In Vivo Antimalarial Activity and Toxicological Profile of LAFIS10, a Piperazine Derivative From Ursolic Acid

Abstract

Background: LAFIS10, N-{3-[4-(3-aminopropyl)piperazinyl]propyl}-3-O-acetylursolamide, previously demonstrated potent in vitro antimalarial activity against Plasmodium falciparum strains with nanomolar IC₅₀ values. This study aimed to assess its in vivo antimalarial efficacy and toxicological profile.

Methods: Female BALB/c mice (n = 6 animals/group) infected with Plasmodium berghei ANKA strain were treated intraperitoneal with LAFIS10 at doses of 15-125 mg/kg for four consecutive days. Chloroquine diphosphate (30 mg/kg) served as the positive control. Parasitemia and survival were monitored for up to 14 and 28 days, respectively. Acute toxicity was evaluated according to OECD guideline 423 at doses of 300 and 2000 mg/kg. In vitro coagulation and hemolysis assays were conducted using human peripheral blood.

Results: LAFIS10 significantly reduced parasitemia in a dose-dependent manner, with reductions of 52.46% and 59.59% at 60 and 125 mg/kg, respectively (p < 0.05). The ED₅₀ was 19.68 mg/kg, and the maximal effect (Emax) was 52.18%. Mice treated with LAFIS10 survived up to 7 days longer than untreated controls. In vitro coagulation assays showed no significant changes in prothrombin time, while a slight decrease in activated partial thromboplastin time was observed at 100 μM. LAFIS10 displayed dose-dependent hemolytic activity, and the in vivo LD₅₀ estimated between 125 and 300 mg/kg, classifying it as toxic (GHS class 3).

Conclusions: LAFIS10 exhibited promising in vivo antimalarial activity but showed hemolytic-related toxicity at higher doses. Further studies are warranted to optimise its structure or formulation to achieve improved efficacy and safety as a potential antimalarial candidate.

Keywords: Plasmodium berghei; hemolysis; malaria; preclinical assays; toxicity; triterpene derivative.