Design, synthesis and molecular modeling study of substituted indoline-2-ones and spiro[indole-heterocycles] with potential activity against Gram-positive bacteria

Abstract

Longstanding and firsthand infectious diseases are challenging community health threats. A new series of isatin derivatives bearing β-hydroxy ketone, chalcone, or spiro-heterocycle moiety, was synthesized in a good yield. Chemical structures of the synthesized compounds were elucidated using spectroscopic techniques and elemental analysis. Antibacterial activities of the compounds were then evaluated in vitro and by in silico modeling. The compounds were more active against Gram-positive bacteria, Staphylococcus aureus (MIC = 0.026–0.226 mmol L−1) and Bacillus subtilis (MIC = 0.348–1.723 mmol L–1) than against Gram-negative bacteria (MIC = 0.817–7.393 mmol L–1). Only 3-hydroxy-3-(2-(2,5-dimethylthiophen-3-yl)-2-oxoethyl)indolin-2-one (1b) was found as active as imipenem against S. aureus (MIC = 0.026 mmol L–1). In silico docking of the compounds in the binding sites of a homology modeled structure of S. aureus histidine kinase-Walk allowed us to shed light on the binding mode of these novel inhibitors. The highest antibacterial activity of 1b is consistent with its highest docking score values against S. aureus histidine kinase.

Bacterial Histidine Kinase and the Development of Its Inhibitors in the 21st Century

“…The activity of 1a against S. aureus was explained by its significant docking score values (glide score −36.231 kcal mol −1 , electrostatic energy −0.697 kcal mol −1 , and van der Waals energy −35.534 kcal mol −1 ) within the binding site of BHK (S. aureus) (PDB: 5C93). Compound 1a could be further optimized for the development and synthesis of more potent antibacterial agents [48].…”

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…The spiro[indoline-3,3′-pyrazoline]-2-ones 33 and spiro[indoline-3,4′-pyrimidin]-2-ones 34 were obtained through reaction of 3-(2-oxo-2-ethylidene)-2-indolinones 32 with hydrazine hydrate in refluxing ethanol containing Et 2 NH or thiourea in refluxing ethanolic KOH, respectively ( Scheme 5 ). Promising antibacterial properties were noticed against B. subtilis (MIC = 0.348–1.809 mM) and S. aureus (MIC = 0.044–0.226 mM) relative to Imipenem (standard reference, MIC = 0.026, 0.026 mM against B. subtilis and S. aureus , respectively) [ 18 ].…”

Insight into Indole‐Based Heterocyclic Scaffolds: A Medicinal Chemistry Perspective

“…Awwad Abdoh Radwan et al [116] developed a protocol for synthesis of series of isatin derivatives having ß-hydroxy ketone, chalcone or spiroheterocycle moiety 565 (a-b) to 568 (a-f). Initially isatin (563) was reacted with aryl methyl ketones (564) in the presence of DEA and ethanol at room temperature to yield 565(a-b) followed by reaction with HCl and ethanol at room temperature to synthesize 566 (a-c).…”

“…Awwad Abdoh Radwan et al [116] . developed a protocol for synthesis of series of isatin derivatives having ß‐hydroxy ketone, chalcone or spiroheterocycle moiety 565 (a–b) to 568 (a–f) .…”