Eugenol derived immunomodulatory molecules against visceral leishmaniasis
| Autor: | Anand Babu Velappan, Mamilla R. Charan Raja, Santanu Kar Mahapatra, Joy Debnath, David Raj Chellappan |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Cell Survival 030106 microbiology Leishmania donovani Antiprotozoal Agents Pharmacology Nitric oxide Immunomodulation 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Immune system Parasitic Sensitivity Tests Amphotericin B Drug Discovery Eugenol medicine Animals Amastigote Cytotoxicity Miltefosine Mice Inbred BALB C biology Dose-Response Relationship Drug Molecular Structure Macrophages Organic Chemistry General Medicine biology.organism_classification medicine.disease 030104 developmental biology Visceral leishmaniasis RAW 264.7 Cells chemistry Immunology Leishmaniasis Visceral medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 139 |
| ISSN: | 1768-3254 |
| Popis: | Visceral leishmaniasis (VL) is a life threatening infectious disease caused by Leishmania donovani. It leads to the 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. In this study, we have synthesized 36 derivatives of eugenol and screened them for their activity against promastigote and amastigote forms of L. donovani. Among the synthesized derivatives, comp.35 showed better antileishmanial activity against extra cellular 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 10-13 fold compared to Amphotericin B and Miltefosine respectively. Treatment with comp.35 (5 μg/ml) enhanced the nitric oxide (NO) generation, iNOS2 mRNA expression (∼8 folds increase) and decreased the arginase-1 activity (∼4 folds) in L. donovani infected peritoneal macrophages. Comp.35 had also increased the IL-12 (∼6 folds) and decreased the IL-10 (∼3 folds) mRNA expression and release in vitro. Results of in vivo studies revealed that comp.35 treatment at 25 mg/kg body weight efficiently cleared the hepatic and splenic parasite burden with enhanced Th1 response in L. donovani infected BALB/c mice. Hence, this study clearly represents comp.35, as an immunomodulatory molecule, can induce host protective immune response against visceral leishmaniasis through enhanced NO generation and Th1 response, which are essentials against this deadly disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect