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NIVAQUINE is a 4-aminoquinoline antimalarial that works by inhibiting the parasite’s ability to detoxify heme, leading to toxic buildup and parasite death inside red blood cells.
Originally developed in 1934 and approved in 1949, NIVAQUINE has also been used for rheumatoid arthritis, lupus erythematosus, and amebic liver abscesses due to its immunomodulatory and anti-inflammatory effects.
Although effective against the erythrocytic stage of malaria, NIVAQUINE is no longer used in areas with known resistance and has largely been replaced by safer alternatives like hydroxychloroquine.
CAS Number: 54-05-7
EC Number: 200-055-4
Molecular Formula: C18H26ClN3
Molecular Weight: 319.87 g/mol
Synonyms: Chloraquine, Chlorochin, Chloroquina, Chloroquinium, Chlorquin, Nivaquine, Aralen, Artrichin, Bipiquin, Malaquin, Quingamine, Reumachlor, Sanoquin, Roquine, RP3377, Aralen, Chloroquine phosphate, chloroquine, 54-05-7, Aralen, Chlorochin, Chloraquine, Artrichin, Chloroquina, Chloroquinium, Capquin, Reumachlor, Chlorquin, Clorochina, Arthrochin, Chingamin, Gontochin, Bipiquin, Klorokin, Mesylith, Sanoquin, Trochin, Amokin, Nivaquine B, Bemaphate, Cloroquina, Khingamin, Resoquine, Chlorochine, Chloroquinum, Chlorochinum, RP 3377, CHEBI:3638, 4-N-(7-chloroquinolin-4-yl)-1-N,1-N-diethylpentane-1,4-diamine, 7-Chloro-4-((4-(diethylamino)-1-methylbutyl)amino)quinoline, N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine, NSC-187208, 886U3H6UFF, SN 7618, Arechine, DTXSID2040446, 7-Chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]quinoline, Quinoline, 7-chloro-4-((4-(diethylamino)-1-methylbutyl)amino)-, 1,4-Pentanediamine, N(4)-(7-chloro-4-quinolinyl)-N(1),N(1)-diethyl-, Chingaminum, N(4)-(7-chloro-4-quinolinyl)-N(1),N(1)-diethyl-1,4-pentanediamine, N'-(7-chloroquinolin-4-yl)-N,N-diethylpentane-1,4-diamine, Quinoline, 7-chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]-, Sulfate, Chloroquine, Sulphate, Chloroquine, 7-chloro-N-(5-(diethylamino)pentan-2-yl)quinolin-4-amine, 7-CHLORO-N-[5-(DIETHYLAMINO)PENTAN-2-YL]QUINOLIN-4-AMINE, DTXCID0020446, P01BA01, 200-191-2, Chemochin, Bemaco, Bemasulph, Benaquin, Cidanchin, Cocartrit, Dichinalex, Heliopar, Iroquine, Lapaquin, Pfizerquine, Quinachlor, Quinercyl, Quinilon, Quinoscan, Silbesan, Solprina, Sopaquin, Tresochin, Elestol, Imagon, Malaren, Malarex, Neochin, Roquine, Siragan, Quingamine, Ronaquine, N4-(7-chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine, Avlochlor, Nivachine, Quinagamin, Quinagamine, Resochen, Resoquina, Reumaquin, Tanakan, WIN 244, 1,4-Pentanediamine, N4-(7-chloro-4-quinolinyl)-N1,N1-diethyl-, W 7618, {4-[(7-chloroquinolin-4-yl)amino]pentyl}diethylamine, MFCD00024009, Chloroin, Miniquine, Rivoquine, Tanakene, Arolen, Gontochin phosphate, CHEMBL76, SN 6718, Ipsen 225, N(sup 4)-(7-Chloro-4-quinolinyl)-N(sup 1),N(sup 1)-diethyl-1,4-pentanediamine, NSC187208, Chloroquine (VAN), Clorochina [DCIT], N4-(7-chloro-4-quinolyl)-N1,N1-diethyl-pentane-1,4-diamine, 3377 RP, CQ, 1,4-Pentanediamine, N(sup 4)-(7-chloro-4-quinolinyl)-N(sup 1),N(sup 1)-diethyl-, ST 21 (pharmaceutical), Chloroquinum [INN-Latin], Cloroquina [INN-Spanish], 1246815-14-4, 3377 RP opalate, Chloroquin, ST 21, C18H26ClN3, (+-)-Chloroquine, CCRIS 3439, HSDB 3029, Chloroquine (USP/INN), EINECS 200-191-2, {4-[(7-chloro(4-quinolyl))amino]pentyl}diethylamine, Malaquin (Diphosphate), NSC 187208, BRN 0482809, UNII-886U3H6UFF, Cloroquine, Chloroquine [USP:INN:BAN], Chloroquine, 17, Arechin (Salt/Mix), Delagil (Salt/Mix), Tanakan (Salt/Mix), RP-3377, Bemaphate (Salt/Mix), Resoquine (Salt/Mix), Chloroquine (Standard), Spectrum_000132, Chloroquine + Proveblue, CHLOROQUINE [MI], Prestwick0_000548, Prestwick1_000548, Prestwick2_000548, Prestwick3_000548, Spectrum2_000127, Spectrum3_000341, Spectrum4_000279, Spectrum5_000707, CHLOROQUINE [INN], (.+/-.)-Chloroquine, CHLOROQUINE [HSDB], Epitope ID:131785, MolMap_000009, CHLOROQUINE [VANDF], SCHEMBL8933, CHLOROQUINE [MART.], Lopac0_000296, BSPBio_000595, BSPBio_002001, CHLOROQUINE [WHO-DD], KBioGR_000778, KBioSS_000592, DivK1c_000404, CU-01000012392-2, SPBio_000174, SPBio_002516, GNF-Pf-4216, BPBio1_000655, GTPL5535, orb1298711, SCHEMBL29363614, BDBM22985, KBio1_000404, KBio2_000592, KBio2_003160, KBio2_005728, KBio3_001221, NINDS_000404, CHLOROQUINE [USP IMPURITY], HMS2090O03, HMS5087M13, HY-17589AR, CHLOROQUINE [USP MONOGRAPH], ALBB-025694, MSK11158, HY-17589A, s6999, SBB072644, AKOS015935106, CCG-204391, CS-W004760, DB00608, KH-0005, SB73098, SDCCGSBI-0050284.P005, IDI1_000404, SMP2_000034, NCGC00015256-02, NCGC00015256-03, NCGC00015256-04, NCGC00015256-05, NCGC00015256-06, NCGC00015256-07, NCGC00015256-08, NCGC00015256-09, NCGC00015256-10, NCGC00015256-13, NCGC00015256-17, NCGC00015256-28, NCGC00162120-01, DA-51857, FC150960, NCI60_000894, SY086904, WLN: T66 BNJ EMY1&3N2&2 IG, SBI-0050284.P004, AB00053436, C3730, CS-0021871, NS00001540, ST45028748, C07625, D02366, EN300-120683, MLS-0466768.0001, AB00053436-05, AB00053436_06, AB00053436_07, 1, N4-(7-chloro-4-quinolinyl)-N1,N1-diethyl-, Q422438, BRD-A91699651-065-01-1, BRD-A91699651-316-06-7, BRD-A91699651-316-09-1, BRD-A91699651-316-10-9, BRD-A91699651-316-11-7, n(sup4)-(7-chloro-4-quinolinyl)-n(sup1),4-pentanediamine, quinoline, 7-chloro-4-(4-diethylamino-1-methyl)butylamino-, Quinoline, 7-chloro-4-(4-diethylamino-1-methyl-butylamino)-, N(4)-(7-chloroquinolin-4-yl)-N(1),N(1)-diethylpentane-1,4-diamine, N4-(7-chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine, 1,4-PENTANEDIAMINE, N(SUP 4)-(7-CHLORO-4-QUINOLINYL)-N(SUP 1),N (SUP 1)-DIETHYL-, 1,4-pentanediamine, N4-(7-chloro-4-quinolinyl)-N1,N1-diethyl-, phosphate (1:2), 7-Chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]quinoline;(+/-)-Chloroquine, N(sup4)-(7-chloro-4-quinolinyl)-N(sup1),N(sup1)-diethyl-1,4-pentanediamine, 117399-83-4
NIVAQUINE is an antiparasitic medication that treats malaria.
