Glutarimidi - biološka aktivnost, opšti postupci za sintezu i fizičko-hemijske karakteristike

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 alpha,beta-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

Sinteza, NMR i DFT proračunavanja i ispitivanje antimikrobne aktivnosti Zn(II) kompleksa sa N-benziloksikarbonil-S-alaninom

In this study, the first complexes of Zn(II) with the N-benzyloxycarbonyl-S-alaninato ligand (N-Boc-S-ala) were synthesized. The new complexes were characterized by elemental analysis, conductometric measurements, IR. (1)H-NMR, (13)C-NMR and 2D-NMR spectroscopy. On the basis of the experimental data, tetrahedral geometry of the Zn(II) complexes was proposed. A very good agreement between the NMR and DFT calculated data was obtained. Investigation of antimicrobial activity of the newly synthesized complexes was also performed. It was established that [Zn(N-Boc-S-ala)(2)] was selective and acts only on Candida aibicans.U ovom radu su sintetizovani prvi kompleksi Zn(II) sa N-benziloksikarbonil-S-alaninato ligandom (N-Boc-S-ala). Kompleksi su okarakterisani elementalnom analizom, konduktometrijskim merenjem, IR, 1H-NMR, 13C-NMR i 2D-NMR spektroskopijom. Tetraedarska geometrija Zn(II) kompleksa pretpostavljena je na osnovu eksperimentalnih podataka. Dobijeno je veoma dobro slaganje između NMR i DFT podataka. Ispitivana je antimikrobna aktivnost novosintetizovanih kompleksa. Ustanovljeno je da je [Zn(N-Boc-S-ala)2] kompleks selektivan i da deluje samo na gljivu Candida albicans

Charge assisted assembly of zwitterionic pyridone hydrates

Two pyridone derivatives, bearing the pyridinium moiety (1), or dimethylpyridinium moiety (2), have been synthesized and their crystal structures have been determined. The compounds crystalize in hydrated zwitterionic forms with either two (1.2H(2)O) or four (2.4H(2)O) water molecules. The zwitteri-onic networks contain different types of water clusters, generated into channels, incorporating them into the network by sandwiching. The type of channel depends on the crystal lattice and the nature of non-covalent interactions established between zwitterions as well as the number of water molecules incorporated into the architecture. 1 affords tubes filled in with water channels formed by water tetramers, contrary to 2, which affords a layered network altering the zwitterionic layer and the layer formed by water tetramers and hexamers. A detailed study of intermolecular interactions of both crystal structures and a quantification of interaction energies has been performed using PIXEL lattice energy calculations, giving an insight to a quantitative evaluation of interactions through Coulombic, disperse, repulsion and polarization energies. The strongest pairwise, in both structures, is found to be a dipole-dipole interaction between oppositely charged heterocyclic rings. The differences in the crystal packings of these hydrates have been elucidated by the fingerplot analysis. The comparative studies between experimental and calculated (DFT) data of molecules 1.H2O and 2.4H(2)O for systems of different complexity are performed. Furthermore, correlations of experimental and calculated bond lengths and the simulation of compound solvation with the CPCM model are done

Novel azo pyridone dyes based on dihydropyrimidinone skeleton: Synthesis, DFT study and anticancer activity

Seven novel azo dyes with 2-pyridone and dihydropyrimidinone moieties have been synthesized and thoroughly characterized. The azo-hydrazone tautomerism has been investigated by experimental and theoretical approaches. The optimizations of geometries have been performed with density functional theory (DFT). The vibrational and NMR spectra were calculated and correlated with experimental ones. Furthermore, quantum chemical descriptors were calculated and MEP maps were plotted to determine biological reactivity of dyes. The antioxidant assay evinced that 5, 6 and 7 are promising antioxidant candidates. In vitro cytotoxic activity was studied against three malignant cell lines: prostate adenocarcinoma (PC-3), lung carcinoma (A549) and chronic myelogenous leukemia (K562), as well as against human normal lung fibroblasts (MRC-5), using MTT assay. Examination of cytotoxic effects on human cancer cell lines showed the concentration dependent cytotoxicity of all investigated compounds. The K562 cells were the most sensitive to the cytotoxicity of the compounds 3, 5 and 6, wherein compound 5 was particularly prominent and selective in cytotoxic action between K562 (24.97 mu M) and PC-3 (48.98 mu M) cancer cells, and normal MRC-5 (91.11 mu M) cells. Moreover, the cell cycle analysis of compound 5 was examined in K562 cells, by flow cytometry, to study its mechanism of anticancer action. Finally, in silico evaluation of physicochemical parameters, druglikeness and ADME properties showed that investigated compounds are orally bioavailable with no permeation to the blood brain barrier

Structure and stereochemistry of electrochemically synthesized poly-(1-naphthylamine) from neutral acetonitrile solution

Poly-(1-naphthylamine) films were synthesized potentiodinamically and potentiostatically from 1-naphthylamine in neutral acetonitrile medium using a platinum electrode. These polymer films were investigated by infrared spectroscopy. Contrary to earlier published results neglecting the stereochemistry of the poly-(1-naphthylamine), we predict on the basis of quantum stereochemical analysis of the possible structural subunits of the polymer, that the ordinary NC(4) coupled product is not predominant in the polymer because it is far removed from the expected planarity. Based on the results of IR investigations and semiempirical quantum chemical calculations, it is propose that the polymer products are formed via mixed NC(4), N-C(5) and NC(7) coupling routes. The heats of formation of the oxidized 1-naphthylamine dimers and hexamers were calculated

Effect of substituents on the 13C-NMR chemical shifts of 3-methylene-4-substituted-1,4-pentadienes. Part I.

The principles of linear free energy relationships were applied to the 13C substituent chemical shifts (SCS) of the carbon atoms in the unsaturated chain of 3-methylene-4-substituted-1,4-pentadienes. Correlations of the SCS with the substituent parameters of Swain and Lupton provide a mutually consistent picture of the electronic effects in these compounds. The pattern of the electronic effects can be fully rationalized by a model based on the direct transmission of substituent effects through-space (direct through-space field effects), and via conjugative interactions (resonance effects), or by substituent-induced polarization of the p-system in the unsaturated chain (p-polarization effect). Semi-empirical MNDO-PM3 calculations suggest the s-cis conformation of 3-methylene-4-substituted-1,4- -pentadienes as the one with minimal heat of formation