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 iden...
| Publicado en: | British Journal of Pharmacology Vol. 177; no. 24; pp. 5569 - 5580 |
|---|---|
| Autores principales: | , , , , , , , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
Dec2020
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=147322132&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 147322132 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00071188 DZ6 jtl: British Journal of Pharmacology issn: 00071188 maglogo: Y pubinfo: dt: Dec2020 vid: 177 iid: 24 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 147322132 147322132 148585095 NLM32959888 147322132 10.1111/bph.15268 NLM32959888 147322132 ppf: 5569 ppct: 11 formats: tig: atl: Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice. aug: au: Wang, Weisi Yao, Junmin Chen, Zhuo Sun, Yiming Shi, Yuqing Wei, Yufen Zhou, Hejun Yu, Yingfang Li, Shizhu Duan, Liping affil: National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, WHO Collaborating Centre for Tropical Diseases, Key Laboratory of Parasitology and Vector Biology of the Chinese Ministry of Health, Shanghai, China sug: subj: Antimalarials Therapeutic Use Malaria Drug Therapy Antimalarials Pharmacodynamics Mice Animal Studies Homicide Protozoa Comparative Studies Multicenter Studies Evaluation Research Validation Studies Clinical Assessment Tools Scales ab: 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. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|