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Eugenol derived immunomodulatory molecules against visceral leishmaniasis
Mamilla R Charan Raja1, Anand Babu Velappan2, Davidraj Chellappan3
1Department of Biotechnology, School of Chemical and Biotechnology, SASTRA University, Thanjavur, India.
European Journal of Medicinal Chemistry
|August 22, 2017
Summary
A novel eugenol derivative, comp.35, shows potent activity against visceral leishmaniasis (VL). This compound effectively clears parasites and enhances host immune responses, offering a promising new therapeutic candidate for this deadly disease.
Area of Science:
- Infectious Diseases
- Immunology
- Medicinal Chemistry
Background:
- Visceral leishmaniasis (VL) is a severe, life-threatening infectious disease caused by Leishmania donovani, leading to significant immune suppression.
- Current antileishmanial drugs exhibit high cytotoxicity, severe side effects, and low therapeutic indexes (TI), necessitating the development of novel therapeutic agents.
- Eugenol derivatives are being explored for their potential antileishmanial properties.
Purpose of the Study:
- To synthesize and screen novel eugenol derivatives for activity against Leishmania donovani.
- To evaluate the antileishmanial efficacy and therapeutic index of promising compounds.
- To investigate the immunomodulatory mechanisms of action of the lead compound.
Main Methods:
- Synthesis of 36 eugenol derivatives.
- Screening of derivatives against promastigote and amastigote forms of Leishmania donovani.
- In vitro assays for nitric oxide (NO) generation, iNOS2 mRNA expression, arginase-1 activity, and cytokine profiles (IL-12, IL-10).
- In vivo studies in Leishmania donovani-infected BALB/c mice to assess parasite burden and host immune response.
Main Results:
- Compound 35 (comp.35) demonstrated significant antileishmanial activity with IC50 of 20.13 ± 0.91 μM against promastigotes and EC50 of 4.25 ± 0.26 μM against amastigotes.
- Comp.35 exhibited a substantially improved TI (82.24 ± 3.77), 10-13 fold higher than Amphotericin B and Miltefosine.
- In vitro, comp.35 enhanced NO generation and iNOS2 mRNA expression while decreasing arginase-1 activity in infected macrophages. It also modulated cytokine expression, increasing IL-12 and decreasing IL-10.
- In vivo, comp.35 treatment effectively reduced hepatic and splenic parasite burden and promoted a Th1 immune response in infected mice.
Conclusions:
- Comp.35 is a potent antileishmanial agent with a favorable therapeutic index.
- Comp.35 acts as an immunomodulator, inducing host-protective immune responses through enhanced NO generation and a Th1-biased immune response.
- Comp.35 represents a promising candidate for the development of new treatments against visceral leishmaniasis.