NIVAQUINE works by increasing the levels of heme in the blood, a substance toxic to the malarial parasite.
This kills the parasite and stops the infection from spreading.
Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication.
While NIVAQUINE has not been formally studied in pregnancy, it appears safe.
NIVAQUINE is taken by mouth.
NIVAQUINE was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the northern summer of 2020, and the NIH does not recommend its use for this purpose.
NIVAQUINE is a member of the drug class 4-aminoquinoline.
As an antimalarial, NIVAQUINE works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell.
How NIVAQUINE works in rheumatoid arthritis and lupus erythematosus is unclear.
NIVAQUINE was discovered in 1934 by Hans Andersag.
NIVAQUINE is on the World Health Organization's List of Essential Medicines.
NIVAQUINE is available as a generic medication.
NIVAQUINE belongs to a group of medicines known as antimalarials.
NIVAQUINE works by preventing or treating malaria, a red blood cell infection transmitted by the bite of a mosquito.
However, this medicine is not used to treat severe or complicated malaria and to prevent malaria in areas or regions where NIVAQUINE is known not to work (resistance).
NIVAQUINE is a 4-aminoquinoline with antimalarial, anti-inflammatory, and potential chemosensitization and radiosensitization activities.
Although the mechanism is not well understood, NIVAQUINE is shown to inhibit the parasitic enzyme heme polymerase that converts the toxic heme into non-toxic hemazoin, thereby resulting in the accumulation of toxic heme within the parasite.
NIVAQUINE may also interfere with the biosynthesis of nucleic acids.
NIVAQUINE's potential chemosensitizing and radiosensitizing activities in cancer may be related to its inhibition of autophagy, a cellular mechanism involving lysosomal degradation that minimizes the production of reactive oxygen species (ROS) related to tumor reoxygenation and tumor exposure to chemotherapeutic agents and radiation.
NIVAQUINE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 1949 and is indicated for malaria and has 24 investigational indications.
NIVAQUINE is an aminoquinoline that is quinoline which is substituted at position 4 by a [5-(diethylamino)pentan-2-yl]amino group at position 7 by chlorine.
NIVAQUINE is used for the treatment of malaria, hepatic amoebiasis, lupus erythematosus, light-sensitive skin eruptions, and rheumatoid arthritis.
NIVAQUINE has a role as an antimalarial, an antirheumatic drug, a dermatologic drug, an autophagy inhibitor and an anticoronaviral agent.
NIVAQUINE is an aminoquinoline, a secondary amino compound, a tertiary amino compound and an organochlorine compound.
NIVAQUINE is a conjugate base of a NIVAQUINE(2+).
NIVAQUINE is an aminoquinolone derivative first developed in the 1940s for the treatment of malaria.
NIVAQUINE was the drug of choice to treat malaria until the development of newer antimalarials such as [pyrimethamine], [artemisinin], and [mefloquine].
NIVAQUINE and its derivative [hydroxyNIVAQUINE] have since been repurposed for the treatment of a number of other conditions including HIV, systemic lupus erythematosus, and rheumatoid arthritis.
The FDA emergency use authorization for [hydroxyNIVAQUINE] and NIVAQUINE in the treatment of COVID-19 was revoked on 15 June 2020.
NIVAQUINE was granted FDA Approval on 31 October 1949.
NIVAQUINE is an Antimalarial.
NIVAQUINE has been reported in Cocos nucifera, Cinchona calisaya, and other organisms with data available.
NIVAQUINE is an antimalarial medicine.
NIVAQUINE is available in the United States by prescription only.
NIVAQUINE is sold under the brand name Aralen, and it is also sold as a generic medicine.
NIVAQUINE is available in tablets of two sizes: 150mg base (250mg salt) and 300mg base (500mg salt).
You should know that the 150mg base tablet is the same as the 250mg salt tablet and the 300mg base tablet is the same as the 500mg salt tablet.
NIVAQUINE is just two different ways of describing the same thing.
NIVAQUINE can be prescribed for either prevention or treatment of malaria.
