Solvent effects on the structure-property relationship of anticonvulsant hydantoin derivatives: A solvatochromic analysis

Considering the pharmaceutical importance of hydantoins, a set of 25 derivatives of phenytoin, nirvanol and 5-methyl-5-phenylhydantoin, the lipophilicities of which were gradually increased by the introduction of different alkyl, cycloalkyl and alkenyl groups in position N3, was synthesized. Their properties under consideration were either estimated empirically, by UV/Vis spectroscopy, or calculated using established medicinal chemistry software. The UV absorption spectra of the investigated compounds were recorded in the region from 200 to 400 nm, in selected solvents of different polarities. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions were analyzed by means of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. Furthermore, the relationships between solvent-solute interactions and selected structural features of the solutes, which are believed to markedly affect the processes of absorption, distribution, metabolism, excretion and toxicity (ADMETox), were discussed. Satisfactory correlations were found between hydrogen bonding properties and solute size and the in silico calculated bioactivity descriptors, in particular %Abs. (human intestinal absorption), log BB (blood-brain barrier permeation) and log k(A )(protein binding affinities) parameters. In view of the results of this study, the investigated hydantoin derivatives met the pharmacokinetic criteria for pre-selection as drug candidates and qualified them for the pharmacodynamic phase of antiepileptic drug development

Free planar vibration of structures composed of rigid bodies and elastic beam segments

Ovaj rad predstavlja analizu slobodnih vibracija struktura sastavljenih od krutih tela međusobno spojenih sa elastičnim gredama. Pretpostavlja se da se centri masa krutih tela ne nalaze na neutralnoj osi nedeformisanog elastičnog grednog segmenta kao i da kruta tela vrše ravno kretanje u istoj ravni i da se njihovi centri masa nalaze u toj istoj ravni. Za određivanje frekvencija sistema, modifikacija klasične 'CTMM' metode je upotrebljena. Elastični gredni segmenti se tretiraju kao Ojler-Bernulijeve grede. Prikazan je numerički primer.This article presents free vibration analysis of structures composed of rigid bodies connected with elastic beam segments. It is assumed that the mass centers of rigid bodies are not located on the neutral axes of undeformed elastic beam segments as well as rigid bodies perform planar motion in the same plane and their mass centers are located in that plane. For determination of natural frequencies of the system, modification of the conventional continuous-mass transfer matrix method has been performed. The elastic beam segments are treated as Euler-Bernoulli beams. Numerical example is presented

Fluorination of aliphatic compounds. Driving force in crystal structures

Statistical analysis of crystal structures from CSD (Crystallographic database) has shown the F...F contacts are the second group of interactions (23050 structures), immediately after the hydrogen bonds (43397 structures), that are mainly of aliphatic C−H...F type. There is no clear tendency of F...F contacts toward some certain values of d parameter, but it is possible to notice noticeable clear tendency of numerous structures to d values greater than 2.9 Å. There is a pronounced maximum in the range of torsion angle T from 160 to 180° corresponding to trans orientation of interacting C−F and X−Y fragments.На основу анализе кристалних структура преузетих из Кембричке базе кристалографских података (CSD) показано је да се алифтичне C−H...F водоничне везе издвајају као најбројније интеракције флуорованих алифатичних група (43397 стуктура). Далеко испод (23050 структура), на другом месту су F...F интеракције. Уочљиво је да су вредности F...F растојања (d параметар) претежно изнад 2,9 Å. Међутим, не постоји јасно изражена тенденција према одређеној вредности d параметра. Пошто се за највећи број структура вредности торзионог угла C-F-X-Y (Т параметар) крећу између 160 и 180° може се закључити да интерагујуће C−F и X−Y групе међусобно заузимају trans оријентациј

Evaluation of solvent and substituent effects on absorption spectra of spirohydantoins derived from α-tetralone

A convenient and efficient approach toward the synthesis of six 3-(4-substituted benzyl)-6,7- benzo-1,3-diazaspiro[4.5]decane-2,4-diones (1‒6) by Bucherer-Bergs reaction and further alkylation at position 3 of the hydantoin ring is reported. Further, their chemical structure was confirmed by melting points, elemental analysis, FT-IR, NMR and UV–Vis spectroscopic methods. To gain an insight into interactions which the investigated spirohydantoins establish with their environment, their absorption spectra were recorded in selected solvents of different polarity and the solvent effects on the UV-Vis absorption band positions, intensity and shape, were discussed. Substiuent effects on the solvatochromism of compounds 1−6 were analyzed using the Hammett's equation. Considering the broad applications of hydantoin derivatives, as well as the fact that their relative importance may increase in the future, results obtained in this study serve as a basis for further investigations

