Derivatives of nonsteroidal anti-inflammatory drugs and amino acids - synthesis, characterization and biological activity

Sintetizirana je serija novih strukturnih analoga 3,5-disupstituiranih hidantoina 5a-h s lipofilnim supstituentima na C-5, N-3 ili na oba atoma intramolekulskom ciklizacijom amida N-(1-benzotriazolkarbonil)aminokiselina 4a-h. Sintetizirani su derivati NSAID 6–12: reducirani derivati ketoprofena 6a,b, NSAID benzotriazolidi 7a-h, NSAID hidroksamske kiseline i njihovi derivati 8a-y, derivati ketoprofena 9a-i, 10a-f, 11a-f i 3-hidroksipropilamidi NSAID 12a-e. Reducirani derivati ketoprofena 6 pripravljeni su katalitičkim hidrogeniranjem ketoprofena uz Pd/C ili Pd/C(en). NSAID s karboksilnom funkcionalnom (ibuprofen, fenoprofen, diklofenak, indometacin, ketoprofen, 6a,b) u reakciji s kloridom 1-benzotriazol-karboksilne kiseline (1) dali su odgovarajuće NSAID benzotriazolide 7, koji su bili polazni spojevi u sintezi derivata NSAID 8–12. Razvijena je nova sintetska metoda za pripravu NSAID hidroksamskih kiselina i derivata 8, reakcijom NSAID benzotriazolida 7 i odgovarajućih hidroksilamina (hidroksilamin, N-metilhidroksilamin, O-metilhidroksilamin, O-etilhidroksilamin i O-benzilhidroksilamin) ili katalitičkim hidrogeniranjem O-benzilnih derivata NSAID hidroksamskih kiselina. Derivati ketoprofena 9, 10 i 3-hidroksipropilamidi NSAID 12 sintetizirani su iz NSAID benzotriazolida 7 i odgovarajućih amina, dok su derivati ketoprofena 11 sintetizirani katalitičkim hidrogeniranjem amida ketoprofena 10 uz Pd/C(en). Provedena su sljedeća biološka ispitivanja: antitumorsko, antimikrobno, antivirusno i antioksidacijsko djelovanje, inhibicija ureaze, lipooksigenaze i lipidne peroksidacije. Najbolje antitumorsko djelovanje pokazao je 8c, najbolje antimikrobno 8b,d, najbolje antivirusno 5a i 8y, a najbolje antioksidacijsko djelovanje 8o. Najjači inhibitor ureaze bio je 8f, a lipooksigenaze 11f. Najbolji inhibitor lipidne peroksidacije bio je 9e.3,5-Disubstituted hydantoin derivatives 5a-h with lipophilic substituents at C-5, N-3 or both atoms were prepared by the intramolecular cyclization of the corresponding N-(1-benzotriazolecarbonyl)amino acid amides 4a-h. The following NSAID derivatives 6–12 were prepared: the reduced ketoprofen derivatives 6a,b, NSAID benzotriazolides 7a-h, NSAID hydroxamic acids and their derivatives 8a-y, ketoprofen derivatives 9a-i, 10a-f, 11a-f and NSAID 3-hydroxypropylamides 12a-e. The reduced ketoprofen derivatives 6 were prepared by the catalytic hydrogenation of ketoprofen with Pd/C or Pd/C(en) catalyst. NSAIDs bearing carboxylic group (ibuprofen, fenoprofen, diclofenac, indomethacin, ketoprofen, 6a,b) reacted with 1-benzotriazole carboxylic acid chloride (1) affording benzotriazolides 7, which were the starting compounds in the synthesis of NSAID derivatives 8–12. A new synthetic method for the synthesis of NSAID hydroxamic acids and their derivatives was developed. They were obtained in the reaction of NSAID benzotriazolides 7 with an appropriate hydroxylamine (hydroxylamine, N-methylhydroxylamine, O-methylhydroxylamine, O-ethylhydroxylamine or O-benzylhydroxylamine) or by the catalytic hydrogenation of O-benzyl derivatives of NSAID hydroxamic acids. Ketoprofen derivatives 9, 10 and NSAID 3-hydroxypropylamides 12 were prepared from NSAID benzotriazolides 7, in the reaction with an appropriate amine, while compounds of the series 11 were obtained by the catalytic hydrogenation of ketoprofen amides 10 with Pd/C(en). The compounds were evaluated for their biological activity: antitumor, antimicrobial, antiviral and antioxidant activity, inhibition of urease, lipoxygenase and linoleic acid lipid peroxidation. The best antitumor activity was exerted by 8c, antimicrobial by 8b,d, antiviral by 5a and 8y, and antioxidant by 8o. The strongest inhibitor of urease was 8f, while 11f was the strongest inhibitor of lipoxygenase. Compoung 9e showed the highest inhibition of linoleic acid lipid peroxidation

