Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

Abstract

Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase. This work highlights the potential usefulness of the threo-difluoroalkane motif as a surrogate for E-alkenes in medicinal chemistry.

Enzymatic synthesis of fluorinated compounds

“…The activity of acetylcholinesterase can be inhibited by piperine. To overcome the poor water solubility and photostability of piperine, a threo -difluoropiperine analog was synthesized and showed higher potency and selectivity than piperine for the treatment of AD (Lizarme-Salas et al 2020 ). Similarly, fluorinated compounds are also the key building blocks of antibiotic, antimalarial, antiinflammatory, asthma, antagonists, migraine, and central nervous system drugs, such as 2,2-bis(6-fluoro-1H-indol-3-yl)ethan-1-amine, fluorinated steroidal, Trifluorothymidine and fluorouracil polytoxin, fluorinated cholesterol, fluorinated galegine, fluorinated bastimolide A, 6(R/S)-fluoropenibruguieramine, fluorinated cyclopropanecarboxylic acid derivatives, aryl-fluoro sulfates, 3-fluoro-4-aminopiperidine, and β-fluoramines (Adler et al 2019 ; Bakhotmah and Abdel-Rahman 2017 ; Campana et al 2020 ; Frank et al 2016 ; Fujino et al 2017 ; Gambini et al 2019 ; Liu et al 2018 ; Molinaro et al 2019 ; Munck Af Rosenschold et al 2019 ; Pupo et al 2019 ; Quintard et al 2018 ; Shao et al 2015 ; Wu et al 2020d ).…”

Discovery of Multitarget-Directed Ligands from Piperidine Alkaloid Piperine as a Cap Group for the Management of Alzheimer’s Disease

“…The compound piperazine is reported to have a broad range of therapeutic uses, particularly in neuroprotective action. Numerous piperazine compounds have been developed for neuroprotective and acetylcholinesterase inhibition effects. − To improve potency and to achieve the multifunctional effect of piperine in AD, various substituted aliphatic and aromatic groups were substituted. Further, compounds were evaluated through in silico molecular docking and dynamic simulation studies to determine the binding interaction profile at active sites of target proteins AChE, BuChE, and BACE1.…”

Asymmetric Synthesis of Monofluorinated Carbocyclic Alcohols and Vicinal Difluorinated Heterocycles and Carbocycles

“…The quinolinol ( 3 ) is an antagonist of the potassium channel [7] and can thus treat arrhythmia and molecules ( 4 ) and ( 5 ) are inhibitors of the hypoxia‐inducible factor subunit α (HIF‐2α) and can be used in the treatment of cancer and inflammatory diseases [8] . The vicinal difluoro pattern can be sequentially formed through the deoxofluorination of chiral diols or diol derivatives obtained from either the chiral pool or via an asymmetric oxidative reaction (epoxidation or dihydroxylation) [9–17] . On the other hand, the direct introduction of the vicinal difluoro motif has been described using an asymmetric, catalytic 1,2‐difluorination of alkenes [18,19] or by I(I)/I(III) catalysis [20] .…”

“…[8] The vicinal difluoro pattern can be sequentially formed through the deoxofluorination of chiral diols or diol derivatives obtained from either the chiral pool or via an asymmetric oxidative reaction (epoxidation or dihydroxylation). [9][10][11][12][13][14][15][16][17] On the other hand, the direct introduction of the vicinal difluoro motif has been described using an asymmetric, catalytic 1,2-difluorination of alkenes [18,19] or by I(I)/ I(III) catalysis. [20] Because of the important features of the motif described above, and as a continuation of our work directed towards the preparation of valuable enantioenriched building blocks, [21][22][23][24] we report herein the synthesis of novel families of enantioenriched cis-monofluorinated carbocyclic alcohols and trans-difluorinated indans, 1,2,3,4-tetrahydronaphthalenes, N-Boc tetrahydroquinolines and chromans 8, by deoxofluorination of the corresponding cis-fluoro alcohols 7 (Scheme 1).…”