{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T14:45:22Z","timestamp":1788187522651,"version":"build-2803163510"},"reference-count":46,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T00:00:00Z","timestamp":1604016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U1803282"],"award-info":[{"award-number":["U1803282"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Malaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread <jats:italic>Plasmodium<\/jats:italic> resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Methnaridine exhibited potent antimalarial activity against <jats:styled-content style=\"fixed-case\"><jats:italic>P. falciparum<\/jats:italic><\/jats:styled-content> (3D7: IC<jats:sub>50<\/jats:sub> = 0.0066 \u03bcM; Dd2: IC<jats:sub>50<\/jats:sub> = 0.0056 \u03bcM). In <jats:italic>P. berghei<\/jats:italic>\u2010infected mice, oral administration effectively suppressed parasitemia (ED<jats:sub>50<\/jats:sub> = 0.52 mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>) and cured the established infection (CD<jats:sub>50<\/jats:sub> = 10.13 mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four\u2010dose oral regimen at a dosage of 25 mg\u00b7kg<jats:sup>\u22121<\/jats:sup> achieved a complete cure of <jats:italic>P. berghei<\/jats:italic> infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT<jats:sub>99<\/jats:sub> = 36.0 h) and showed no cross\u2010resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long\u2010lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg\u00b7kg<jats:sup>\u22121<\/jats:sup>). In addition, following methnaridine treatment, infection\u2010induced Th1 immune response was almost fully alleviated in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Methnaridine is an orally bioavailable, fast\u2010acting and long\u2010lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15268","type":"journal-article","created":{"date-parts":[[2020,9,22]],"date-time":"2020-09-22T11:52:14Z","timestamp":1600775534000},"page":"5569-5579","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Methnaridine is an orally bioavailable, fast\u2010killing and long\u2010acting antimalarial agent that cures <i>Plasmodium<\/i> infections in mice"],"prefix":"10.1111","volume":"177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7112-0160","authenticated-orcid":false,"given":"Weisi","family":"Wang","sequence":"first","affiliation":[{"name":"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 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