Deep Eutectic Solvents as Effective Reaction Media for the Synthesis of 2-Hydroxyphenylbenzimidazole-Based Scaffolds en Route to Donepezil-Like Compounds

Abstract

An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer’s disease (AD) treatment. Building upon these findings, we have now designed and completed the whole synthesis of PZ1 in the so-called deep eutectic solvents (DESs), which have emerged as an unconventional class of bio-renewable reaction media in green synthesis. Under optimized reaction conditions, the preparation of a series of 2-hydroxyphenylbenzimidazole-based nuclei has also been perfected in DESs, and comparison with other routes which employ toxic and volatile organic solvents (VOCs) provided. The functionalization of the aromatic ring can have implications on some important biological properties of the described derivatives and will be the subject of future studies of structure-activity relationships (SARs).

Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease

“…The preparation of the c-series of intermediates, hydroxyphenylbenzimidazole acid derivatives, involved the cyclization of diaminobenzoic acid derivatives with diverse salicylaldehydes, in the presence of sodium metabissulfite and N,N-dimethylacetamide (DMA) (method A) [22]. However, for some compounds (6c, 7c, 9c), an eutectic solvent mixture, choline chloride/glycerol (ChCl/Gly), was used (method B) instead of DMA, with improved effectiveness [25]. The last reaction step involved the coupling of amine intermediate moieties (b-series) with carboxylic intermediate moieties (c-series), via amide formation, and it was carried out in dry DMF, using NHS and DCC as activators.…”

“…Molecules 2020, 24, x 6 of 26 (6c, 7c, 9c), an eutectic solvent mixture, choline chloride/glycerol (ChCl/Gly), was used (method B) instead of DMA, with improved effectiveness [25]. The last reaction step involved the coupling of amine intermediate moieties (b-series) with carboxylic intermediate moieties (c-series), via amide formation, and it was carried out in dry DMF, using NHS and DCC as activators.…”

Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer’s Disease Agents

“…In particular, starting from commercial aminoacids and ethyl malonyl chloride, we have synthesized the linear intermediates 1a – 3a , which were subsequently cyclized in presence of sodium ethoxide under reflux to afford 1 – 3 [ 23 , 24 , 25 , 26 , 27 , 28 ]. Compounds 4 and 5 were obtained through reaction of 1 and 2 , respectively, with the crucial intermediate 6 [ 13 , 23 , 29 ]. The intermediate 6 was synthesized starting from the commercial N -aminoethylpiperazine as previously reported [ 12 , 29 ].…”

“…Compounds 4 and 5 were obtained through reaction of 1 and 2 , respectively, with the crucial intermediate 6 [ 13 , 23 , 29 ]. The intermediate 6 was synthesized starting from the commercial N -aminoethylpiperazine as previously reported [ 12 , 29 ].…”

Novel Donepezil–Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer’s Disease

“…The subsequent step towards the preparation of compounds 3 and 4 consisted in the removal of the phthalimide group, to leave the primary amine free for the next reaction (coupling of the two main moieties). To perform this, a well reported procedure was carried out, using MeNH 2 in 40% aqueous solution, to afford 3 and 4 in 97% and 69% yield, respectively ( Scheme 2 , step c) [ 26 ]. The last reaction ( Scheme 2 , step d) involved the coupling of the free amine intermediates ( 3, 4 ) with the different commercially available aryl-sulfonyl chlorides, via sulfonamide formation.…”