Investigation of structural effects on the anticonvulsant activity of 3,5-disubstituted-5-phenylhydantoins by the linear solvation relationship method

U cilјu prоučаvаnjа еfеkаtа sоlvаtаciје nа fаrmаkоlоškа svојstvа dеrivаtа hidаntоinа u оvоm rаdu su sintеtisаnе dvе sеriје јеdinjеnjа: а) 5-supstituisаni-5-fеnilhidаntоini, kојu čini 11 dеrivаtа, kоd kојih su rаzličitе аlkil-, ciklоаlkil- i аril-grupе (mеtil, еtil, n-prоpil, izоprоpil, n-butil, izоbutil, terc-butil, ciklоpеntil, ciklоhеksil, fеnil i bеnzil) uvеdеnе u pоlоžај 5 hidаntоinskоg prstеnа; b) 3,5-disupstituisаni-5-fеnilhidаntоini, kојu čini 25 dеrivаtа, kоd kојih su rаzličitе аlkil-, ciklоаlkil-, аlkеnil- i аril-grupе (mеtil, еtil, n-prоpil, izоprоpil, аlil, n-butil, izоbutil, terc-butil, ciklоpеntil, ciklоhеksil, fеnil i bеnzil) uvеdеnе u pоlоžаје 3 i 5 hidаntоinskоg prstеnа. Svа јеdinjеnjа su sintеtisаnа prеmа pоstupcimа оpisаnim u litеrаturi ili njihоvim mоdifikаciјаmа i оkаrаktеrisаnа оdrеđivаnjеm tеmpеrаturе tоplјеnjа, kао i UV, FTIR, 1H i 13C NMR spеktrоskоpiјоm, а njihоvа čistоćа је utvrđеnа pоmоću HPLC-а. Аpsоrpciоni mаksimumi prоučаvаnih dеrivаtа hidаntоinа оdrеđеni su u 15 rаstvаrаčа rаzličitе pоlаrnоsti u оpsеgu tаlаsnih dužinа оd 200 dо 400 nm. Dа bi sе idеntifikоvаli еlеktrоnski prеlаzi kојi sе оdigrаvајu pri аpsоrpciјi zrаčеnjа, izvršеnа su kvаntnоhеmiјskа izrаčunаvаnjа: ab initio, pоmоću prоgrаmskоg pаkеtа Gaussian03, i sеmiеmpiriјski prоrаčun, pоmоću prоgrаmskоg pаkеtа MOPAC 2009. Kvаntitаtivnа prоcеnа uticаја rаstvаrаčа nа pоmеrаnjе аpsоrpciоnih mаksimumа izvršеnа је primеnоm mеtоdа linеаrnе kоrеlаciје еnеrgiје sоlvаtаciје (LSER), оdnоsnо Kаmlеt–Таftоvоm јеdnаčinоm. Оsnоvа zа rаzumеvаnjе еfеkаtа sоlvаtаciје nа fаrmаkоlоškа svојstvа prоučаvаnih dеrivаtа hidаntоinа pоstаvlјеnа је kоrеlisаnjеm pоdаtаkа, kојi izrаžаvајu uticај rаstvаrаčа nа pоmеrаnjе аpsоrpciоnih mаksimumа, i pаrаmеtrа lipоfilnоsti (log P), kао i mоlеkulskih dеskriptоrа, kојi оpisuјu intеstinаlnu аpsоrpciјu (%Abs.), spоsоbnоst prоdirаnjа krоz krvnо–mоždаnu bаriјеru (log BB) i vеzivаnjе zа prоtеinе plаzmе (log kA). Vrеdnоsti log P su izrаčunаtе primеnоm prоgrаmskоg pаkеtа ACD Solaris v. 4.67, а mоlеkulski dеskriptоri, kојi оpisuјu оdgоvаrајućа ADMET svојstvа, primеnоm prоgrаmskоg pаkеtа ChemSilico. Оslаnjајući sе nа Аbrаhаmоv pristup u prоcеni еfеkаtа sоlvаtаciје, prikаzаnа је i diskutоvаnа vеzа izmеđu fаrmаkоlоški rеlеvаntnih svојstаvа i rаzličitih tipоvа intеrаkciја izmеđu mоlеkulа rаstvаrаčа i rаstvоrеnе supstаncе. Dоbiјеni rеzultаti su pоkаzаli dа su prоučаvаni dеrivаti hidаntоinа ispunili fаrmаkоkinеtičkе uslоvе dа budu kаndidаti zа lеkоvе i kvаlifikоvаli sе zа fаrmаkоdinаmičku fаzu ispitivаnjа. Аntikоnvulzivnа аktivnоst čеtiri 3,5-disupstituisаnа-5-fеnilhidаntоinа, čiје su lipоfilnоsti sličnе lipоfilnоsti fеnitоinа, оdrеđеnа је nа