A brief report on eugenol oleate is an oral immunomodulatory molecule against visceral leishmaniasis

Abstract

Visceral Leishmaniasis (VL) is a life-threatening infectious disease and is acclaimed as a neglected tropical disease, caused by Leishmania donovani. It leads to severe immune suppression in the host defense system. Higher cytotoxicity, rigorous side effects, and lower therapeutic indexes (TI) of current antileishmanial drugs have created a necessity to develop new molecules with better antileishmanial activity and high TI value. We synthesized a plenty number of derivatives of Eugenol and screened them for their activity against promastigote and amastigote forms of L. donovani. Among the synthesized derivatives, Eugenol oleate showed better antileishmanial activity against extracellular promastigotes (IC50- 20.13 ± 0.91 μM) and intracellular amastigotes (EC50-4.25 ± 0.26 μM). The TI value (82.24 ± 3.77) was found to improve by 10 to 13-folds compared to amphotericin B and miltefosine, respectively. Treatment with Eugenol oleate activated the PKC-βII–p38 MAPK and produced IL-12 and IFN-γ, which activated the iNOS2 to produce NO free radicals that cleared the intracellular parasite. Eugenol oleate was found safe with an appreciable pharmacokinetic profile for the oral anti-VL agent. This molecule increased the Th1 cytokine profile and decreased the Th2 cytokine profile observed from ELISA and qPCR, suggesting that the Eugenol oleate induced the parasite clearance through the activation of the host immune system. Hence, this study represented that Eugenol oleate, an oral immunomodulatory molecule, could induce a host protective immune response against visceral leishmaniasis through enhanced NO generation and Th1 response, essential against this deadly disease.