Antimicrobial Activity and In Silico Molecular Docking Studies of Pentacyclic Spiro[oxindole-2,3′-pyrrolidines] Tethered with Succinimide Scaffolds

Sonia Askri,Emmanuel Roulland,Rafik Gharbi,Olivier Laprévote,Nathalie Saffon-Merceron,Michael Knorr,Sarra Boudriga,Amal Dbeibia,Chadlia Mchiri

doi:10.3390/app12010360

Abstract

Three-component cascade reactions of (E)-3-arylidene-1-methyl-pyrrolidine-2,5-diones, L-valine and various isatin derivatives are described. A series of 17 spiropyrrolidine derivatives with wide structural complexity and diversity have been thus obtained in moderate to excellent yields under mild reaction conditions. The structure and stereochemistry of these N-heterocyclic cycloadducts has been established by spectroscopic techniques and unambiguously confirmed by a single-crystal X-ray diffraction analysis performed on one derivative. UV-visible spectra have been recorded for all new compounds. Furthermore, the synthesized N-heterocyclic compounds have been screened for their in vitro antibacterial and antifungal activities. Several derivatives exhibited moderate to good activities, comparable to those of the known standard drugs Amphotericin B and Tetracycline. Structural activity relationships (SARs) and molecular docking of the most promising derivatives into the binding sites of glucosamine 6-phosphate synthase (GlcN6P) and methionyl-trna-synthetase (1PFV) were also established. Furthermore, pharmacokinetic studies indicate that the heterocycles exhibit acceptable predictive ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and good drug ability.

Highlights

Spirocyclic oxindoles, which are widely distributed in natural alkaloids and bioactive compounds, represent attractive synthetic targets [1,2,3,4,5,6,7]
We showed that some spirooxindolepyrrolidine and spirooxindolepyrrolizidine derivatives incorporating the pyrrolidine-2,5-dione motif are promising for acetylcholinesterase (AChE) inhibition [33] and possess both antimicrobial and anticoagulant activities [34]
We reported the synthesis of a series spiro[oxindole-2,30 -pyrrolidine] tethered with succinimide scaffolds via a three component 1,3-dipolar cycloaddition reaction of (E)-3-arylidene-1-methyl-pyrrolidine-2,5-diones, L-valine and cyclic ketones of the isatin type

Summary

Introduction

As a subset of this family, spiro[oxindole-2,30 -pyrrolidine] constitute a privileged structural unit which is present in numerous natural isolates and synthetic bioactive compounds [8,9]. They exhibit a wide spectrum of biological properties, such as antitumoral [10,11], anti-inflammatory [12], antimycobacterial [13], antimicrobial and anticancer activities (Figure 1) [14,15,16,17]. They are known for acetylcholinesterase inhibition [18,19]

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Discussion

Conclusion