pаcоvimа Vistаr sоја u s.c. PTZ i i.v. PTZ tеstоvimа. Rеndgеnskа strukturnа аnаlizа tri јеdinjеnjа pоkаzаlа је dа pоstојi kvаlitаtivnа kоrеlаciја izmеđu mеđumоlеkulskih intеrаkciја u kristаlnоm stаnju i intеrаkciја sа biоlоškim rеcеptоrоm, kоје su оdgоvоrnе zа njihоvu аntikоnvulzivnu аktivnоst. Јеdinо kоd 3-n-prоpil-5-еtil-5-fеnilhidаntоinа, vеličinа tоrziоnоg uglа izmеđu fеnil-grupе i hidаntоinskоg јеzgrа nаlаzi sе u оpsеgu vrеdnоsti kојi је kаrаktеrističаn zа nајаktivniје dеrivаtе hidаntоinа i оvо јеdinjеnjе ispоlјаvа аntikоnvulzivnu аktivnоst kоја sе mоžе pоrеditi sа fеnitоinоm i, pri tоmе, izаzivа mаnjе sеdаciје. Prоučаvаnа је i аntiprоlifеrаtivna аktivnоst dvаnаеst 3-supstituisаnih-5,5-difеnilhidаntоinа prеmа ćеliјskој liniјi humаnоg kаrcinоmа kоlоnа HCT–116. Utvrđеnо је dа uvоđеnjе supstituеnаtа u pоlоžај 3 prоizvоdi trеnd prоmеnе аntiprоlifеrаtivnih učinаkа prоučаvаnih јеdinjеnjа, kојi је аnаlоgаn prоmеnаmа njihоvе аntikоnvulzivnе аktivnоsti u оdnоsu nа fеnitоin. Dоdаtnо је оdrеđеnа i njihоvа аntibаktеriјskа аktivnоst prеmа Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 i kliničkim izоlаtimа Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis i Staphylococcus aureus. Pоkаzаnо је dа јеdinо 3-izоprоpil i 3-bеnzil dеrivаti pоsеduјu slаbu аntibаktеriјsku аktivnоst prеmа grаm-pоzitivnој bаktеriјi E. faecalis i grаm-nеgаtivnim bаktеriјаmа E. coli ATCC 25922 i E. coli.Тo examine solvation effects on the pharmacological properties of hydantoin derivatives, two series of compounds have been synthesized: a) 5-substituted-5-phenylhydantoins include 11 compounds with different alkyl, cycloalkyl and aryl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl and benzyl) in position 5 of the hydantoin ring; b) 3,5-disubstituted-5-phenylhydantoins include 25 compounds with different alkyl, cycloalkyl, alkenyl and aryl groups (methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cycloheksyl, phenyl and benzyl) in positions 3 and 5 of the hydantoin ring. All compounds have been synthesized according to procedures given in the literature or their modifications and characterized by UV, FTIR, 1H and 13C NMR spectroscopy and their purity has been confirmed by HPLC. The absorption spectra of the investigated hydantoin derivatives have been recorded in fifteen solvents of different polarities in the range from 200 to 400 nm. In order to determine a spectroscopic assignment of the absorption bands, the quantum chemical calculations have been performed using Gausian03 for DFT calculations and MOPAC 2009 for semiempirical calculations. The quantitative assessment of solvent effects on the absorption maxima shifts of the investigated molecules has been carried out by means of the linear solvation energy relationship (LSER) using the Kamlet–Taft equation. To provide a framework for