Drug Information

Drug (ID: DG00041) and It's Reported Resistant Information

• Name: Quinine
• Synonyms: Aflukin; Chinin; Chinine; Chininum; Conchinin; Conquinine; Quindan; Quinidex; Quinidine; Quinimax; Quinina; Quinineanhydrous; Quinora; Quniacridine; Chinin [German]; Kinder Quinina; QUININE MONO HCL; Quinine Dab; Quinine [BAN]; Quinine anhydrous; Quinine bisulfate; Quinine sulfate; Quinine sulphate; Quinoline alkaloid; LT00645788;Q0028; SB01652; Beta-Quinine; Cin-Quin; Coco-Quinine; IBS-L0034250; Kinder Quinina (TN); Legatrin (TN); Quinine (BAN); Quinine, Anhydrous; Quinine, polymers; Quinine, tannate; Biquinate (*Bisulfate heptathydrate*); Dentojel (*Bisulfate heptathydrate*); Quinamm (*2:1 Sulfate salt*), dihydrate; Quine (*2:1 Sulfate salt*, dihydrate); Quinsan (*2:1 Sulfate salt*), dihydrate; Alpha-(6-Methoxy-4-quinoyl)-5-vinyl-2-quinclidinemethanol; Cinchonan-9-ol, 6'-methoxy-, (8.alpha.,9R)-, sulfate; (+)-Quinidine; (-)-Quinine; (1R)-(6-Methoxyquinolin-4-yl)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methanol; (3A,8A,9r)-6'-methoxycinchonan-9-ol; (5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl)-(6-methoxyquinolin-4-yl)methanol; (8-alpha,9R)-6'-Methoxycinchonan-9-ol; (8.alpha.,9R)-6'-Methoxycinchonan-9-ol; (8S,9R)-6'-Methoxycinchonan-9-ol; (8S,9R)-Quinine; (9R)-6'-methoxy-8alpha-cinchonan-9-ol; (R)-(-)-Quinine, 6-methoxycinchonidine; (R)-(-)-quinine; (R)-(6-Methoxy-quinolin-4-yl)-((2S,5S)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methanol; (R)-(6-methoxyquinolin-4-yl)((2S,4S,8R)-8-vinylquinuclidin-2-yl)methanol; (R)-[(2S,4R,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol; (R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol; (R)-[(2S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol; (S)-(5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl)-(6-methoxyquinolin-4-yl)methanol; (S)-[(2R,4R,5S)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol; 6'-Methoxycinchonan-9-ol; 6'-Methoxycinchonidine; 6'-Methoxycinchonine; 6-Methoxycinchonine
• Indication:
  In total 1 Indication(s)
  Malaria [ICD-11: 1F45]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [3]
• Formula: C20H24N2O2
• IsoSMILES: COC1=CC2=C(C=CN=C2C=C1)[C@H]([C@@H]3C[C@@H]4CCN3C[C@@H]4C=C)O
• InChI: 1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19-,20+/m0/s1
• InChIKey: LOUPRKONTZGTKE-WZBLMQSHSA-N
• PubChem CID: 3034034
• ChEBI ID: CHEBI:15854
• TTD Drug ID: D03DDR
• VARIDT ID: DR00054
• DrugBank ID: DB00468

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Astrocytoma [ICD-11: 2F36]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Chloroquine resistance transporter (CRT) [3], [4]

• Molecule Alteration: Missense mutation; p.76T
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR; Genotypic characterization assay
• Mechanism Description: Pfcrt is involved in the transport of quinine and that SNPs in pfcrt, including 76T, decrease P. falciparum susceptibility to quinine.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [5]

• Molecule Alteration: Missense mutation; p.M908L
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Experiment for Molecule Alteration: In vitro drug assay
• Experiment for Drug Resistance: Analysis of genetic polymorphisms assay
• Mechanism Description: The pvmdr1 M908L substitutions in pvmdr1 in our samples was associated with reduced sensitivity to chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartem.

Key Molecule: Chloroquine resistance transporter (CRT) [6]

• Molecule Alteration: Missense mutation; p.I356T
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Drug Resistance: Malaria Ag Celisa kit assay
• Mechanism Description: The mutation I356T, identified in 54.7% (n = 326) of the African isolates, was significantly associated with reduced susceptibility to quinine (p < 0.02) and increased susceptibility to mefloquine.

Key Molecule: Chloroquine resistance transporter (CRT) [7]

• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Phosphorylation of Ser-33 augments the level of PfCRT-conferred resistance to the antimalarial drugs chloroquine and quinine via stimulation of the transport velocity.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Molecule Alteration: Missense mutation; p.184F
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pfmdr1-86Y, Pfmdr1-184F, and Pfcrt-76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pfmdr1-N86, Pfmdr1-Y184, and Pfcrt-k76, respect.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Molecule Alteration: Missense mutation; p.86Y
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pfmdr1-86Y, Pfmdr1-184F, and Pfcrt-76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pfmdr1-N86, Pfmdr1-Y184, and Pfcrt-k76, respect.

