Synthesis, bioactivity and binding energy calculations of novel 3-ethoxysalicylaldehyde based thiosemicarbazone derivatives.

Abstract

In recent decade, the entrance of α-N-heterocyclic thiosemicarbazones derivates (Triapne, COTI-2 and DpC) in clinical trials for cancer and HIV-1 has vastly increased the interests of medicinal chemists towards this class of organic compounds. In the given study, a series of eighteen new (3a-r) 3-ethoxy salicylaldehyde-based thiosemicarbazones (TSC), bearing aryl and cycloalkyl substituents, were synthesized and assayed for their pharmacological potential against carbonic anhydrases (hCA I and hCA II), cholinesterases (AChE and BChE) and α-glycosidase. The hCA I isoform was inhibited by these novel 3-ethoxysalicylaldehyde thiosemicarbazone derivatives (3a-r) in low nanomolar levels, the Ki of which differed between 144.18±26.74 and 454.92±48.32nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 110.54±14.05 to 444.12±36.08nM. Also, these novel derivatives (3a-r) effectively inhibited AChE, with Ki values in the range of 385.38±45.03 to 983.04±104.64nM. For BChE was obtained with Ki values in the range of 400.21±35.68 to 1003.02±154.27nM. For α-glycosidase the most effective Ki values of 3l, 3n, and 3q were with Ki values of 12.85±1.05, 16.03±2.84, and 19.16±2.66nM, respectively. Moreover, the synthesized TCSs were simulated using force field methods whereas the binding energies of the selected compounds were estimated using MM-GBSA method. The findings indicate the present novel 3-ethoxy salicylaldehyde-based thiosemicarbazones to be excellent hits for pharmaceutical applications.