NIVAQUINE is a medication that treats and prevents malaria infections.
Malaria occurs after mosquitos deposit parasites into your body.
You can take NIVAQUINE by mouth with a glass of water as directed.
NIVAQUINE is, synthetic drug used in the treatment of malaria.
NIVAQUINE, discovered in 1934 and introduced into medicine in the 1940s, is a member of an important series of chemically related antimalarial agents, the quinoline derivatives.
NIVAQUINE is administered orally as NIVAQUINE phosphate.
NIVAQUINE also can be given by intramuscular injection as NIVAQUINE hydrochloride.
NIVAQUINE is effective against susceptible strains of the malarial parasites Plasmodium vivax, P. ovale, and P. falciparum as well as certain parasitic worms and amoebas.
NIVAQUINE is a synthetic antimalarial medication that was first developed in 1934.
In addition to its antimalarial effects, NIVAQUINE has been used extensively in rheumatology and dermatology since the 1950s.
Despite its early successes, the use of NIVAQUINE has mostly been superseded by hydroxyNIVAQUINE, a safer hydroxylated analogue, and its availability is now limited.
NIVAQUINE has immunomodulatory and anti-inflammatory effects and may also have a photoprotective effect.
NIVAQUINE is an antiprotozoal agent belonging to the 4-aminoquinoline class of drugs, derived from the chemical quinoline, known for its antimalarial properties.
The precise mechanism of NIVAQUINE is not known.
NIVAQUINE may exert its effect against Plasmodium by accumulating inside the parasite’s acid vesicles which help digest blood, and inhibit the parasite’s ability to breakdown hemoglobin and draw nutrition for their survival and growth.
NIVAQUINE is effective only against the blood stage (erythrocytic) of the malarial parasite, and is ineffective against other stages including gametocyte and hypnozoite stages.
Other antimalarial therapies must be used in regions where the Plasmodium species have developed resistance to NIVAQUINE.
NIVAQUINE is effective against the trophozoite stage of E. histolytica.
NIVAQUINE is only found in individuals that have used or taken this drug.
NIVAQUINE is a prototypical antimalarial agent with a mechanism that is not well understood.
NIVAQUINE has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses.
The mechanism of plasmodicidal action of NIVAQUINE is not completely certain.
Like other quinoline derivatives, NIVAQUINE is thought to inhibit heme polymerase activity.
This results in accumulation of free heme, which is toxic to the parasites.
Inside red blood cells, the malarial parasite must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism.
Digestion is carried out in a vacuole of the parasite cell.
During this process, the parasite produces the toxic and soluble molecule heme.
The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP).
To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a non-toxic molecule.
Hemozoin collects in the digestive vacuole as insoluble crystals.
NIVAQUINE enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion.
NIVAQUINE then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); NIVAQUINE then cannot leave by diffusion.
NIVAQUINE caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup.
NIVAQUINE binds to heme (or FP) to form what is known as the FP-NIVAQUINE complex; this complex is highly toxic to the cell and disrupts membrane function.
Action of the toxic FP-NIVAQUINE and FP results in cell lysis and ultimately parasite cell autodigestion.
In essence, the parasite cell drowns in NIVAQUINE's own metabolic products.
The prototypical antimalarial agent with a mechanism that is not well understood.
NIVAQUINE has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses.
NIVAQUINE is a drug belonging to the pharmacological family of amino-4-quinolines.
Hydroxy NIVAQUINE = HCQ (marketed in France as Plaquenil) is a by-product.
NIVAQUINE mainly treats malaria, but is also a treatment for various autoimmune inflammatory diseases (such as Lupus or Rheumatoid Arthritis).
NIVAQUINE is a chemical substitute for quinine, an alkaloid substance of plant origin made from extracts of cinchona which comes from the bark of the cinchona tree.
This tree, which is native to Peru in high altitudes (Andes Cordillera).
NIVAQUINE's therapeutic properties (especially antipyretics) have been known since as early as the 17th century.
Quinine, a molecule extracted from this plant, serves as the basis for the synthesis of several drugs, such as:
NIVAQUINE (antimalarial)
Mefloquine (antimalarial)
HydroxyNIVAQUINE (anti-inflammatory)
Quinidine (antiarrhythmic), etc.