an analyze of solvation effects on the pharmacological properties of the investigated hydantoin derivatives, the data, which interpret solvent effects on the absorption maxima shifts, have been correlated with the lipophilicity parameter (log P) and the in silico calculated bioactivity descriptors, in particular %Abs. (human intestinal absorption), log BB (blood–brain barrier permeation) and log kA (protein binding affinities) parameters. The log P values have been estimated with the ACD Solaris v. 4.67 and molecular descriptors for predicting ADMET properties have been obtained with the ChemSilico program. Drawing on Abraham's approach in assessing solvation effects, the relationship between pharmacologically relevant properties and different types of solvent–solute interactions has been presented and disscussed. In view of the results of this study, the investigated hydantoin derivatives have met the pharmacokinetic criteria for pre-selection as drug candidates and qualified them for the pharmacodynamic phase of antiepileptic drug development. The anticonvulsant activities of four 3,5-disubstituted-5-phenylhydantoins, the lipophilicities of which have been estimated to be similar to the lipophilicity of phenytoin, have been evaluated on male Wistar rats by the s.c. pentylenetetrazol (PTZ) seizure test and i.v. PTZ threshold test and the spontaneous locomotor activity test was used to assess the possible sedative effects. The X-ray analysis of three compounds has suggested that certain analogies might be drawn between interactions in crystal packing and biological interactions, which are responsible for their anticonvulsant activity. Only the value of the torsion angle of the phenyl ring in 3-n-propyl-5-ethyl-5-phenylhydantoin is in the range, which is characteristic for the most active hydantoin derivatives, and it exerts anticonvulsant activity comparable to phenytoin with lower liability for the induction of sedation in rats. The antiproliferative effects of a series of eleven 3-substituted-5,5-diphenylhydantoins, including some whose anticonvulsant activities have already been reported in the literature, against HCT–116 human colon carcinoma cells have been evaluated. It has been found that the introduction of a substituent at position 3 produces a trend of changes in the antiproliferative potencies of compounds analogous to that in their anticonvulsant activities. Moreover, their antibacterial activities in vitro against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and clinical isolates of Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus aureus have been evaluated. Only the 3-isopropyl and 3-benzyl derivatives show weak antibacterial activities against the Gram-positive bacterium E. faecalis and the Gram-negative bacteria E. coli ATCC 25922 and E. coli