Sukcinimidi - dobijanje, svojstva i antikonvulzivna aktivnost

Succinimide is a cycle imide of succinic acid that is present in numerous biologically active compounds including anticonvulsants, antitremor, anti-Parkinson's agents. This paper describes different ways of synthesis of succinimide derivatives, their physical properties and reactivity. Also, the most widely used succinimide anticonvulsants and the analysis of structure-activity relationships of anticonvulsant drugs in terms of lipophilicity and hydrogen bonding are presented here.Sukcinimidi su ciklični imidi ćilibarne (sukcinske) kiseline, koji se primenjuju u medicini kao antikonvulzivi. Mogu se, takođe, koristiti u tretiranju drugih cerebralnih oboljenja, kao na primer tremora, Parkinsonove bolesti, itd. U ovom radu su prikazani postupci dobijanja sukcinimida, koji se upotrebljavaju u medicini, kao i njihova struktura i fizičke i hemijske osobine. Razmatran je uticaj strukture na antikonvulzivnu aktivnost različitih derivata sukcinimida sa aspekta lipofilnosti i mogućnosti uspostavljanja vodoničnih veza

Uticaj rastvarača na apsorpcione spektre prehrambenih azo boja

The solvent influence on absorption spectra of food azo dyes was examined by the method of Linear Solvation Energy Relationships (LSER). For this purpose, six azo dyes were used: tartrazine (E 102), ponceau 4R (E 124), azorubin (E 122), brilliant black (E 151), amaranth (E 123) and gelb orange S (E 110). Absorption spectra of dissolved azo dye have been recorded in the wavelength range of visible radiation, or from 380 to 760 nm, in eight solvent of different polarity. The choice of the solvent was limited due to the high polarity of the azo dye molecules themselves. The effect of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interaction are analysed by means of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. The linear correlation of the absorption maxima with parameters of Kamlet-Taft solvatochrome equation yielded satisfactory results.Uticaj polarnosti rastvarača na apsorpcione spektre prehrambenih azo boja ispitivan je metodom linearne korelacije energije solvatacije (LSER). U ovu svrhu korišćeno je šest prehrambenih azo boja i to: tartrazin (E 102), ponceau 4R (E 124), azorubin (E 122), brilijant crna (E 151), amarant (E 123) i gelb oranž S (E 110). Apsorpcioni spektri rastvorenih azo boja određeni su u talasnom opsegu vidljivog zračenja, odnosno u opsegu od 380 do 760 nm, u osam rastvarača različite polarnosti. Polarnost samih boja je uticala na izbor malog broja polarnih rastvarača. Spektre ispitivanih azo boja karakteriše jedan apsorpcioni maksimum. Efekat polarnosti rastvarača i efakat vodoničnog vezivanja rastvarač-rastvorena supstanca ispitivan je primenom KamletTaftove solvatohromne jednačine. Linearna korelacija apsorbcionih maksimuma sa parametrima Kamlet-Taftove solvatohromne jednačine dala je zadovoljavajuće rezultate

Fluorination of aromatic groups. The effects of coordination on fluorine interactions

Statistical analysis of crystal structures obtained from Cambridge Structural Database (CSD) showed that the most numerous are structures in which carbon atom is bound to interacting fluorine atom.Statistička analiza kristalnih struktura iz Kembričke baze strukturnih podataka pokazuje da su najbrojnije one strukture kod kojih je ugljenikov atom vezan za interagujući atom fluora. One u kojima je fluor vezan za aromatičnu grupu su malo manje zastupljene

Electrochemical Characterization of Oxaprozin on Bare Gold Electrode and Electrode Modified with Bovine Serum Albumin

As the very first electrochemical investigation of oxaprozin, nonsteroidal anti-inflammatory drug, using cyclic voltammetry on gold electrode in 0.05 mol dm(-3) NaHCO3, the synthesized drug, its analytical standard and its content in Duraprox (R) tablets were characterized with one oxidation reaction and the three reduction reactions. All they exhibited the linear concentration dependency of anodic currents at 0.83V for the analytical standard and 0.85V for Duraprox (R) tablets in the range of concentrations 8.44 - 32.78x10(-6) mol dm(-3). The strong adsorption of bovine serum albumin (BSA) on gold electrode in 0.1 mol dm(-3) phosphate buffer solution (pH 7.4) is shown and concentration dependency of anodic currents of oxaprozin standard on BSA/Au is studied. Following the Langmuir adsorption thermodynamic equation, the binding constants of oxaprozin on BSA/Au electrode was calculated with the results 1.23x10(5) dm(3) mol(-1)

