Drug Information

General Information of This Drug
Drug ID DRG00005
Drug Name Primaquine
Synonyms
PRIMAQUINE; 90-34-6; Primachin; Neo-Quipenyl; 8-(4-Amino-1-methylbutylamino)-6-methoxyquinoline; Primaquin; Primachinum; Primaquinum; Primaquina; Kanaprim; Primachina; (+/-)-Primaquine; 1,4-Pentanediamine, N4-(6-methoxy-8-quinolinyl)-; Maliride; SN 13,272; 6-Methoxy-8-(4-amino-1-methylbutylamino)quinoline; Primaquinum [INN-Latin]; Primaquina [INN-Spanish]; 4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine; N-(5-aminopentan-2-yl)-6-methoxyquinolin-8-amine; NSC 27296; CCRIS 4109; CHEBI:8405; S. N. 13272; HSDB 6516; 8-((4-Amino-1-methylbutyl)amino)-6-methoxyquinoline; EINECS 201-987-2; UNII-MVR3634GX1; NSC-27296; Primaquine (INN); WR 2975; MVR3634GX1; N4-(6-Methoxy-8-quinolinyl)-1,4-pentanediamine; Quinoline, 8-(4-amino-1-methylbutylamino)-6-methoxy; WR-2975; SN-13272; DTXSID8023509; N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine; (+)-Primaquine; (-)-Primaquine; NSC27296; N(4)-(6-methoxyquinolin-8-yl)pentane-1,4-diamine; 1,4-Pentanediamine, N(4)-(6-methoxy-8-quinolinyl)-; 8-[(4-Amino-1-methylbutyl)amino]-6-methoxyquinoline; Quinoline, 8-(4-amino-1-methylbutylamino)-6-methoxy-; N-[(S)-4-Amino-1-methylbutyl]-6-methoxy-8-quinolinamine; Quinoline, 8-((4-amino-1-methylbutyl)amino)-6-methoxy-; Primachina [DCIT]; dl-Primaquine; PRIMAQUINE [INN]; Primaquinum (INN-Latin); Primaquina (INN-Spanish); Primaquine [INN:BAN]; BRN 0019337; Maliride; NSC 27296; Neo-Quipenyl; Primachin; N4-(6-methoxy-8-quinolyl)pentane-1,4-diamine; 6-Methoxy-8-[(4-amino-1-methylbutyl)amino]quinoline; N~4~-[6-(methyloxy)quinolin-8-yl]pentane-1,4-diamine; CHEMBL506; MLS001334045; Kanaprim (TN); n4-[6-methoxy-8-quinolinyl]-1,4-pentanediamine; 4-22-00-05817 (Beilstein Handbook Reference); NCGC00178754-06; N~4~-(6-methoxyquinolin-8-yl)pentane-1,4-diamine; SMR000875314; 6-Methoxy-8-((4-amino-1-methylbutyl)amino)quinoline; Quinoline, 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-; (RS)-primaquine; TG1-296; TG1-297; Spectrum_000830; PRIMAQUINE [MI]; Prestwick0_000476; Prestwick1_000476; Prestwick2_000476; Prestwick3_000476; Spectrum2_000887; Spectrum3_000552; Spectrum4_000484; Spectrum5_001363; PRIMAQUINE [VANDF]; Epitope ID:131792; PRIMAQUINE [WHO-DD]; Oprea1_546209; SCHEMBL22207; BSPBio_000612; BSPBio_002223; KBioGR_000967; KBioSS_001310; 4-amino-1-methylbutyl(6-methoxy-8-quinolyl)amine; DivK1c_000806; SPBio_000674; SPBio_002551; (+)-N4-(6-Methoxy-8-quinolinyl)-1,4-pentanediamine; (-)-N4-(6-Methoxy-8-quinolinyl)-1,4-pentanediamine; BPBio1_000674; cid_359247; DTXCID903509; GTPL9952; BDBM71542; KBio1_000806; KBio2_001310; KBio2_003878; KBio2_006446; KBio3_001723; P01BA03; NINDS_000806; HMS2090J17; BCP29271; BBL011330; HY-12651A; MFCD00598906; STL146416; 