Supplementary data for the article: Marković, J. M.; Trišović, N. P.; Tóth-Katona, T.; Milčić, M. K.; Marinković, A. D.; Zhang, C.; Jákli, A. J.; Fodor-Csorba, K. A Structure-Property Relationship Study of Bent-Core Mesogens with Pyridine as the Central Unit. New Journal of Chemistry 2014, 38 (4), 1751–1760. https://doi.org/10.1039/c3nj01430d

Supplementary material for: [https://doi.org/10.1039/c3nj01430d]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1518

Supplementary data for the article: Marković, J. M.; Trišović, N. P.; Tóth-Katona, T.; Milčić, M. K.; Marinković, A. D.; Zhang, C.; Jákli, A. J.; Fodor-Csorba, K. A Structure-Property Relationship Study of Bent-Core Mesogens with Pyridine as the Central Unit. New Journal of Chemistry 2014, 38 (4), 1751–1760. https://doi.org/10.1039/c3nj01430d

Supplementary material for: [https://doi.org/10.1039/c3nj01430d]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1518

Sinteza i karakterizacija 1-(4-supstituisanih benzil)-3’,4’-dihidro-2’H-spiro[imidazolidin-4,1’-naftalen]-2,5-diona potencijalnih antikonvulzivnih agenasa

Among the diverse pharmacological activity reported for spirohydantoin and the closely related spirosuccinimides, their anticonvulsant and antiproliferative activities are commonly encountered. Of all cyclic ureide derivatives, Phenytoin (5,5-diphenylhydantoin) is one of the well-known commercially available anticonvulsants, which is also widely used as an antiarrhythmic agent. However, the clinical use of 5,5-diphenylhydantoin is limited by its central nervous adverse effects in addition to a wide variety of drug interactions [1]. With the aim of developing new analogs with a more efficient therapeutic effect, a series of 1-(4-substitutedbenzyl)-3’,4’-dihydro-2’H-spiro[imidazolidine-4,1’-naphtalene]-2,5-diones, have been synthesized, characterized by melting points, FT-IR, 1H and 13C NMR spectroscopic techniques, and evaluated for anticonvulsant activity. The objective of the present investigation is to identify the pharmacological impact of the spirocyclic attachment of a semi-rigid tetralin residue at C-5 of the imidazolidine-2,4-dione ring and to explore the effect of substitution at N-3 on anticonvulsant activity

Supramolecular architectures of selected xanthenedione derivatives

The wide range of pharmacological activities (e.g. antiviral, antifungal, antibacterical, antiinflamatory, leishmanicidal and antidepresant) has already been attributed to the xanthenediones, a group of synthetic heterocyclic compounds possessing a pyran nucleus fused on either side with cyclohex-2-enone rings [1]. In this work, two 3,3,6,6- tetramethyl-9-substituted-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-diones (Figure 1) were synthesized and their crystal stuctures were determined by single crystal X-ray diffraction. The main structural feature in compound 1 is a supramolecular chain along the a-axis formed by O4–H4···O2 hydrogen bond and C13–H13···O4 and Br1···Br2 interactions between the adjacent asymmetric units, while the formation of supramolecular network is further achieved by C–H···π interactions between the adjacent chains. The main motif in 2 is a dimer formed via O4–H4···O2 hydrogen bond and Cl1···π interactions. The neighbouring dimers are connected through strong C7– H7A···π interactions, thus resulting in formation of a zigzag chain parallel to the c-axis. Weak C–H···π interactions link the adjacent chains into a supramolecular layer. This work may provide a basis for design of new biologically active xanthenediones both at the molecular and supramolecular level

Substituent and solvent effects on intramolecular charge transfer of 5-arylidene-2,4-thiazolidinediones

The absorption spectra of twelve 5-arylidene-2,4-thiazolidinediones were recorded in twenty one solvents in the range from 300 to 600 nm. The effect of specific and non-specific solvent-solute interactions on the absorption maxima shifts were evaluated by using the Catalan solvent parameter set. Furthermore, the experimental findings were interpreted with the aid of ab initio MP2 and time-dependent density functional (TD-DFT) methods. It was found that different substituents significantly change the extent of conjugation in the molecules and further affect their intramolecular charge transfer character. (C) 2011 Elsevier B.V. All rights reserved

Experimental and theoretical study of substituent effect on C-13 NMR chemical shifts of 5-arylidene-2,4-thiazolidinediones

