Synthesis, crystallographic study, molecular docking, ADMET, DFT and biological evaluation of new series of aurone derivatives as anti-leishmanial agents

A new series of aurone derivatives (4a-l) was synthesized and their structures were established on the basis of IR, NMR, mass spectra and elemental analysis. In addition, the identity of the representative compound 4g was successfully characterized with the aid of X-ray crystallography. All the synthesised compounds were docked in the binding pocket of Leishmania L-arginine amidinohydrolase enzyme (PDB ID: 5HJA). Docking score and molecular interaction studies revealed a good picture of compounds' affinity and fitting inside the binding pocket of enzyme. In silico ADME, toxicity and DFT studies were also performed for the compound 4g, having highest docking score. The compound did not violate Lipinski's rule of five. Results showed good intestinal absorption and human serum binding. Compound was also found non-carcinogenic in acute and chronic rat and mice model studies, predicted using Maestro 9.6 software. All the derivatives were tested for anti-leishmanial activity against Leishmania donovani (L. donovani) promastigotes. Compound 4g exhibited more than 90 percent inhibition (IC 50 4.97 +/- 0.856 mu M) in L. donovani promastigotes inhibition assay and was further evaluated for axenic amastigote study, changes in the cellular morphology and cytotoxicity. Compound 4g demonstrated better anti-leishmanial activity and lesser cytotoxicity as compared to standard drug miltefosine. (C) 2022 Elsevier B.V. All rights reserved.