Synthesis, X-ray Single Crystal, Conformational Analysis and Cholinesterase Inhibitory Activity of a New Spiropyrrolidine Scaffold Tethered Benzo[b]Thiophene Analogue

Abstract

Described herein is a one-pot protocol for the synthesis of a substituted spiropyrrolidine scaffold tethered benzo [b]thiophene analogue from (E)-3-(benzo[b]thiophen-2-yl)-1-(4-fluoro-phenyl)prop-2-en-1-one. The described protocol has the advantage of the high purity of the cyclized adduct and high chemical yield. To assign the chemical structure, different spectrophotometric tools have been applied, including 1 H-NMR, 13 C-NMR, FTIR, and the X-ray single crystal technique. The X-ray structure showed that the studied compound exist in two disordered parts with equal partial occupancies. The energies of the two conformers were found to be very similar and not exceed 1 kcal/mol, which justifies their coexistence in the crystal with equal percentage. The molecular packing in the crystal was analyzed using Hirshfeld topology analysis. The packing described as two dimensional hydrogen bond network extended along the ac-plane in both conformers but the intermolecular interactions included in each conformer are not similar. The synthesized spiropyrrolidine scaffold tethered benzo[b]thiophene analogue was examined against cholinesterase inhibitory activity and show moderate activity compared to standard drug galantamine. a wide range of pharmaceutical applications, including anti-cancer drugs, and also in the material chemistry applications [6]. Some examples of commercially available compounds that contains the benzo[b]thiophene core structure are: raloxifene [7] (trade name: Evista; as anti-cancer agent for breast cancer), sertaconazole [8], zileuton [9] and tamoxifen [10]. Additionally, several reports have disclosed the importance in medicinal chemistry of the benzo[b]thiophene scaffold which can act as an inhibitor for acetyl-CoA carboxylase [11], tubulin polymerisation [12,13], and also as a modulator for the estrogen receptor [14]. On the other hand, benzo[b]thiophenes have been used as anticonvulsant [15], antidepressant, antidiabetic [16], anti-tubercular [17], anti-fungal [18], enzyme inhibitor [19], and anti-malarial drugs [20], and are used in asthma treatment too [8].In this paper we combined different pharmacophores including spiroindoline, pyrrole, thiazole, and benzo[b]thiophene moieties into one molecule which has been assessed in vitro for its AChE enzyme inhibition for AD treatment. The structure of the newly synthesized compound was confirmed using the single crystal X-ray diffraction technique. Hirshfeld topology analysis of molecular packing was performed to determine the different intermolecular contacts in the crystal structure. DFT calculations were carried out to study the structural aspects of the studied compound.

Straightforward Regio- and Diastereoselective Synthesis, Molecular Structure, Intermolecular Interactions and Mechanistic Study of Spirooxindole-Engrafted Rhodanine Analogs

“…The key step of this strategy is the generation of azomethine ylides (AYs) which then react with electron-deficient ethylene to produce pyrrolidine-spirooxindole with contiguous stereocenters. These pyrrolidine-spirooxindole molecules in particular have shown a panoply of significant pharmaceutical targets and applications, such as MDM2 inhibitors [ 20 , 21 , 22 ], anti-cancer treatment [ 7 , 23 ], AChE inhibitors [ 24 , 25 , 26 ] and prospective activity against SARS-CoV-2 [ 27 ]. Structural modifications have emerged as attractive synthetic targets for researchers.…”

Synthesis of Spirooxindole Analogs Tethered Pyrazole Scaffold as Acetylcholinesterase Inhibitors

“…On the other hands, Barakat and his team synthesized a new series of spirooxindole based benzo[ b ]thiophene motif, subsequently evaluated against AChE inhibitory activity, in between these series, compound VI possessed moderate potential against the AChE disease (Figure 1). [30h,32a] Replacement benzo[ b ]thiophene motif and the aromatic ring from VII [32a] into the indole and pyrazole scaffolds as shown in hybrid VIII [32b] significantly improved the reactivity (IC 50 : 20840 μM L −1 and 24.1 μM respectively). Taking the advantages of the two hybrids pyrazole and oxindole scaffolds and their structures ability to bind efficiently with target binding pockets, we aimed to synthesis a new lead molecule which could be act as AChE inhibitors by studding the effect both pyrazoles rings entire the final structure.…”

Synthesis and characterization of a new spirooxindole grafted pyrrolidino/piperidine moiety

“…It provides an opportunity to regulate many physicochemical properties and the liposolubility of spirooxindole (e.g: anti-inflammatory, anticancer, analgesic, antimicrobial, antimalarial, antioxidant, antiviral, antidiabetic, antiatherosclerotic, and insecticidal activities) and unique spatial architecture of spirooxindole have got a remarkable attention of many pharmacologists and chemists (Tantawy et al, 2017). Accordingly, the significant biological activities (Arun et al, 2013), (Lotfy et al 2017(Lotfy et al ), (maiulo et al, 2018 (Barakat et al, 2018), (Lotfy et al, 2018), (Lotfy et al, 2019), (Barakat et al, 2020).…”