Azacarbazole n-3 and n-6 polyunsaturated fatty acids ethyl esters nanoemulsion with enhanced efficacy against Plasmodium falciparum

• Main Authors: Anna Jaromin, Silvia Parapini, Nicoletta Basilico, Magdalena Zaremba-Czogalla, Agnieszka Lewińska, Agnieszka Zagórska, Maria Walczak, Bożena Tyliszczak, Aleksandra Grzeszczak, Marcin Łukaszewicz, Łukasz Kaczmarek, Jerzy Gubernator
• Format: Article
• Language: English
• Published: KeAi Communications Co., Ltd. 2021-04-01
• Series: Bioactive Materials
• Subjects: Azacarbazoles; Flax oil; n-3 and n-6 polyunsaturated fatty acids ethyl esters; Nanoemulsion; P. falciparum; Malaria
• Online Access: http://www.sciencedirect.com/science/article/pii/S2452199X20302553

Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance. However, many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery systems, which seriously limits their activity. To address this problem, we synthesized a series of azacarbazoles that were evaluated for antimalarial activity against D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains of P. falciparum. The most active compound, 9H-3-azacarbazole (3), was encapsulated in a novel o/w nanoemulsion consisting of ethyl esters of polyunsaturated fatty acids n-3 and n-6 obtained from flax oil as the oil phase, Smix (Tween 80 and Transcutol HP) and water. This formulation was further analyzed using transmission electron microscopy, dynamic light scattering and in vitro and in vivo studies. It was shown that droplets of the 3-loaded nanosystem were spherical, with satisfactory stability, without cytotoxicity towards fibroblasts and intestinal cell lines at concentrations corresponding to twice the IC50 for P. falciparum. Moreover, the nanoemulsion with this type of oil phase was internalized by Caco-2 cells. Additionally, pharmacokinetics demonstrated rapid absorption of compound 3 (tmax = 5.0 min) after intragastric administration of 3-encapsulated nanoemulsion at a dose of 0.02 mg/kg in mice, with penetration of compound 3 to deep compartments. The 3-encapsulated nanoemulsion was found to be 2.8 and 4.2 times more effective in inhibiting the D10 and W2 strains of the parasite, respectively, compared to non-encapsulated 3. Our findings support a role for novel o/w nanoemulsions as delivery vehicles for antimalarial drugs.