In vitro trypanocidal potency and in vivo treatment efficacy of oligomeric ethylene glycol-tethered nitrofurantoin derivatives

• Published in: European journal of pharmaceutical sciences Vol. 192; p. 106668
• Main Authors: Janse van Rensburg, Helena D., N'Da, David D., Suganuma, Keisuke
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2024
• Subjects: African trypanosome; Ethylene glycol; Nitrofurantoin; Nitroheterocycle; Trypanocidal potency; African trypanosome; Ethylene glycol; Trypanocidal potency; Nitroheterocycle; Nitrofurantoin
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2023.106668

•T. congolense trypomastigotes were most susceptible to oligomeric ethylene glycol-tethered nitrofurantoin derivatives.•Arylated derivatives showed the best intrinsic activity against T. congolense trypomastigotes.•T. congolense infected mouse treated with 2k survived 9 days longer than control mice.•No cure was achieved due to 2k’s poor solubility in the in vivo testing medium. African trypanosomiasis is a significant vector-borne disease of humans and animals in the tsetse fly belt of Africa, particularly affecting production animals such as cattle, and thus, hindering food security. Trypanosoma congolense (T. congolense), the causative agent of nagana, is livestock's most virulent trypanosome species. There is currently no vaccine against trypanosomiasis; its treatment relies solely on chemotherapy. However, pathogenic resistance has been established against trypanocidal agents in clinical use. This underscores the need to develop new therapeutics to curb trypanosomiasis. Many nitroheterocyclic drugs or compounds, including nitrofurantoin, possess antiparasitic activities in addition to their clinical use as antibiotics. The current study evaluated the in vitro trypanocidal potency and in vivo treatment efficacy of previously synthesized antileishmanial active oligomeric ethylene glycol derivatives of nitrofurantoin. The trypanocidal potency of analogues 2a-o varied among the trypanosome species; however, T. congolense strain IL3000 was more susceptible to these drug candidates than the other human and animal trypanosomes. The arylated analogues 2k (IC50 0.04 µM; SI >6365) and 2l (IC50 0.06 µM; SI 4133) featuring 4-chlorophenoxy and 4-nitrophenoxy moieties, respectively, were revealed as the most promising antitrypanosomal agents of all analogues against T. congolense strain IL3000 trypomastigotes with nanomolar activities. In a preliminary in vivo study involving T. congolense strain IL3000 infected BALB/c mice, the oral administration of 100 mg/kg/day of 2k caused prolonged survival up to 18 days post-infection relative to the infected but untreated control mice which survived 9 days post-infection. However, no cure was achieved due to its poor solubility in the in vivo testing medium, assumably leading to low oral bioavailability. These results confirm the importance of the physicochemical properties lipophilicity and water solubility in attaining not only in vitro trypanocidal potency but also in vivo treatment efficacy. Future work will focus on the chemical optimization of 2k through the investigation of analogues containing solubilizing groups at certain positions on the core structure to improve solubility in the in vivo testing medium which, in the current investigation, is the biggest stumbling block in successfully treating either animal or human Trypanosoma infections. [Display omitted]