Uses of NIVAQUINE:
NIVAQUINE is used off-label for certain autoimmune disorders.
NIVAQUINE also accumulates inside organelles of human immune cells, which prevents the proliferation of inflammatory T helper cells and the presentation of unique proteins (antigens) that autoimmune antibodies recognize and attack in autoimmune disorders.
This reduces inflammatory activity, including the activation of killer T-cells and the release of inflammatory proteins (cytokines).
The uses of NIVAQUINE include: Treatment of uncomplicated malaria due to susceptible strains of Plasmodium falciparum, P. malariae, P. ovale, and P. vivax
Prophylaxis of malaria in geographic areas where resistance to NIVAQUINE is not present
Treatment of extraintestinal amebiasis
NIVAQUINE is used to prevent and treat malaria.
NIVAQUINE is also used to treat liver infection caused by protozoa (extraintestinal amebiasis).
Using NIVAQUINE alone or with other medicines (eg, azithromycin) may increase your risk of heart rhythm problems (eg, QT prolongation, ventricular fibrillation, ventricular tachycardia).
Do not take any medicine that contains NIVAQUINE unless prescribed by your doctor.
NIVAQUINE is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus.
NIVAQUINE is an aminoquinoline used for the prevention and therapy of malaria.
NIVAQUINE is also effective in extraintestinal amebiasis and as an antiinflammatory agent for therapy of rheumatoid arthritis and lupus erythematosus.
NIVAQUINE is not associated with serum enzyme elevations and is an extremely rare cause of clinically apparent acute liver injury.
NIVAQUINE is also used in the treatment of inflammatory rheumatic diseases, such as lupus erythematosus and rheumatoid arthritis.
NIVAQUINE is closely related to hydroxyNIVAQUINE, another type of quinoline derivative.
HydroxyNIVAQUINE is also used in the treatment of malaria and inflammatory rheumatic diseases.
HydroxyNIVAQUINE has many of the same side effects as NIVAQUINE, including an elevated risk of retinopathy, but generally is considered to be less toxic.
NIVAQUINE is used to treat or prevent malaria infections.
NIVAQUINE is also used to treat amebiasis.
NIVAQUINE may be used for other purposes; ask your health care provider or pharmacist if you have questions.
NIVAQUINE is used to treat or prevent malaria, a disease caused by parasites that enter the body through the bite of a mosquito.
NIVAQUINE is not effective against all strains of malaria, or against malaria in areas where the infection has been resistant to a similar drug called hydroxyNIVAQUINE.
NIVAQUINE is also used to treat amebiasis (infection caused by amoebae).
NIVAQUINE may also be used for purposes not listed in this medication guide.
NIVAQUINE is a 4‑aminoquinoline derivative first developed in the 1940s, primarily used as an antimalarial agent—effective against Plasmodium vivax, P. ovale, P. malariae, and susceptible P. falciparum.
NIVAQUINE’s also used to treat extra‑intestinal amebiasis, and off‑label for rheumatoid arthritis and lupus erythematosus.
NIVAQUINE was once considered for COVID‑19 treatment, but emergency use authorizations were revoked by mid‑2020.
Medical Uses:
Malaria:
NIVAQUINE has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae.
NIVAQUINE is generally not used for Plasmodium falciparum as there is widespread resistance to it.
NIVAQUINE has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance.
NIVAQUINE is recommended to check if NIVAQUINE is still effective in the region prior to using it.
In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead.
The Centers for Disease Control and Prevention recommend against treatment of malaria with NIVAQUINE alone due to more effective combinations.
Amebiasis:
In treatment of amoebic liver abscess, NIVAQUINE may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within five days or intolerance to metronidazole or a nitroimidazole.
Rheumatic Disease:
As it mildly suppresses the immune system, NIVAQUINE is used in some autoimmune disorders, such as rheumatoid arthritis and has an off-label indication for lupus erythematosus.
NIVAQUINE is an antimalarial drug used to treat susceptible infections with P. vivax, P. malariae, P. ovale, and P. falciparum.
NIVAQUINE is also used for second line treatment for rheumatoid arthritis.
NIVAQUINE is an aminoquinolone derivative first developed in the 1940s for the treatment of malaria.
NIVAQUINE was the drug of choice to treat malaria until the development of newer antimalarials such as pyrimethamine, artemisinin, and mefloquine.
NIVAQUINE and its derivative hydroxyNIVAQUINE have since been repurposed for the treatment of a number of other conditions including HIV, systemic lupus erythematosus, and rheumatoid arthritis.
Benefits of NIVAQUINE:
NIVAQUINE offers several clinical and pharmaceutical advantages, particularly in the management of cardiovascular diseases.
Here are NIVAQUINE's key benefits:
Prevention of Life-Threatening Cardiovascular Events:
NIVAQUINE significantly reduces the risk of heart attacks, ischemic strokes, and arterial thrombosis in patients with a history of myocardial infarction (MI), stroke, or peripheral arterial disease (PAD).
Essential in Dual Antiplatelet Therapy (DAPT):
When used alongside aspirin, NIVAQUINE forms the cornerstone of dual antiplatelet therapy, especially after coronary stent placement or percutaneous coronary intervention (PCI), reducing the risk of stent thrombosis.
Irreversible Platelet Inhibition:
By irreversibly inhibiting the P2Y₁₂ ADP receptor on platelets, clopidogrel ensures sustained antiplatelet effects, making it effective for long-term prevention of thrombotic events.
Oral Administration and Once-Daily Dosing:
NIVAQUINE is administered orally, typically once daily, providing convenience and high patient compliance.
Prodrug with Targeted Activation:
As a prodrug, clopidogrel requires activation by liver enzymes (CYP450), allowing selective action with minimal systemic effects outside platelet inhibition.
Use in Aspirin-Intolerant Patients:
Clopidogrel is often used as a safer alternative to aspirin in individuals who are allergic or intolerant to it.
Well-Studied and Widely Prescribed:
With extensive clinical trial support (e.g., CAPRIE, CURE, COMMIT), clopidogrel is a WHO essential medicine, ensuring broad availability, reliability, and evidence-based efficacy.
Veterinary Applications:
In veterinary medicine, NIVAQUINE is used off-label to prevent thromboembolism in cats, particularly those with hypertrophic cardiomyopathy (HCM).
Production
NIVAQUINE is produced through a multi-step chemical synthesis that involves the preparation of clopidogrel base, followed by conversion to the bisulphate salt for improved stability, solubility, and pharmaceutical usability.
Synthesis of Clopidogrel Base:
The core structure of clopidogrel (a thienopyridine derivative) is synthesized via a multi-step process involving:
Thienopyridine ring formation through cyclization of intermediates containing sulfur and nitrogen atoms.
Esterification reactions to introduce the methyl ester group.
Introduction of a 2-chlorophenyl group at the appropriate position on the thienopyridine scaffold.
Stereoselective control is crucial, as the (S)-enantiomer is the active pharmaceutical form.
Salt Formation (Bisulphate Form):
Once the base is synthesized and purified:
NIVAQUINE is reacted with sulfuric acid (H₂SO₄) under controlled conditions to form NIVAQUINE, the hydrogen sulfate salt of the base.
The reaction typically occurs in a polar solvent, such as ethanol or methanol.
The resulting crystalline salt is filtered, washed, and dried to obtain a white to off-white powder of pharmaceutical-grade purity.
Purification and Formulation:
NIVAQUINE undergoes further purification steps to remove impurities, including unwanted stereoisomers and residual solvents.
The purified NIVAQUINE is then formulated into tablets using excipients like microcrystalline cellulose, lactose monohydrate, and magnesium stearate.
Quality Control and Packaging:
The final product is subject to strict quality control (QC) measures, including:
Chiral purity testing
Content uniformity
Dissolution profiles
Residual solvent analysis
The API (Active Pharmaceutical Ingredient) is then packaged or sent for further formulation into dosage forms like 75 mg or 300 mg tablets.
History of NIVAQUINE:
NIVAQUINE has a notable history in the field of cardiovascular pharmacology, representing a major advancement in antiplatelet therapy:
Discovery and Development:
Clopidogrel was developed in the late 1980s by Sanofi-Synthelabo (now part of Sanofi) and Bristol-Myers Squibb, as a follow-up to the earlier thienopyridine ticlopidine.
