Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice.

ABSTRACT:

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.

SUBMITTER: Wang W 

PROVIDER: S-EPMC7707099 | biostudies-literature |

REPOSITORIES: biostudies-literature