Glutarimides: Biological activity, general synthetic methods and physicochemical properties

• Published in: Hemijska industrija 2015-01, Vol.69 (5), p.523
• Main Authors: Popović-Đorđević, Jelena B, Vitnik, Vesna D, Vitnik, Željko J, Ivanović, Milovan D
• Format: Article
• Language: eng ; srp
• Subjects: Amides; Ammonia; Biological activity; Chlorides; Derivatives; Dicarboxylic acids; Electronic properties; Energy gap; Esters; Fourier transforms; Methacrylamide; Molecular orbitals; Nitriles; NMR; Nuclear magnetic resonance; Oxidation; Pharmacology; Thalidomide; X ray analysis
• ISSN: 0367-598X; 2217-7426
• DOI: 10.2298/HEMIND140701073P

Glutarimides, 2,6-dioxopiperidines are compounds that rarely occur in natural sources, but so far isolated ones exert widespread pharmacological activities, which makes them valuable as potential pharmacotherapeutics. Glutarimides act as androgen receptor antagonists, anti-inflammatory, anxiolytics, antibacterials, and tumor suppressing agents. Some synthetic glutarimide derivatives are already in use as immunosuppressive and sedative (e.g., thalidomide) or anxiolytics (buspirone) drugs. The wide applicability of this class of compounds, justify the interest of scientists to explore new pathways for its syntheses. General methods for synthesis of six-membered imide ring, are presented in this paper. These methods include: a) reaction of dicarboxylic acids with ammonia or primary amine, b) reactions of cyclization: amido-acids, diamides, dinitriles, nitrilo-acids, amido-nitriles, amido-esters, amidoacyl-chlorides or diacyl-chlorides, c) adition of carbon-monoxide on a,b-unsaturated amides, d) oxidation reactions, e) Michael adition of active methylen compounds on methacrylamide or conjugated amides. Some of the described methods are used for closing glutarimide ring in syntheses of farmacological active compounds sesbanimide and aldose reductase inhibitors (ARI). Analyses of the geometry, as well as, the spectroscopic analyses (NMR and FT-IR) of some glutarimides are presented because of their broad spectrum of pharmacological activity. To elucidate structures of glutarimides, geometrical parameters of newly synthesized tert-pentyl-1-benzyl-4-methyl-glutarimide-3-carboxylate (PBMG) are analyzed and compared with the experimental data from X-ray analysis for glutarimide. Moreover, molecular electrostatic potential (MEP) surface which is plotted over the optimized geometry to elucidate the reactivity of PBMG molecule is analyzed. The electronic properties of glutarimide derivatives are explained on the example of thalidomide. The Frontier Molecular Orbital (FMO) and their energies are presented, as well as the energy gap between them.