Identical and Nonidentical Twin Drugs

Dvojni lijekovi su lijekovi koji sadrže dvije farmakoforne skupine povezane kovalentnom vezom u jednu molekulu. Farmakoforne skupine mogu biti jednake (dvojni lijekovi s identičnim podjedinicama) ili različite (dvojni lijekovi s neidentičnim podjedinicama). Identični dvojni lijekovi mogu djelovati na receptore (receptori biogenih amina, peptidni receptori, Ca2+ kanali, σ-receptori u mozgu, leukotrienski B4-receptori), inhibirati razlieite enzime (enzimi HIV-a, protein-kinaze, prolil-hidrolaza, acil-CoA kolesterol aciltransferaza, spermidin-spermin-N1-acetiltransferaza, S-adenozilmetionin dekarboksilaza), te kao ligandi DNA. Neidentični dvojni lijekovi mogu djelovati na dva različita receptora, dva vezna mjesta na jednom receptoru, dva enzima ili na receptor i enzim.Twin drugs contain two pharmacophoric groups combined covalently in a single molecule. Pharmacophoric groups can be identical moieties (identical twin drugs) or different (nonidentical twin drugs). Identical twin drugs can act on receptors (biogenic amine receptors, peptide receptors, Ca2+ channel, σ receptors in the brain, leukotriene B4 receptors), as enzyme inhibitors (HIVenzyme, protein kinase, prolyl hydrolase, acyl-CoA cholesterol acyl transferase, spermidine- spermine-N1-acetyltransferase, S-adenosylmethionine decarboxylase), and as DNA ligands. Nonidentical twin drugs exert their dual action on two different receptors, on two binding sites of a single receptor, on two enzymes, or on both a receptor and an enzyme

Makromolekulski prolijekovi. XII. Konjugati primakina: Sinteza i preliminarno ispitivanje antimalarijskog djelovanja

New primaquine conjugates 5-7 with glucosamine and two polymers of polyaspartamide type, poly/a,b-(N-2-hydroxyethyl-DL-aspartamide)/ (PHEA) and poly/a,b-(N-3-hydroxypropyl-DL-aspartamide)/ (PHPA), were synthesized, characterized and screened for their antimalarial activity. The conjugates differed in type of covalent bounding, length of spacer between the polymeric carrier and drug, molecular mass and drug-loading. Blood-schizontocidal activity of the prepared conjugates was tested against Plasmodium berghei infection in Swiss mice. The polymeric conjugates showed better antimalarial activity than glucosamine conjugate.U radu je opisana sinteza, karakterizacija i ispitivanje antimalarijskog djelovanja novih konjugata primakina 5-7 s glukozaminom i dva polimera poliaspartamidnog tipa, poli/a,b-(N-2-hidroksietil-DL-aspartamidom)/ (PHEA) i poli/a,b-(N-3-hidroksipropil-DL-aspartamidom)/ (PHPA). Konjugati su se razlikovali u vrsti kovalentne veze, duljini razmaknice između polimernog nosača i ljekovite tvari, molekulskoj masi i količini vezanog lijeka. Šizontocidno djelovanje pripravljenih konjugata ispitano je na miševima inficiranim Plasmodium berghei. Polimerni konjugati pokazali su jače antimalarijsko djelovanje nego konjugat s glukozamino