1, N4-(6-methoxy-8-quinolinyl)-; AKOS005721199; DB01087; WLN: T66 BNJ HO1 JMY1&3Z; IDI1_000806; SMP1_000263; NCGC00178754-01; NCGC00178754-02; NCGC00178754-03; AC-23007; AS-30679; NCI60_001035; NCI60_005887; SBI-0051491.P003; AB00053529; CS-0013754; NS00000469; C07627; D08420; EN300-144245; AB00053529-11; AB00053529_12; AB00053529_14; N-(6-Methoxy-8-quinolinyl)-1,4-pentanediamine; A843518; N4-(6-methoxyquinolin-8-yl)pentane-1,4-diamine; Q419834; BRD-A55913614-316-06-2; SR-05000001864-11; N4-(6-methoxy-8-quinolyl)pentane-1,4-diamine;Primaquine; N4-(6-Methoxyquinolin-8-yl)pentane-1,4-diamine (2 H3PO4); N4-(6-methoxy-8-quinolinyl)pentane-1,4-diamine;phosphoric acid; N4-(6-methoxyquinolin-8-yl)pentane-1,4-diamine;phosphoric acid; (4-amino-1-methyl-butyl)-(6-methoxy-8-quinolyl)amine;phosphoric acid
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Target(s) Plasmodium Deoxyribonucleic acid (Malaria DNA)  Target Info 
Structure
Formula
C15H21N3O
#Ro5 Violations (Lipinski): 0 Molecular Weight (mw) 259.35
Lipid-water partition coefficient (xlogp) 2.2
Hydrogen Bond Donor Count (hbonddonor) 2
Hydrogen Bond Acceptor Count (hbondacc) 4
Rotatable Bond Count (rotbonds) 6
PubChem CID
4908
Canonical smiles
CC(CCCN)NC1=C2C(=CC(=C1)OC)C=CC=N2
InChI
InChI=1S/C15H21N3O/c1-11(5-3-7-16)18-14-10-13(19-2)9-12-6-4-8-17-15(12)14/h4,6,8-11,18H,3,5,7,16H2,1-2H3
InChIKey
INDBQLZJXZLFIT-UHFFFAOYSA-N
IUPAC Name
4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine
The activity data of This Drug
Standard Type Value Administration times Cell line Cell line ID Ref.
Half Maximal Inhibitory Concentration (IC50) 2.07 µM 18-24 h Plasmodium falciparum strain 3D7 5833 [1]
Half Maximal Cytotoxicity Concentration (CC50) 120.03 uM N.A. Hep-G2 cell CVCL_0027 [2]
Half Maximal Inhibitory Concentration (IC50) 6.9 uM N.A. MCF-7 cell CVCL_0031 [3]
Half Maximal Inhibitory Concentration (IC50) 69.7 uM N.A. HT29 cell CVCL_A8EZ [3]
Half Maximal Inhibitory Concentration (IC50) ≥100 uM N.A. SW620 cell CVCL_0547 [4]
Each Peptide-drug Conjugate Related to This Drug
Full Information of The Activity Data of The PDC(s) Related to This Drug
PDIP-DBCO-SS-PQ [Investigative]
 PDC Info 
Obtained from the Model Organism Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Malaria
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 4.25 µM
Evaluation Method Flow cytometry assay
Administration Time 18-24 h
MOA of PDC
As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum.

