LAUSR

BACKGROUND Lymphatic filariasis continues to be one of the major health problems in tropical and subtropical countries despite the use of standard drugs diethylcarbamazine and ivermectin because they are microfilaricides with poor or no activity on 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 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.