Glucosamine-6-phosphate synthase inhibiting C3-β-cholesterol tethered spiro heterocyclic conjugates: Synthesis and their insight of DFT and docking study

Govindasami Periyasami; Subban Kamalraj; Ramanathan Padmanaban; Santhakumar Yeswanth Kumar; Antony Stalin; Natarajan Arumugam; Raju Suresh Kumar; Mostafizur Rahaman; Periyan Durairaju; Abdulaziz Alrehaili; Ali Aldalbahi

doi:10.1016/j.bioorg.2019.102920

Glucosamine-6-phosphate synthase inhibiting C3-β-cholesterol tethered spiro heterocyclic conjugates: Synthesis and their insight of DFT and docking study

Bioorg Chem. 2019 Jul:88:102920. doi: 10.1016/j.bioorg.2019.102920. Epub 2019 Apr 9.

Affiliations

¹ Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia; Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai, India. Electronic address: [email protected].
² Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, India; Centre for Advanced Studies in Botany & Centre for Herbal Sciences, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India.
³ Department of Chemistry, School of Physical, Chemical & Applied Sciences, Pondicherry University, Puducherry, India.
⁴ Division of Bioinformatics, Entomology Research Institute, Loyola College, Chennai 600 034, Tamil Nadu, India; Centre for Advanced Studies in Botany & Centre for Herbal Sciences, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India.
⁵ Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
⁶ Department of Chemistry, Thiruvalluar Government Arts College, Periyar University, Raispuram, India.
⁷ Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia. Electronic address: [email protected].

PMID: 30991194
DOI: 10.1016/j.bioorg.2019.102920

Abstract

A series of novel covalent cholesterol-spiro pyrrolidine/pyrrolizidine heterocyclic hybrids possessing biologically active oxindole, indanedione, and acenaphthylene-1-one have been synthesized by the reaction of C3-β-cholesteroalacrylate with heterocyclic di- and tri-ketones. All the sixteen compounds were obtained as a single isomer in good yield through a stereo- and regio- selective 1,3-dipolar cycloaddition methodology. Stereochemistry of the spiranic cycloadducts has been established by spectroscopic analysis and the regioselectivity outcome of the spiro adducts has been accomplished by DFT calculations at B3LYP/6-31G (d,p) level study. In vitro antibacterial activity of the newly synthesized cycloadducts were evaluated against highly pathogenic Gram-positive and Gram-negative bacteria and the most active compounds 5a, 13, and 14 underwent automated in silico molecular docking analysis in order to validate their effective orientation as a inhibitors bound in the active site of glucosamine-6-phosphate synthase (1XFF) enzyme by employing AutoDock Tools.

Keywords: 1XFF enzyme; Cycloaddition; DFT; HOMO-LUMO; Molecular docking; Spiro steroid hybrids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / pharmacology*
Bacteria / drug effects
Catalytic Domain
Cholesterol / analogs & derivatives*
Cholesterol / pharmacology*
Cycloaddition Reaction
Density Functional Theory
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / antagonists & inhibitors*
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / chemistry
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / metabolism
Models, Chemical
Molecular Docking Simulation
Protein Binding
Spiro Compounds / chemical synthesis
Spiro Compounds / pharmacology*
Stereoisomerism

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Spiro Compounds
Cholesterol
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)