Glutarimides: Biological activity, general synthetic methods and physicochemical properties

Abstract

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, amidonitriles, amido-esters, amidoacyl-chlorides or diacyl-chlorides, c) addition of carbon- monoxide on α, β-unsaturated amides, d) oxidation reactions, e) Michael addition of active methylen compounds on methacrylamide or conjugated amides. Some of the described methods are used for closing glutarimide ring in syntheses of pharmacological 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 due to 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.

U ovom radu dat je prikaz metoda za sintezu šestočlanih cikličnih imida. Glutarimidi, 2,6-dioksopiperidini, su značajna biološka jedinjenja i deluju kao antagonisti adrenogenih receptora, antiinflamatorni agensi, anksiolitici, antivirotici, antibiotici i agensi koji sprečavaju rast pojedinih vrsta tumora. Prikazana je i njihova spektralna analiza (FT-IR i NMR), zbog potvrde stukture, kao i analiza graničnih molekulskih orbitala koja daje prikaz elektronskih svojstava ovih molekula, što je važno zbog njihove biološke aktivnosti. Da bi se predstavila hemijska reaktivnost glutarimida predstavljen je molekulski elektronski potencijal (MEP) iz prethodno optimizovane geometrije reprezentativnog primera terc-pentil-1- -benzil-4-metil-glutarimid-3-karboksilata (skraćenica PBMG). Elektronska svojstva su objašnjena na primeru talidomida.