Structure–activity relationship, in vitro and in vivo evaluation of novel dienyl sulphonyl fluorides as selective BuChE inhibitors for the treatment of Alzheimer's disease

Abstract

To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC 50 = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) o - > m - > p -; –OCH 3 > –CH 3 > –Cl (–Br) for δ -aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE ( K i = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the A β 1-42 -induced cognitive dysfunction to the normal level, and the assessment of total amount of A β 1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.

Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors

“…Recently, new aliphatic sulphonyl fluorides containing a triazole moiety were efficiently synthesised through the region-selective cycloaddition reaction of but-3-ene-1,3-disulfonyl difluoride and organic azides 19 . Primary screening of compounds T1–T17 ( Scheme 1 ) was performed with equine BuChE (eqBuChE) and electrophorus electricus AChE (eeAChE) using modified Ellman’s method 20 . As shown in Supplementary Table S1 and Figure 2(A) , all of compounds T1–T17 exhibited inhibitory activity against AChE and BuChE.…”

“…The reaction products were directly screened for eqBuChE and ee AChE inhibitory activity using modified Ellman’s method 20 . Scatter plots of the screening results showed that the compounds had better AChE inhibitory activity, and quinolyl triazolyl sulfonylfluoride ( T14 ) was more potent than phenyl triazolyl sulfonylfluorides ( T2 , T3, and T11 ) in Figure 4(A and B) .…”

“…Briefly, 40 μL of buffer, 10 μL of different concentrations of the compounds for testing, and 10 μL of human AChE (hAChE)/ human BuChE (hBuChE) were added to a 96-well plate. DTNB ( 20 μL) was added after 10 min of incubation at 37 °C and incubated for another 10 min. In the end, 20 μL of ACh or BuCh was added and the absorbance was measured at 412 nm.…”

Chemoselective Reactions of Functionalized Sulfonyl Halides

“…1-Bromo-or 1-iodovinyl sulfonyl fluorides were also introduced into Suzuki [80,[121][122][123][124] and Sonogashira [80,121,123] reactions that did not affect the SO 2 F moiety (Scheme 15, A). For the parent vinyl sulfonyl fluoride 7, a possibility of Heck reactions, [80,125,126] oxidative Heck-type reactions with arylboronic acids (Scheme 15, B), [127,128] or palladium-catalyzed CÀ H bond activation in aromatic [125,[129][130][131][132] and aliphatic [133] systems was demonstrated (Scheme 15, C).…”

“…In particular, base-mediated intra- [26] and intermolecular [152][153][154][155] alkylations (Scheme 18), as well as Knoevenagel-type condensations with aromatic aldehydes providing styryl [156] or α-halostyryl [121,123,157] sulfonyl fluorides should be mentioned (Scheme 19).…”