Key Molecule: Na+/H+ exchanger-1 (PFNHE1) [3]

• Molecule Alteration: Missense mutation + Chromosome variation; ms4760+ 3 DNNND repeats
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pfmdr1-86Y, Pfmdr1-184F, and Pfcrt-76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pfmdr1-N86, Pfmdr1-Y184, and Pfcrt-k76, respect.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1], [2]

• Molecule Alteration: Missense mutation; p.184F
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: [3H]-hypoxanthine assay; In vitro sensitivity assay
• Mechanism Description: 86Y allele exhibited significantly increased QN sensitivity compared with the wild-type counterpart. The parasites with the pfmdr1 184F allele exhibited approximately twice less susceptible to QN than the parasites with the pfmd.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1], [2]

• Molecule Alteration: Missense mutation; p.86Y
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Genotypic characterization assay
• Experiment for Drug Resistance: [3H]-hypoxanthine assay; In vitro sensitivity assay
• Mechanism Description: 86Y allele exhibited significantly increased QN sensitivity compared with the wild-type counterpart. The parasites with the pfmdr1 184F allele exhibited approximately twice less susceptible to QN than the parasites with the pfmd.

Key Molecule: Chloroquine resistance transporter (CRT) [8], [9]

• Molecule Alteration: Missense mutation; p.K76I
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Sequence assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: In addition to producing CQ resistance in P. falciparum, a novel PfCRT k76I mutation resulted in a dramatic increase in QN susceptibility, reversing the normally observed potency order of QD > QN.

Key Molecule: Chloroquine resistance transporter (CRT) [10]

• Molecule Alteration: Missense mutation; p.T93S+p.H97Y+p.F145I+p.I218F
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Drug combination assay
• Mechanism Description: The presence of novel pfcrt mutations (T93S, H97Y, F145I, and I218F) with E415G-Exo mutation can confer PPQ-resistance, in the absence of pfpm2 amplification. In vitro testing of PPQ resistant parasites demonstrated a bimodal dose-response, the existence of a swollen digestive vacuole phenotype, and an increased susceptibility to quinine, chloroquine, mefloquine and lumefa.

Key Molecule: Chloroquine resistance transporter (CRT) [7]

• Molecule Alteration: Missense mutation; p.S33A
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Substituting Ser-33 with alanine reduced chloroquine and quinine resistance by 50% compared with the parental P. falciparum strain Dd2, whereas the phosphomimetic amino acid aspartic acid could fully and glutamic acid could partially reconstitute the level of chloroquine/quinine resistance.

Key Molecule: Chloroquine resistance transporter (CRT) [11]

• Molecule Alteration: Missense mutation; p.C101F
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum asexual blood-stage parasites; 5833
• Experiment for Molecule Alteration: DNA clones asssay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: This mutation (C101F) also reversed Dd2-mediated CQ resistance, sensitized parasites to amodiaquine, quinine, and artemisinin, and conferred amantadine and blasticidin resistance.

Key Molecule: Chloroquine resistance transporter (CRT) [12]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Mechanism Description: This study describes the activities of a series of dimeric quinine compounds. These agents were found to be the most potent inhibitors of PfCRTCQR described to date with IC50 values between 1 and 5 M but are not themselves substrates of the transporter.

References

• Ref 1: Distribution of pfmdr1 polymorphisms in Plasmodium falciparum isolated from Southern Thailand. Malar J. 2014 Mar 27;13:117. doi: 10.1186/1475-2875-13-117.
• Ref 2: Phenotypic and genotypic characterization of Thai isolates of Plasmodium falciparum after an artemisinin resistance containment project. Malar J. 2018 May 15;17(1):197. doi: 10.1186/s12936-018-2347-9.
• Ref 3: Polymorphisms in Pfmdr1, Pfcrt, and Pfnhe1 genes are associated with reduced in vitro activities of quinine in Plasmodium falciparum isolates from western Kenya. Antimicrob Agents Chemother. 2014 Jul;58(7):3737-43. doi: 10.1128/AAC.02472-14. Epub 2014 Apr 21.
• Ref 4: Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine in Guinea-Bissau between 2003 and 2012. Antimicrob Agents Chemother. 2015 Feb;59(2):872-9. doi: 10.1128/AAC.03554-14. Epub 2014 Nov 24.
• Ref 5: Ex vivo susceptibilities of Plasmodium vivax isolates from the China-Myanmar border to antimalarial drugs and association with polymorphisms in Pvmdr1 and Pvcrt-o genes. PLoS Negl Trop Dis. 2020 Jun 12;14(6):e0008255. doi: 10.1371/journal.pntd.0008255. eCollection 2020 Jun.
• Ref 6: Prevalence of mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, and association with ex vivo susceptibility to common anti-malarial drugs against African Plasmodium falciparum isolates. Malar J. 2020 Jun 5;19(1):201. doi: 10.1186/s12936-020-03281-x.
• Ref 7: Phosphomimetic substitution at Ser-33 of the chloroquine resistance transporter PfCRT reconstitutes drug responses in Plasmodium falciparum. J Biol Chem. 2019 Aug 23;294(34):12766-12778. doi: 10.1074/jbc.RA119.009464. Epub 2019 Jul 8.
• Ref 8: Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine. Mol Microbiol. 2007 Jan;63(1):270-82. doi: 10.1111/j.1365-2958.2006.05511.x. Epub 2006 Dec 5.
• Ref 9: Mutation in the Plasmodium falciparum CRT protein determines the stereospecific activity of antimalarial cinchona alkaloids. Antimicrob Agents Chemother. 2012 Oct;56(10):5356-64. doi: 10.1128/AAC.05667-11. Epub 2012 Aug 6.
• Ref 10: Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization. Malar J. 2020 Jul 25;19(1):269. doi: 10.1186/s12936-020-03339-w.
• Ref 11: A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine. mBio. 2017 May 9;8(3):e00303-17. doi: 10.1128/mBio.00303-17.
• Ref 12: Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum. ACS Chem Biol. 2014 Mar 21;9(3):722-30. doi: 10.1021/cb4008953. Epub 2014 Jan 6.