The electronic structure of 5-arylidene-2,4-thiazolidinediones has been studied by using experimental and theoretical methodology. The theoretical calculations of the investigated 5-arylidene-2,4-thiazolidinediones have been performed by the use of quantum chemical methods. The calculated C-13 NMR chemical shifts and NBO atomic charges provide an insight into the influence of such a structure on the transmission of electronic substituent effects. Linear free energy relationships (LFERs) have been further applied to their C-13 NMR chemical shifts. The correlation analyses for the substituent-induced chemical shifts (SCS) have been performed with sigma using SSP (single substituent parameter), field (sigma(F)) and resonance (sigma(R)) parameters using DSP (dual substituent parameter), as well as the Yukawa-Tsuno model. The presented correlations account satisfactorily for the polar and resonance substituent effects operative at C-beta. and C-7 carbons, while reverse substituent effect was found for C-alpha. The comparison of correlation results for the investigated molecules with those obtained for seven structurally related styrene series has indicated that specific cross-interaction of phenyl substituent and groups attached at C-alpha carbon causes increased sensitivity of SCS C-beta to the resonance effect with increasing of electron-accepting capabilities of the group present at C-beta

Oxaprozin: Synthesis, SAR study, physico-chemical characteristics and pharmacology

Oxaprozin (3-(4,5-difeniloksazol-2-yl)propanoic acid) is a nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of numerous inflammatory musculoskeletal diseases, including rheumatoid arthritis, osteoarthritis, tendonitis, ankylosing spondylitis and bursitis. It is the first representative member of the diaryl-substituted heterocyclic compounds, which have found clinical use as selective cyclooxygenase-2 (COX-2) inhibitors. U.S. Food and Drug Administration (FDA) approved its official use in 1992. Both anti-inflammatory and analgesic properties of oxaprozin are mainly due to the potent inhibition of COX. However, oxaprozin-induced benefits might be also regulated by other COX-independent pathways. It has been shown that oxaprozin induced direct proapoptotic effects in CD40L-treated human monocytes independently of COX inhibition. It also has several advantages in the treatment of inflammatory diseases in comparison to other NSAIDs such as aspirin, naproxen, indomethacin and phenylbutazone, which enabled oxaprozin to become one of the most used NSAIDs in America. Oxaprozin, as other members of the group of NSAIDs, can cause gastrointestinal complications, but significantly lower due to relatively high pKa value. In this paper, importance of oxaprozin in the treatment of arthritis and its pharmacokinetic properties were described, therewith its activity and side effects were compared with other commercially available anti-inflammatory drugs

Introducing the azocinnamic acid scaffold into bent-core liquid crystal design: A structure–property relationship study

A series of bent-core liquid crystals possessing the azocinnamoyl unit in both elongating side arms was synthesized. The chain length was kept fixed for each molecule (C12H25), whereas the substituents at the central and outer rings were varied. The LC phases were assigned by polarizing optical microscopy, differential scanning calorimetry and X-ray diffraction. The investigated compounds are suitably diverse to reveal some aspects of the relationship between molecular structure and the mesomorphic properties. Namely, non-substituted parent compound is crystalline only and the methyl group in position 2 or the chlorine atom in position 4 of the central ring suppresses LC phase formation. Introduction of the strong electron-withdrawing nitro group between the side arms on the central ring leads to a B7 phase. Compounds possessing a bromine atom or two chlorine atoms in the neighbourhood of the ester groups form LC phases typical for rod-like molecules, namely a nematic – smectic phase sequence. The results are compared with those reported for the azobenzoyl analogues

Solvent effects on the absorption spectra of potentially pharmacologically active 5-alkyl-5-arylhydantoins: A structure-property relationship study

To obtain an insight into the interactions of potential anticonvulsant drugs with their surrounding, two series of 5-methyl-5-aryl- and 5-ethyl-5-arylhydantoins were synthesized and their absorption spectra were recorded in the region from 200 to 400 nm in a set of selected solvents. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions on the absorption maxima shifts were analyzed by means of the linear solvation energy relationship (LSER) concept of Kamlet and Taft. The ratio of the contributions of specific and nonspecific solvent-solute interactions were correlated with the corresponding ADME properties of the studied compounds. The correlation equations were combined with different physicochemical parameters to generate new equations, which demonstrate the reasonable relationships between solvent-solute interactions and the structure-activity parameters. [Projekat Ministarstva nauke Republike Srbije, br. 172013