairuA, ShallangwaGA, AbechiSE. Pharmacokinetic predictions and docking studies of substituted aryl amine-based triazolopyrimidine designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). Future J. Pharm. Sci.7(1), 1–10 (2021).
   Web of Science ®Google Scholar
• Desai KR , ShaikhMS, CoutinhoEC. Molecular modeling studies, synthesis and biological evaluation of derivatives of N-phenylbenzamide as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. Med. Chem. Res.20(3), 321–332 (2011).
   Web of Science ®Google Scholar
• Singh IV , MishraS. Molecular docking studies of benzamide derivatives for PfDHODH inhibitor as potent antimalarial agent. Am. J. Biochem. Mol. Biol.9(1), 1–6 (2019).
   Google Scholar
• Vyas VK , ParikhH, GhateM. 3D QSAR studies on 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as P. falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. Med. Chem. Res.22(5), 2235–2243 (2013).
   Web of Science ®Google Scholar
• Tseng TS , LeeYC, HsiaoNW, LiuYR, TsaiKC. Comparative study between 3D-QSAR and docking-based pharmacophore models for potent Plasomodium falciparum dihydroorotate dehydrogenase inhibitors. Bioorg. Med. Chem. Lett.26(2), 265–271 (2016).
   PubMed Web of Science ®Google Scholar
• Manhas A , LoneMY, JhaPC. Multicomplex-based pharmacophore modeling coupled with molecular dynamics simulations: an efficient strategy for the identification of novel inhibitors of PfDHODH. J. Mol. Graph. Model.75, 413–423 (2017).
   PubMed Web of Science ®Google Scholar
• Vyas VK , QureshiG, GhateM, PatelH, DalaiS. Identification of novel PfDHODH inhibitors as antimalarial agents via pharmacophore-based virtual screening followed by molecular docking and in vivo antimalarial activity. SAR QSAR Environ. Res.27(6), 427–440 (2016).
   PubMed Web of Science ®Google Scholar
• Wadood A , GhufranM, HassanSF, KhanH, AzamSS, RashidU. In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase for treatment of falciparum malaria. Pharm. Biol.55(1), 19–32 (2017).
   PubMed Web of Science ®Google Scholar
• Pavadai E , ElMazouni F, WittlinS, de KockC, PhillipsMA, ChibaleK. Identification of new human malaria parasite Plasmodium falciparum dihydroorotate dehydrogenase inhibitors by pharmacophore and structure-based virtual screening. J. Chem. Inf. Model.2(12), 548–562 (2016).
   Google Scholar
• Hou X , ChenX, ZhangM, YanA. QSAR study on the antimalarial activity of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. SAR QSAR Environ. Res.27(2), 101–124 (2016).
   PubMed Web of Science ®Google Scholar
• Brandão GC , RochaMissias FC, ArantesLMet al. Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds. Eur. J. Med. Chem.145, 191–205 (2018).
   PubMed Web of Science ®Google Scholar
• Rawat R , VermaSM. An exclusive computational insight toward molecular mechanism of MMV007571, a multitarget inhibitor of Plasmodium falciparum. J. Biomol. Struct. Dyn.38(18), 5362–5373 (2020).
   PubMed Web of Science ®Google Scholar
• Agoni C , SalifuEY, MunsamyG, OlotuFA, SolimanM. CF3-pyridinyl substitution on antimalarial therapeutics: probing differential ligand binding and dynamical inhibitory effects of a novel triazolopyrimidine-based inhibitor on Plasmodium falciparum dihydroorotate dehydrogenase. Chem. Biodivers.16(12), e1900365 (2019).
   PubMed Web of Science ®Google Scholar
• Rawat R , VermaSM. High-throughput virtual screening approach involving pharmacophore mapping, ADME filtering, molecular docking and MM-GBSA to identify new dual target inhibitors of PfDHODH and PfCytbc1 complex to combat drug resistant malaria. J. Biomol. Struct. Dyn.39(14), 5148–5159 (2021).
   PubMed Web of Science ®Google Scholar
• Koumpoura CL , NguyenM, BijaniCet al. Design of anti-infectious agents from lawsone in a three-component reaction with aldehydes and isocyanides. ACS Omega7, 35635–35655 (2022).
   PubMed Web of Science ®Google Scholar
• Vyas VK , ShuklaT, TulsianK, SharmaM, PatelS. Integrated structure-guided computational design of novel substituted quinolizin-4-ones as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. Comput. Biol. Chem.101, 107787 (2022).
   PubMed Web of Science ®Google Scholar
• Clemente CM , RobledoSM, RavettiS. Menthol carbonates as potent antiparasitic agents: synthesis and in vitro studies along with computer-aided approaches. BMC Complement. Med. Ther.8, 1–14 (2022).
   Google Scholar
• Clemente CM , PinedaT, YepesLMet al. Eugenol carbonate activity against Plasmodium falciparum, Leishmania braziliensis, and Trypanosoma cruzi. Arch. Pharm. (Weinheim)355(3), e2100432 (2022).
   PubMed Web of Science ®Google Scholar
• Akinnusi PA , OlubodeSO, AdebesinAO, OsadipeTJ. Structure-based scoring of anthocyanins and molecular modeling of PfLDH, PfDHODH, and PfDHFR reveal novel potential P. falciparum inhibitors. Inform. Med. Unlocked38, 101206 (2023).
   Google Scholar
• Ng CL , FidockDA. Plasmodium falciparum in vitro drug resistance selections and gene editing. Methods Mol. Biol.2013, 123–140 (2019).
   PubMedGoogle Scholar
• Tse EG , KorsikM, ToddMH. The past, present and future of anti-malarial medicines. Malar. J.18(1), 93 (2019).
   PubMedGoogle Scholar