In Vitro and In Silico Studies of Glycyrrhetinic Acid Derivatives as Anti- Filarial Agents

Abstract

Background: Lymphatic filariasis is one of the chronic diseases in many parts of the tropics and sub-tropics of the world despite the use of standard drugs diethylcarbamazine and ivermectin because they kill microfilaries and not the adult parasites. Therefore, new leads with activity on adult parasites are highly desirable. Objective: Anti-filarial lead optimization by semi-synthetic modification of glycyrrhetinic acid (GA). Methods: The GA was first converted into 3-O-acyl derivative, which was further converted into 12 amide derivatives. All these derivatives were assessed for their antifilarial potential by parasite motility assay. The binding affinity of active GA derivatives on trehalose-6-phosphate phosphatase (Bm-TPP) was assessed by molecular docking studies. Results: Among 15 GA derivatives, GAD-2, GAD-3, and GAD-4 were found more potent than the GA and standard drug DEC. These derivatives reduced the motility of Brugia malayi adult worms by up to 74% while the GA and DEC reduced only up to 49%. Further, GA and most of its derivatives exhibited two times more reduction in MTT assay when compared to the standard drug DEC. These derivatives also showed 100% reduction of microfilariae and good interactions with Bm-TPP protein. Conclusion: The present study suggests that 3-O-acyl and linear chain amide derivatives of glycyrrhetinic acid may be potent leads against B. malayi microfilariae and adult worms. These results might be helpful in developing QSAR model for optimizing a new class of antifilarial lead from a very common, inexpensive, and non toxic natural product.

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“…The AutoDock Vina 4.2 software includes procedures for optimizing proteins and ligands, such as allowing atomic charges to make proteins more polar [26][27][28][29]. Proteins and ligands were adjusted through the charge and rotatable bond authorization, consideration of the energy contribution of desolvation through the binding of a ligand to the protein and previous naming of grid maps of the protein surface for synergy ligands by the auto grid.…”

“…Proteins and ligands were adjusted through the charge and rotatable bond authorization, consideration of the energy contribution of desolvation through the binding of a ligand to the protein and previous naming of grid maps of the protein surface for synergy ligands by the auto grid. These tools increase the speed and accuracy of docking with a unique scoring capacity, optimize effectively and perform the multithreading of the molecular docking [26][27][28][29].…”

Glycyrrhetinic amides and their cytotoxicity

“…Amide 13 52,53,[58][59][60] was not functioning, and amine 14 [61][62][63][64][65][66] showed EC50 values 11.3 and 20.1 M, respectively. For most active compound 2 67,68 (EC50 2.0-4.3 M), several additional assays were performed, e.g., an acridine orange/propidium staining (AO/PI) using A2780 tumor cells. Thereby, a red-colored nucleus indicated necrotic cells while a green fluorescence is indicative for apoptotic cells.…”

Recent Advances in Medicinal Chemistry to Treat Filariasis and Helminthiasis

“…These derivatives also showed 100% reduction of microfilariae and good interactions with Bm-TPP protein. These results may be of great help in developing QSAR model for optimizing a new class of antifilarial lead from a very common, inexpensive, and non toxic natural product [1].…”