While ticlopidine was effective, NIVAQUINE was associated with serious adverse effects such as neutropenia and thrombotic thrombocytopenic purpura (TTP).
Clopidogrel was developed to provide a safer and better-tolerated alternative.
Clopidogrel was patented in 1986 and received FDA approval in 1997 under the brand name Plavix.
Mechanistic Milestone:
Clopidogrel represented a new generation of thienopyridine antiplatelet drugs, offering irreversible inhibition of the P2Y₁₂ ADP receptor on platelets—a mechanism crucial in preventing thrombus formation.
NIVAQUINE is a prodrug, requiring metabolic activation in the liver, which was a unique concept at the time and laid the groundwork for pharmacogenetic research in antiplatelet therapy.
Clinical Impact:
The CAPRIE trial (1996) established clopidogrel’s superiority over aspirin in reducing ischemic events in patients with atherosclerotic vascular disease.
NIVAQUINE soon became a standard of care in dual antiplatelet therapy (DAPT)—especially after coronary stenting procedures—alongside aspirin.
Over time, NIVAQUINE became one of the most prescribed cardiovascular drugs worldwide.
Patent Expiry and Generics:
The original patent for Plavix expired in 2012, leading to the global availability of generic NIVAQUINE, significantly reducing cost and increasing access.
Genetic Considerations:
Following NIVAQUINE's widespread use, researchers discovered that genetic polymorphisms (particularly in the CYP2C19 enzyme) significantly influence the drug’s efficacy.
This led to increased interest in personalized medicine, especially in populations with known CYP2C19 loss-of-function alleles, who may not respond adequately to clopidogrel.
Handling and Storage of NIVAQUINE:
Handling:
Handle in accordance with good industrial hygiene and safety practices.
Avoid contact with skin, eyes, and clothing.
Do not inhale dust or powder.
Work in a well-ventilated area or under a fume hood.
Storage:
Store in a cool, dry, and well-ventilated place.
Keep container tightly closed.
Protect from light, heat, moisture, and incompatible substances.
Store at controlled room temperature, typically 15–30°C (59–86°F).
Stability and Reactivity of NIVAQUINE:
Chemical Stability:
NIVAQUINE is stable under normal temperatures and pressures.
Reactivity:
Not reactive under normal conditions.
Incompatible Materials:
Strong oxidizing agents, strong acids, and strong bases.
Hazardous Decomposition Products:
May produce carbon monoxide (CO), carbon dioxide (CO₂), sulfur oxides (SOₓ), hydrogen chloride (HCl), and nitrogen oxides (NOₓ) when heated to decomposition.
First Aid Measures of NIVAQUINE:
Inhalation:
Move person to fresh air.
If breathing is difficult, give oxygen.
Seek medical attention.
Skin Contact:
Immediately wash skin with soap and plenty of water.
Remove contaminated clothing.
Seek medical advice if irritation develops.
Eye Contact:
Rinse cautiously with water for several minutes.
Remove contact lenses if present and easy to do.
Continue rinsing and consult a physician.
Ingestion:
Rinse mouth with water.
Do not induce vomiting unless directed by medical personnel.
Seek immediate medical attention.
Firefighting Measures of NIVAQUINE:
Suitable Extinguishing Media:
Use water spray, carbon dioxide (CO₂), dry chemical powder, or alcohol-resistant foam.
Specific Hazards:
May emit toxic fumes under fire conditions (e.g., CO, CO₂, SOₓ).
Protective Equipment:
Wear self-contained breathing apparatus (SCBA) and full protective clothing.
Avoid inhalation of smoke or vapors.
Accidental Release Measures of NIVAQUINE:
Personal Precautions:
Avoid contact with spilled material.
Wear appropriate PPE (gloves, mask, goggles, lab coat).
Ensure adequate ventilation.
Spill Cleanup:
Carefully sweep up or absorb with an inert material (e.g., vermiculite, sand) and place in a chemical waste container.
Avoid generating dust.
Wash area with water.
Environmental Precautions:
Prevent entry into drains, sewers, or waterways.