Role of structural motifs in formation of the supramolecular architecture of 3-(4-tert-butylbenzoyl)-1,3-diazaspiro[4.5]Decane-2,4-dione

Proučavano jedinjenje (slika 1) sintetisano je polazeći od cikloheksanona Bučerer- Bergsovom reakcijom i naknadnim acilovanjem dobijenog spirohidantoina. Izgradnja kristalne strukture ovog jedinjenja proučavana je sa aspekta doprinosa jednostavnih dimernih motiva koji se uspostavljaju preko različitih intermolekulskih interakcija.Intermolekulske interakcije dodatno su proučavane pomoću Hiršfeldovih površina i 2D grafičkih prikaza otisaka interakcija. Kristalna struktura, naime, zadržava motiv koji se često sreće kod derivata hidantoina, u kome su dva inverzano orijentisana molekula povezana parom N–H···O vodoničnih veza. Ovaj motiv formira dva tipa dvostrukih lanaca, koji dalje grade sloj (slika 2). Osim toga, slabe C–H⋯O interakcije zajedno sa disperzionim interakcijama (π-π i hidrofobne interakcije) identifikovane su u ovoj kristalnoj strukturi. Kristalografski podaci: C19H24N2O3, Mr = 328,4, trikliničan sistem, prostorna grupa P–1, a = 6,2810(2), b = 12,0586(4), c = 12,1852(5) Å,α = 77,624(3), β = 81,039(3), γ = 79,111(3) °, V = 878.81(6) Å3, Z = 2, F(000) = 352, ρx = 1,380 g cm–3,µ(MoKα) = 0,084 mm–1. Utačnjavanje sa F2 (220 parametara) dalo je R1 = 0,0520, wR2 = 0,1199, S = 1,033 za sve podatke i R1 = 0,0443 za 3232 uočenih refleksija sa I ≥ 2σ(I).The title compound (Figure 1) was prepared from cyclohexanone in the Bucherer-Bergs reaction, followed by acylation of the obtained spirohydantoin. Formation of the crystal structure of this compound was analysed in terms of a number of simple dimeric motifs which are associated with different intermolecular interactions. The crystal structure retains the motif commonly found in hydantoin derivatives, where two molecules related by inversion are linked by a pair of N–H O hydrogen bonds. This motif is involved in two types of double chains, whichfurther form a layer (Figure 2). Intermolecular interactions were also investigated using Hirshfeld surface analysis and 2D fingerprint analysis. Weak C–H⋯O interactions together with thedispersion interactions (π-π and hydrophobic) as the source of attraction are identified in this crystal structure.Crystal data: C19H24N2O3, Mr = 328.4, triclinic system, space group P–1, a = 6.2810(2), b = 12.0586(4), c = 12.1852(5) Å, a = 77.624(3), β = 81.039(3), γ = 79.111(3) °, V = 878.81(6) Å3, Z = 2, F(000) = 352,ρx = 1.380 g cm–3, µ(MoKa) == 0.084 mm–1. The refinement on F2 (220 parameters) yielded R1 = 0.0520, wR2 = 0.1199,S = 1.033 for all data, and R1 = 0.0443 for 3232 observed reflections with I ≥ 2σ(I)

Insights into conformational and cristal structure features of selected cyclohexane-5-spirohydantoin derivatives

Derivat cikloheksan-5-spirohidantoina (Slika 1) je sintetisan, određena je njegova kristalnastruktura i urađena kvantno-hemijska analiza. Kristalno pakovanje grade mrežesupramolekulskih R64(32) prstenova postavljenih međusobno paralelno, pri čemu seformiraju linearni kanali. Određene su vrednosti energije intermolekulskih interakcija zarazličite dimerne motive dobijene iz kristalne strukture. Uzimajući u razmatranjeprethodno strukturno okarakterisane srodne spirohidantoine [1], dobijena je serijajedinjenja koja je omogućila procenu uticaja supstituenata na njihovu molekulsku ikristalnu strukturu.A spirohydantoin derivative (Figure 1) was synthesized and its crystal structure wasdetermined by single crystal X-ray diffraction and analysed by DFT calculations. Thecrystal packing is made of supramolecular nets of R64(32) rings linked together to formstacks that enclose linear channels. The intermolecular interaction energies are quantifiedfor various dimeric motifs. By including the previously reported structurally-relatedspirohydantoins [1], we created a set of compounds that enabled us to evaluate substituenteffects on both molecular and crystal structures