4548-45-2Relevant articles and documents
Deaminative chlorination of aminoheterocycles
Cornella, Josep,Faber, Teresa,Gómez-Palomino, Alejandro,Ghiazza, Clément
, (2021/12/23)
Selective modification of heteroatom-containing aromatic structures is in high demand as it permits rapid evaluation of molecular complexity in advanced intermediates. Inspired by the selectivity of deaminases in nature, herein we present a simple methodology that enables the NH2 groups in aminoheterocycles to be conceived as masked modification handles. With the aid of a simple pyrylium reagent and a cheap chloride source, C(sp2)?NH2 can be converted into C(sp2)?Cl bonds. The method is characterized by its wide functional group tolerance and substrate scope, allowing the modification of >20 different classes of heteroaromatic motifs (five- and six-membered heterocycles), bearing numerous sensitive motifs. The facile conversion of NH2 into Cl in a late-stage fashion enables practitioners to apply Sandmeyer- and Vilsmeier-type transforms without the burden of explosive and unsafe diazonium salts, stoichiometric transition metals or highly oxidizing and unselective chlorinating agents. [Figure not available: see fulltext.]
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 (2020/11/03)
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.
Preparation method of high-yield 2-chloro-5-nitropyridine
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Paragraph 0052-0057, (2019/04/02)
The invention relates to a preparation method of high-yield 2-chloro-5-nitropyridine. According to the method, 2-halogenated acrylate serves as an initial raw material and is sequentially condensed with nitromethane and triethyl orthoformate and cyclized with pyridine to obtain 2-hydroxy-5-nitropyridine, and then the 2-chloro-5-nitropyridine is prepared by chlorination. Used raw materials are lowin cost and easy to obtain, operation is simple and convenient, conditions are mild, nitration reaction is omitted, wastewater quantity is small, operation safety is high, product yield and purity arehigh, and the cost is low.