74847-35-1

Basic information

• Product Name: Pyronaridine
• Synonyms: Pyronaridine;4-(2-Methoxy-6-chloro-1,10-diazaanthracene-9-ylamino)-2,6-bis(pyrrolizinomethyl)phenol;4-[(7-Chloro-2-methoxybenzo[b]-1,5-naphthyridin-10-yl)amino]-2,6-bis(1-pyrrolidinylmethyl)phenol;Malaridine phosphate;4-(7-chloro-2-Methoxybenzo[b][1,5]naphthyridin-10-ylaMino)-2,6-bis(pyrrolidin-1-ylMethyl)phenol;4-[(7-CHLORO-2-METHOXY-1,5-DIHYDROBENZO[B][1,5]NAPHTHYRIDIN-10-YL)IMINO]-2,6-BIS(PYRROLIDIN-1-YLMETHYL)CYCLOHEXA-2,5-DIEN-1-ONE
• CAS NO: 74847-35-1
• Molecular Formula: C29H32ClN5O2
• Molecular Weight: 518.11
• EINECS: 1533716-785-6
• Mol File: 74847-35-1.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 657.2oC at 760 mmHg
• Flash Point: 351.3oC
• Appearance: solid
• Density: 1.356±0.06 g/cm3 (20℃ 760 Torr)
• Vapor Pressure: 3.8E-17mmHg at 25°C
• Refractive Index: 1.5650 (estimate)
• PKA: 8.20±0.50(Predicted)
• Stability: Incompatible with strong oxidizing agents.
• CAS DataBase Reference: Pyronaridine(CAS DataBase Reference)
• NIST Chemistry Reference: Pyronaridine(74847-35-1)
• EPA Substance Registry System: Pyronaridine(74847-35-1)

Safety Data

• Hazardous Substances Data: 74847-35-1(Hazardous Substances Data)

Usage

Chemical Properties

solid

Antimicrobial activity

Pyronaridine is active against the asexual erythrocytic stage of P. falciparum with little or no activity against gametocytes or the hepatic stage. In-vitro blood schizonticide activities are in the range of 0.001–0.03 mg/L, showing a moderate correlation to chloroquine resistance. However, this correlation varies between studies and does not seem to be clinically significant. It is also active against P. vivax, P. ovale and P. malariae. Antagonistic interactions with artemisinins were reported in vitro, but synergy with artesunate has been observed in rodent models.

Acquired resistance

Decreasing in-vitro sensitivity has been observed in China.

Pharmaceutical Applications

An aza-aminoacridine formulated for oral use. A Mannichbase derivative of mepacrine.

Pharmacokinetics

Peak plasma concentrations are reached after 3–14 h depending upon the formulation; there is also considerable interindividual variation. Elimination half-lives of 63–190 h have been reported, again dependent upon the formulation.

Clinical Use

Treatment of uncomplicated P. falciparum and P. vivax malaria A fixed-dose combination with artesunate (Pyramax) is being developed for uncomplicated P. falciparum and P. vivax malaria.

Side effects

It is well tolerated and no outstanding toxic effects have been reported.

InChI:InChI=1/C29H32ClN5O2/c1-37-26-9-8-24-28(33-26)27(23-7-6-21(30)16-25(23)32-24)31-22-14-19(17-34-10-2-3-11-34)29(36)20(15-22)18-35-12-4-5-13-35/h6-9,14-16,32-33H,2-5,10-13,17-18H2,1H3

Upstream product

• 6628-77-9 6-methoxy-pyridin-3-ylamine 
• 123-75-1 pyrrolidine 
• 50-00-0 formaldehyd 
• 6626-07-9 4-chloro-2-(6-methoxy-pyridin-3-yl-amino)-benzoic acid 
• 123-30-8 4-amino-phenol 
• 50-84-0 2,4 dichlorobenzoic acid 
• 6626-40-0 2-methoxy-7,10-dichloropyrido<3,2-b>quinoline 
• 100-02-7 4-nitro-phenol 
• 5446-92-4 2-methoxy-5-nitropyridine 
• 4548-45-2 2-chloro-5-nitropyridine 
• 5418-51-9 5-nitro-2-hydroxypyridine 
• 4214-76-0 5-nitro-pyridin-2-ylamine 
• 504-29-0 2-aminopyridine 
• 81935-60-6 2-methoxy-7-chloro-10-(4'-hydroxyphenyl)aminobenzo[b]-1,5-naphthyridine 

Relevant articles and documents

Synthesis of carbon-14-labelled pyronaridine tetraphosphate

Pyronaridine tetraphosphate is an antimalarial drug which is currently being widely investigated for use in the chemotherapy of malaria. We synthesized carbon-14-labelled pyronaridine tetraphosphate (14C-PNDP, 5) by a classical method and also

Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice

Background and Purpose: Malaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy. Experimental Approach: An integrated pharmacological approach was used to evaluate the antimalarial profile of methnaridine. The pharmacokinetic properties of methnaridine were investigated along with the associated safety profile. Host immune response patterns were also analysed. Key Results: Methnaridine exhibited potent antimalarial activity against P. falciparum (3D7: IC50 = 0.0066 μM; Dd2: IC50 = 0.0056 μM). In P. berghei-infected mice, oral administration effectively suppressed parasitemia (ED50 = 0.52 mg·kg?1·day?1) and cured the established infection (CD50 = 10.13 mg·kg?1·day?1). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four-dose oral regimen at a dosage of 25 mg·kg?1 achieved a complete cure of P. berghei infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT99 = 36.0 h) and showed no cross-resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long-lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg·kg?1). In addition, following methnaridine treatment, infection-induced Th1 immune response was almost fully alleviated in mice. Conclusion and Implications: Methnaridine is an orally bioavailable, fast-acting and long-lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.

Improved manufacturing process for pyronaridine tetraphosphate

Pyronaridine tetraphosphate (1) is a well-known antimalarial drug. However, it required a carefully optimized production process for the manufacture of pyronaridine tetraphosphate. Each step of its manufacturing process was reinvestigated. For the cyclization of 4-chloro-2-(6-methoxy-pyridin-3-yl-amino) -benzoic acid 6 to 7,10- dichloro-2-methoxybenzo[b]-1,5-naphthyridine 5, an improved process was developed to eliminated critical process impurity (BIA). By the redesign of the formation of triphosphate salt, the purity as API grade was increased. Thus, a robust manufacturing process with an acceptable process performance has been developed to produce high quality pyronaridine tetraphosphate.