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

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.

Inhibitors of glucosamine-6-phosphate synthase as potential antimicrobials or antidiabetics – synthesis and properties

“…Recently Askri and co-workers 132 reported antimicrobial activity of some spiro-derivatives based on pyrrolidine scaffold. A three-component cascade reaction of ( E )-3-arylidene-1-methylpyrrolidine-2–5-diones, l -valine and isatine derivatives, involving 1,3-dipolar cycloaddition was applied for the synthesis of 197 and 198 ( Scheme 41 ) 132 .…”

“…Recently Askri and co-workers 132 reported antimicrobial activity of some spiro-derivatives based on pyrrolidine scaffold. A three-component cascade reaction of ( E )-3-arylidene-1-methylpyrrolidine-2–5-diones, l -valine and isatine derivatives, involving 1,3-dipolar cycloaddition was applied for the synthesis of 197 and 198 ( Scheme 41 ) 132 . Obtained compounds exhibited good activity (MIC = 3.9 µg/mL) against S. aureus, compared to that of the standard drug, tetracycline (24 µg/mL) and moderate activity against C. albicans (MIC = 78 µg/mL).…”

“…Obtained compounds exhibited good activity (MIC = 3.9 µg/mL) against S. aureus, compared to that of the standard drug, tetracycline (24 µg/mL) and moderate activity against C. albicans (MIC = 78 µg/mL). Molecular docking experiments accomplished on GlcN-6-P synthase (pdbid: 1jxa) revealed that derivatives 197 and 198 interacted with several amino acid residues via H-bonding, including Asp192 and Glu351 in the case of 197 (docking score −15.33) and Pro377 in the case of 198 (docking score −13.4) 132 .…”

“… Synthesis of spiro pyrrolidine-based putative inhibitor of GlcN-6-P synthase, according to Askri et al . 132 …”

Yeni Piridin Bazlı N-Açil Hidrazon Türevlerinin Sentezi ve Spektroskopik Karakterizasyonu ve Glukozamin-6-Fosfat Üzerine Moleküler Yerleştirme Çalışmaları

“…Compounds including N-benzyl-2,2,2 trifluoroacetamide (Fikrika et al, 2016), N-heterocyclic (Askri et al, 2022), novel 2,5-disubstituted-1,3,4-oxadiazole derivatives (Tok et al, 2021) have been investigated as a potential inhibitor of Glucosamine-6-Phosphate synthase to suppress the production of glucosamine-6-phosphate.…”