Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors

• A series of novel hybrid of pyrazolobenzothiazines was designed and synthesized.
• Newly synthesized derivatives with benzimidazoles were investigated as potent cholinesterases.
• Binding mode of pyrazolobenzothiazines hybrids was observed using docking studies.

Two series of novel pyrazolobenzothiazine-based hybrid compounds were efficiently synthesized starting from saccharin sodium salt. Pyrazolo[4,3-c][1,2]benzothiazine scaffolds were N-arylated by using p-fluorobenzaldehyde, followed by the incorporation of a benzimidazole or similar ring systems by treatment with arylenediamines. These phenylene-connected hybrid compounds were investigated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compounds 12d and 12k were the most potent AChE inhibitors with IC50 values of 11 and 13 nM, respectively, while 6j (IC50 = 17 nM) proved to be the most active inhibitor against BuChE with remarkable selectivity for BuChE over AChE. Molecular docking studies were also performed on human AChE and BuChE to suggest possible binding modes in which the inhibitor's extended structure is accommodated along the active site gorge of both enzymes.

Putative binding modes of compound 2-[4-(1H-Benzimidazol-2-yl)phenyl]-4-methyl-3-phenyl-2,4-dihydropyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide (12d) in the active sites of AChE.Figure optionsDownload as PowerPoint slide