Ishaq_2020_Bioorg.Chem_100_103924

In recent decade, the entrance of alpha-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 alpha-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 +/- 48.32 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 110.54 +/- 14.05 to 444.12 +/- 36.08 nM. Also, these novel derivatives (3a-r) effectively inhibited AChE, with Ki values in the range of 385.38 +/- 45.03 to 983.04 +/- 104.64 nM. For BChE was obtained with Ki values in the range of 400.21 +/- 35.68 to 1003.02 +/- 154.27 nM. For alpha-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 +/- 2.66 nM, 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.