Structure Report for: 6TT0

Marco Catto, Leonardo Pisani, Eugenio De La Mora, Benny Danilo Belviso, Giuseppe Felice, Felice Mangiatordi, Andrea Pinto, Annalisa De Palma, Nunzio Denora, Rocco Caliandro, Jacques-Philippe Colletier, Israel Silman, Orazio Nicolotti, and Cosimo Damiano Altomare

Title: Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor
Catto M, Pisani L, De la Mora E, Belviso BD, Mangiatordi GF, Pinto A, Palma A, Denora N, Caliandro R and Altomare CD <3 more author(s)> Catto M, Pisani L, De la Mora E, Belviso BD, Mangiatordi GF, Pinto A, Palma A, Denora N, Caliandro R, Colletier JP, Silman I, Nicolotti O, Altomare CD (- 3)
Ref: ACS Med Chem Lett, 11:869, 2020 : PubMed
Abstract


ESTHER: Catto_2020_ACS.Med.Chem.Lett_11_869
PubMedSearch: Catto 2020 ACS.Med.Chem.Lett 11 869
PubMedID: 32435398
Inhibitor(s) related to this paper: MC1420

Abstract

Acetylcholinesterase (AChE) inhibitors (AChEIs) still remain the leading therapeutic options for the symptomatic treatment of cognitive deficits associated with mild-to-moderate Alzheimer's disease. The search for new AChEIs benefits from well-established knowledge of the molecular interactions of selective AChEIs, such as donepezil and related dual binding site inhibitors. Starting from a previously disclosed coumarin-based inhibitor (+/-)-cis-1, active as racemate in the nanomolar range toward AChE, we proceeded on a double track by (i) achieving chiral resolution of the enantiomers of 1 by HPLC and (ii) preparing two close achiral analogues of 1, i.e., compounds 4 and 6. An eudismic ratio as high as 20 was observed for the (-) enantiomer of cis-1. The X-ray crystal structure of the complex between the (-)-cis-1 eutomer (coded as MC1420) and T. californica AChE was determined at 2.8 A, and docking calculation results suggested that the eutomer in (1R,3S) absolute configuration should be energetically more favored in binding the enzyme than the eutomer in (1S,3R) configuration. The achiral analogues 4 and 6 were less effective in inhibiting AChE compared to (+/-)-cis-1, but interestingly butylamide 4 emerged as a potent inhibitor of butyrylcholinesterase (BChE).