Dispose of waste in accordance with local, regional, and national regulations.
Exposure Controls / Personal Protective Equipment of NIVAQUINE:
Engineering Controls:
Use in a chemical fume hood or well-ventilated area.
Ensure eyewash stations and safety showers are available.
Personal Protection:
Eye/Face Protection:
Safety goggles or face shield.
Skin Protection:
Chemical-resistant gloves (e.g., nitrile or neoprene).
Clothing:
Protective lab coat or gown.
Respiratory Protection:
If dust is generated or ventilation is inadequate, wear an approved respirator (e.g., NIOSH-certified).
Identifiers of NIVAQUINE:
IUPAC Name: 7-chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]quinoline
Molecular Formula: C18H26ClN3
Molecular Weight: 319.87 g/mol
CAS Number: 54-05-7
PubChem CID: 2719
UNII (FDA): K3UL8S4EIQ
InChI Key: KCYNMZROWNVIMV-UHFFFAOYSA-N
SMILES Notation: CCN(CC)CCCCN1C=C(C2=CC=CC=C2Cl)C=NC1
ChEBI ID: CHEBI:3638
DrugBank ID: DB00608
ChemSpider ID: 2618
ATC Code: P01BA01
EC Number: 200-055-4
ChemBL ID: CHEMBL521
KEGG Drug: D07658
MeSH ID: D002640
Common Salt Form: NIVAQUINE phosphate (C18H26ClN3·2H3PO4)
Chemical Name: NIVAQUINE diphosphate or NIVAQUINE phosphate
Molecular Formula: C18H26ClN3·2H3PO4
Molecular Weight: 515.86 g/mol
CAS Number: 50-63-5
PubChem CID: 64927
UNII: 8E0A0JLU5R
DrugBank ID: DB01611
ChemSpider ID: 58438
IUPAC Name (salt): (7-chloroquinolin-4-yl)-N,N-diethyl-N-methylpentane-1,4-diamine dihydrogen phosphate
Properties of NIVAQUINE:
CAS Number: 54-05-7 (free base) / 50-63-5 (phosphate salt)
EC Number: 200-055-2 (NIVAQUINE phosphate)
Molecular Formula: C₁₈H₂₆ClN₃
Molecular Weight: ~319.87 g/mol (free base)
IUPAC Name: N⁴-(7-chloro-4-quinolinyl)-N¹,N¹-diethyl-pentane-1,4-diamine (aka N'-(7-chloroquinolin-4-yl)-N,N-diethyl-1,4-pentane-diamine)
Appearance: White to off-white crystalline powder (bitter taste), odourless
Melting Point: ~87–92 °C
Solubility: Very slightly soluble in water; soluble in organic solvents
XLogP3: ~4.27 (lipophilicity)
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 3
Rotatable Bond Count: ~8
Topological Polar Surface Area: ~28.16 Ų
Exact Mass: 319.1815 Da
Monoisotopic Mass: 319.1815 Da
Heavy Atom Count: 22
Complexity: 309
Isotope Atom Count: 0
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 1
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Covalently-Bonded Unit Count: 1
Compound Is Canonicalized: Yes
IUPAC Name: N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine
Molecular Formula: C18H26ClN3
Molecular Weight: 319.87 g/mol
Appearance: White to pale yellow crystalline powder
Odor: Odorless
Melting Point: ~87–90°C
Boiling Point: Decomposes before boiling
Solubility:
Slightly soluble in water
Freely soluble in ethanol, chloroform, and methanol
Practically insoluble in ether
LogP (octanol/water): 4.7 (indicating high lipophilicity)
pKa values:
~8.4 (tertiary amine)
~10.2 (secondary amine)
Flash Point: Not applicable (decomposes)
Molecular Formula: C18H26ClN3·2H3PO4
Molecular Weight: 515.86 g/mol
Appearance: White to slightly yellow, odorless crystalline powder
Melting Point: ~190°C (decomposes)
Solubility:
Freely soluble in water
Insoluble in alcohol and ether
Stability: Stable under normal conditions, but sensitive to light and air (can darken upon exposure)
Taste: Bitter
Storage Conditions: Store in a tightly closed container, protected from light and moisture
