Design and synthesis of N-acyl and dimeric N-Arylpiperazine derivatives as potential antileishmanial agents

Activity data analysis out of twenty nine compounds, 4a, 4d and 4e demonstrated excellent inhibition activity with both promastigote and amastigote form of L. donovani. Results demonstrated that compound 4d (amastigote IC50 = 2.0 µM, SI = 42) is a promising lead candidate for further development as antileishmanial drug. [Display omitted] •A series of twenty nine homo and hetero dimeric and N-acyl aryl piperazines were synthesized efficiently with high purity.•The in silico study of designed compounds demonstrated good ADME properties.•Out of twenty nine compounds, 4a, 4d and 4e demonstrated excelent inhibition activity with both promastigote and amastigote form of L. donovani.•Results demonstrated that compound 4d (amastigote IC50 = 2.0 µM, SI = 42) is a promising lead candidate for further development as antileishmanial drug. The current regime for leishmaniasis is associated with several adverse effects, expensive, parenteral treatment for longer periods and the emergence of drug resistance. To develop affordable and potent antileishmanial agents, a series of N-acyl and homodimeric aryl piperazines were synthesized with high purity, predicted druggable properties by in silico methods and investigated their antileishmanial activity. The in vitro biological activity of synthesized compounds against clinically validated intracellular amastigote and extracellular promastigote form of Leishmania donovani parasite showed eight compounds inhibited 50% amastigotes growth below 25 µM. The half maximal inhibitory concentration (IC50) and cytotoxicity assessment of eight active compounds, 4a, 4d and 4e demonstrated activity with an IC50 2.0 – 9.1 µM and selectivity index 10 – 42. Compound 4d (IC50 2.0 µM, SI = 42) found to be the best among them with four-folds more potent and eight-folds less toxic than the control drug miltefosine. Overall, results demonstrated that compound 4d is a promising lead candidate for further development as antileishmanial drug.