The discovery of highly potent acetylcholinesterase and butyrylcholinesterase inhibitors: A comprehensive experimental and molecular modeling study on newly synthesized benzimidazolylphenols, Schiff bases and salophens

Three benzimidazolylphenols (3Bz, 4Bz, 5Bz), three ONO type Schiff bases (3SB, 4SB, 5SB), three half-salophens (NNO type Schiff bases; 3Sal1, 4Sal1, 5Sal1) and three salophens (NOON type Schiff bases; 3Sal2, 4Sal2, 5Sal2) were synthesized and characterized. Besides antimicrobial and antioxidant effects, biological evaluation of the aforementioned compounds was also investigated against human carbonic anhydrase I (hCA I) and II (hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). As per inhibition constant values, particularly, compounds 2-(5-tert-butyl-1H-benzimidazol-2-yl)-6-methoxyphenol (3Bz) and 2,2′-{4-tert-butylbenzene-1,2-diylbis[nitrilomethylylidene]}bis(6-methoxyphenol) (3Sal2) emerged as the most potent derivatives being ∼80-fold more active than the standard drug Tacrine against AChE and BChE, respectively. Notably, the compounds did not have a significant toxic effect on the human fibroblast cell line within the concentration range tested (78 – 625 µg/mL). The 3Bz/AChE docked complex was also subjected to molecular docking and then to 300 ns of molecular dynamics simulations which predicted the stability of the complex in biological conditions and the binding region to be peripheral site. Overall, we conclude that these compounds might be very promising agents for the treatment of Alzheimer's disease (AD).