4214-76-0Relevant articles and documents
Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice
Wang, Weisi,Yao, Junmin,Chen, Zhuo,Sun, Yiming,Shi, Yuqing,Wei, Yufen,Zhou, Hejun,Yu, Yingfang,Li, Shizhu,Duan, Liping
, p. 5569 - 5579 (2020)
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.
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Sagitullin et al.
, p. 4135 (1978)
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One-pot synthesis method for synthesizing 2-hydroxy-5-nitropyridine
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Paragraph 0027-0031, (2021/05/05)
The invention discloses a one-pot synthesis method for synthesizing 2-hydroxy-5-nitropyridine. The method comprises the following specific reaction steps: adding 2-aminopyridine into concentrated sulfuric acid in batches, controlling the temperature at 10-20 DEG C, adding concentrated nitric acid, keeping the temperature at 40-50 DEG C, and stirring; after nitration is completed, adding reaction liquid into water for quenching, controlling the temperature to be 0-10 DEG C, dropwise adding a sodium nitrite aqueous solution, and carrying out diazo reaction; adding a proper amount of ammonia water to adjust the acid concentration; and filtering the solution after the acid concentration is adjusted, and drying a filter cake to obtain the product. The invention provides a novel preparation method of 2-hydroxy-5-nitropyridine. The method has the advantages that the post-treatment is simple, isomers are separated by utilizing the concentration of acid, and the isomers generated by nitration reaction do not need to be independently purified, the nitration reaction and the diazotization reaction are continuously operated, and thus the waste water generated in the amplified production is greatly reduced, and the production cost is saved; the preparation method is never reported in literatures, is a brand-new preparation method of the 2-hydroxy-5-nitropyridine, and provides a new synthesis thought for similar compounds of the 2-hydroxy-5-nitropyridine.
Transition-metal-free access to 2-aminopyridine derivatives from 2-fluoropyridine and acetamidine hydrochloride
Li, Yibiao,Huang, Shuo,Liao, Chunshu,Shao, Yan,Chen, Lu
supporting information, p. 7564 - 7567 (2018/11/02)
Under catalyst-free conditions, an efficient method for the synthesis of 2-aminopyridine derivatives through the nucleophilic substitution and hydrolysis of 2-fluoropyridine and acetamidine hydrochloride has been developed. This amination uses inexpensive acetamidine hydrochloride as the ammonia source and has the advantages of a high yield, high chemoselectivity and wide substrate adaptability. The results suggest that other N-heterocycles containing fluorine substituents can also complete the reaction via these reaction conditions and yield the target products.
