Design, Synthesis and Bioassays of 3‐Substituted‐3‐Hydroxyoxindoles for Cholinesterase Inhibition

Abstract

Based on the positive bioassay results of the known oxindole hit compound rac‐1‐benzyl‐3‐hydroxy‐3‐phenylindolin‐2‐one which showed significant inhibition of butyrylcholinesterase (BuChE) (IC50=7.41 μM), a library of 31 analogues of 3‐substituted‐3‐hydroxyoxindoles was synthesized and screened for both acetylcholinesterase (AChE) and BuChE activity. Our bioassays revealed that some of the new compounds exhibited moderate inhibition of eel AChE (EeAChE) and very good inhibition of equine serum BuChE (EqBuChE) with a best IC50 of 1.02 μM. On the basis of these results, the lead compound 1‐((1‐benzylpiperidin‐4‐yl)methyl)‐3‐hydroxy‐3‐phenylindolin‐2‐one was designed, which was shown to interact well with the enzymes active sites by molecular docking, was synthesized and upon bioassay gave an IC50 of 6.61 μM for BuChE. Interestingly, when we separated rac‐benzyl‐3‐hydroxy‐3‐phenylindolin‐2‐one into the individual enantiomers (R)‐ and (S)‐benzyl‐3‐hydroxy‐3‐phenylindolin‐2‐one it was the latter enantiomer that gave the best IC50 of 6.19 μM for BuChE.

Recent advances in the asymmetric catalytic synthesis of chiral 3-hydroxy and 3-aminooxindoles and derivatives: Medicinally relevant compounds

“…The best result was achieved with 1-((1-benzylpiperidin-4-yl)-methyl)-3-hydroxy-3-phenylindolin-2-one (the lead compound) (Scheme 43). While both enantiomers were more active towards the inhibition of BuChE, the (S)-enantiomer proved to be more potent by nine fold (IC 50 ¼ 6.19 mM, while for the (R)-enantiomer value was 54 mM) [160]. good yields and with very good stereocontrol (up to 95% ee) [165].…”

Isatina: “Bloco de Construção” Promissor no Desenvolvimento de Novos Fármacos

“…Começou por usar-se a 1-benzilindolina--2,3-diona (sintetizada facilmente a partir da isatina por meio de uma reação de alquilação com brometo de benzilo e uma base) numa reação de arilação assimétrica utilizando Rh como catalisador e N,N-di--isopropiletilamina (DIPEA) como base em condições reacionais suaves (Esquema 4). Utilizando o ligando BINAP (aplicado com sucesso em reações semelhantes -ver Esquema 3) foi possível obter o respetivo produto, 1-benzil-3-fenil-3-hidroxi-indolin-2-ona, com muito bom rendimento e enantiosseletividade [42]. Como este composto mostrou potencial atividade em enzimas do tipo ChE (os pormenores serão discutidos a posteriori), decidiu-se fazer várias modificações nas posições N1, C3, C4 e C5 da unidade estrutural.…”

“…Tabela 1 -Resultados in vitro de IC 50 relativos à inibição de eeAChE, eqBuChE e hBuChE, determinados para compostos do tipo oxindole-3-substituídos [42,51,53]. De uma forma geral, todos os compostos testados não mostraram atividade relevante na inibição da enzima AChE.…”

“…De uma forma geral, todos os compostos testados não mostraram atividade relevante na inibição da enzima AChE. Foram obtidos resultados bastante promissores relativamente à inibição da enzima BuChE em compostos do tipo 3-hidroxi-oxindoles (compostos 1, 2, 3 e 5) [42]. O enantiómero (S) da 1-benzil-3-fenil-3-hidroxi-indolin-2-ona (1b) mostrou ser mais ativo que o enantiómero (R), 1a.…”

Catalytic Enantioselective Addition of Me2Zn to Isatins

“…The synthesis includes allylation [14,15], crotylation [16], arylation [17,18] and decarboxylative cyanomethylation [19] of isatines, as well as the palladium catalyzed intramolecular arylation [20]. The particular interest is the 3-hydroxy-3-methyl-2-oxindole structure, which is present in several natural products such as convolutamydine C [21] and synthetic compounds with biological activities or drug candidates such as compound 2a [22], compound A [23] and compound B [24] (Figure 1). There are few methodologies for the synthesis of chiral 3-hydroxy-3-methyl-2-oxindoles in the literature, and the number of catalytic enantioselective examples is scarce.…”