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Description
The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity.

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In Vivo Model Plasmodium falciparum 3D7.
Half life period 4.55 h
PDIP-DBCO-triox-PQ [Investigative]
 PDC Info 
Obtained from the Model Organism Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Malaria
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 4.68 µM
Evaluation Method Flow cytometry assay
Administration Time 18-24 h
MOA of PDC
As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum.

   Click to Show/Hide
Description
The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity.

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In Vivo Model Plasmodium falciparum 3D7.
Half life period 3.99 h
PDIP-PEG3-PQ [Investigative]
 PDC Info 
Obtained from the Model Organism Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Malaria
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 8.81 µM
Evaluation Method Flow cytometry assay
Administration Time 18-24 h
MOA of PDC
As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum.

   Click to Show/Hide
Description
The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity.

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In Vivo Model Plasmodium falciparum 3D7.
PDIP-PEG1-PQ [Investigative]
 PDC Info 
Obtained from the Model Organism Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Malaria
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 11.3 µM
Evaluation Method Flow cytometry assay
Administration Time 18-24 h
MOA of PDC
As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum.

   Click to Show/Hide
Description
The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity.

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In Vivo Model Plasmodium falciparum 3D7.
PDIP-alk-PQ [Investigative]
 PDC Info 
Obtained from the Model Organism Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Malaria
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 12.9 µM
Evaluation Method Flow cytometry assay
Administration Time 18-24 h
MOA of PDC
As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum.

   Click to Show/Hide
Description
The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity.

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In Vivo Model Plasmodium falciparum 3D7.
[GG]PDIP-alk-PQ [Investigative]
 PDC Info 
Obtained from the Model Organism Data
Click To Hide/Show 1 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Malaria
Efficacy Data Half Maximal Inhibitory Concentration (IC50) 22.5 µM
Evaluation Method Flow cytometry assay
Administration Time 18-24 h
MOA of PDC
As a proof of concept, we aimed to produce first-generation PDCs by conjugating the antimalarial drug primaquine (PQ) onto PDIP. Although PQ is one of the few drugs without clinically relevant resistance, it does not have widespread use because it causes hemolysis in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), a genetic trait common in malaria-endemic areas. Furthermore, PQ is metabolized into carboxyprimaquine in the body, which does not have any activity against the parasite. The proposed PDC approach provides the potential to deliver PQ directly to the parasite, which could prevent its interaction with healthy tissues and slow the conversion of PQ into inactive byproducts. Further, the combination of the peptide and drug, each with distinct antiplasmodial mechanisms of action, provides the potential to avoid the formation of drug-resistant parasites. Herein, we report the design, synthesis, and biological evaluation of a library of PDIP-PQ conjugates. Various design elements of the PDCs were probed to investigate their effect on biological activity, including: (i) the location of the PDIP conjugation site, (ii) the hydrophilicity of the linker between the peptide and drug, (iii) the spacing between the peptide and drug, and (iv) whether the linker can be cleaved to release the drug cargo under conditions which mimic the intracellular environment of infected RBCs. This work demonstrates that conjugation within the flexible interhelix spacer of PDIP and incorporation of traceless cleavable linkersbearing either a disulfide or trioxolane moietyare important for maintaining the low micromolar potency of the PQ drug cargo against P. falciparum.

   Click to Show/Hide
Description
The six PDIP-PQ conjugates were analyzed for their ability to inhibit the in vitro growth of P. falciparum asexual blood stage parasites (strain 3D7) in RBCs and were compared to the activity of the parent drug and peptide. We were encouraged to discover that most of the PDIP-PQ PDCs retained antiplasmodial activity similar to PDIP, with IC50 values in the low micromolar range. Notably, the various design elements probed provided valuable information regarding which PDC characteristics can be modified to improve activity.

   Click to Show/Hide
In Vivo Model Plasmodium falciparum 3D7.
References
Ref 1 Development of Antiplasmodial Peptide-Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells. Bioconjug Chem. 2023 Jun 21;34(6):1105-1113. doi: 10.1021/acs.bioconjchem.3c00147. Epub 2023 May 26.
Ref 2 Novel antimalarial chloroquine- and primaquine-quinoxaline 1,4-di-N-oxide hybrids: Design, synthesis, Plasmodium life cycle stage profile, and preliminary toxicity studies. Eur J Med Chem. 2018 Oct 5;158:68-81. doi: 10.1016/j.ejmech.2018.08.063. Epub 2018 Aug 30.
Ref 3 Anti-tumoral activity of imidazoquines, a new class of antimalarials derived from primaquine. Bioorg Med Chem Lett. 2009 Dec 15;19(24):6914-7. doi: 10.1016/j.bmcl.2009.10.081. Epub 2009 Oct 22.
Ref 4 Urea and carbamate derivatives of primaquine: synthesis, cytostatic and antioxidant activities. Bioorg Med Chem. 2009 Aug 1;17(15):5605-13. doi: 10.1016/j.bmc.2009.06.030. Epub 2009 Jun 21.