- Synthesis of carbon-14-labelled pyronaridine tetraphosphate
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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
- Park, Sang Hyun,Pradeep, Kannampalli,Seung, Ho Jang
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- TLR7/8 ANTAGONISTS AND USES THEREOF
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The present invention relates to compounds of the invention and pharmaceutically acceptable compositions thereof, useful as TLR7/8 antagonists.
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- Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice
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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.
- Wang, Weisi,Yao, Junmin,Chen, Zhuo,Sun, Yiming,Shi, Yuqing,Wei, Yufen,Zhou, Hejun,Yu, Yingfang,Li, Shizhu,Duan, Liping
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p. 5569 - 5579
(2020/11/03)
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- A method of preparing malaridine
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The present invention relates to a method for preparing pyronaridine, and specifically, discloses a method for preparing high-purity pyronaridine. The method comprises the steps of: in an inert solvent, reacting a compound of formula II with acid salt of a compound of formula III to form pyronaridine of formula I, wherein n ranges from 1 to 3. The method according to the present invention has features of a short synthetic route, moderate reaction conditions, simple operations, a high product yield, high purity, low contents of an impurity 1 and an impurity 2, a low cost and the like, and is suitable for industrial production.
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- Improved manufacturing process for pyronaridine tetraphosphate
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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.
- Lee, Dong Won,Lee, Seung Kyu,Cho, Jun Ho,Yoon, Seung Soo
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p. 521 - 524
(2014/03/21)
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- Synthesis of [2H]- and [13C]-labeled pyronaridine tetraphosphate - An antimalarial drug
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The increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs, necessitates the need for developing novel antimalarial drugs with a potent pharmacological activity. Pyronaridine tetraphosphate (PNDP) is one such drug that is currently undergoing preclinical and clinical trials for use in a chemotherapy treatment of malaria. The present investigation was carried out with the objective of synthesizing carbon-13 [13C]- and deuterium [2H]-labeled PNDP for use in studying the ADME and pharmacokinetics of the drug. Here, we present a methodology to synthesize [13C]- and [2H]-PNDP using a microwave irradiation technique as this method was found to be more advantageous than the classical method. The labeled compounds thus synthesized had a chemical purity of >99% as determined by HPLC and were also found to be relatively stable up to 3 months when stored under standard conditions. Further they also revealed satisfactory instrumental analysis data. Copyright
- Sang, Hyun Park,Yeon, Jun Jeong,Pradeep, Kannampalli
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experimental part
p. 56 - 62
(2009/10/17)
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