Chapter House of the Franciscan Monastery in Pula Archaeological and Anthropological Studies

Kapitularna dvorana crkve i samostana sv. Franje u Puli najpoznatija je po rimskom mozaiku datiranom u 2.-3. st. poslije Krista, a pronađenom u istraživanju 1963. godine. Od 2011. do 2014. godine arheološki se istraživala cijela dvorana, osim dijela s mozaikom, koji zauzima skoro četvrtinu prostorije. Tijekom istraživanja ispod recentnog su poda pronađeni mnogobrojni ostaci pokojnika, koji su bili položeni na antičku arhitekturu.The chapter house of the church and monastery of St. Francis in Pula is most known for the Roman mosaic dated to the 2nd-3rd century AD, discovered during excavations in 1963. From 2011 to 2014 the entire chapter house was investigated archaeologically, except the part with the mosaic covering almost a quarter of the area. During this investigation, below the recent floor numerous remains of deceased, situated on the remains of Antique architecture, were discovered

A Case of Childhood Tuberculosis from the Site of St. Martin`s Square in Umag

U radu je opisan slučaj tuberkuloze na kosturu djeteta starosti 10 do 12 godina s arheološkog nalazišta na Trgu sv. Martina u Umagu. Na kosturu su uočene patološke promjene karakteristične za tuberkulozu: destruktivne lezije na kralješcima i križnoj kosti te poroznost na dugim i plosnatim kostima. Na kostima glave i lopatici također su vidljive promjene koje mogu nastati kao posljedica skorbuta, odnosno upućuju na nedostatak vitamina C u prehrani.This paper describes a case of tuberculosis in the skeleton of a child aged 10 to 12 years from the archaeological site of St. Martin`s Square in Umag. The remains present pathological changes characteristic of tuberculosis: destructive lesions on the vertebrae and sacrum and porosity on long and flat bones. The cranium and scapula present additional pathological changes suggestive of scurvy, caused by a diet lacking vitamin C

FIVE BURIALS FROM PALAGRUŽA

Prilikom arheoloških iskopavanja nalazišta Salamandrija na Palagruži pronađeno je pet skeletnih grobova. Njihovo datiranje obuhvaća razdoblje od kasne antike do modernog doba. Najvjerojatnije ih se može povezati s povremenim, diskontinuiranim, a ponekad možda i trajnijim, boravkom ljudi koji su se bavili specijaliziranim aktivnostima poput plovidbe, ribarenja, gradnje i ratovanja. U većini slučajeva moglo bi se raditi o ad hoc zbrinjavanju posmrtnih ostataka, prije nego li o pravom formalnom pogrebu. Spomenuti grobovi upotpunjuju saznanja o ljudskoj prisutnosti na otoku i otvaraju nova pitanja o razdobljima za koja do sada na Palagruži nije bilo arheoloških podataka.Archaeological excavations at the Salamandrija site on Palagruža Island yielded five inhumation burials. They date from periods between Late Antiquity and the Modern Age. Most probably, they can be related to occasional, discontinuous, or sometimes perhaps more permanent occupation by people involved in specialized activities such as navigation, fishing, construction work and warfare. In most cases, we may be dealing with ad hoc disposal of human remains, rather than with formal burials. These burials complement what is already known about human presence on the island and open new questions about periods which previously have not been archaeologically attested on Palagruža

Benzotriazole as a Synthetic Auxiliary

Benzotriazole is a very useful synthetic auxiliary with versatile applications in organic chemis¬try. We have used benzotriazole in the synthesis of various heterocyclic compounds (benzoxazine, quinazoline, triazinetrione, hydantoin, oxadiazine and diazepane derivatives), amino acid derivatives, car¬bamates, ureas, semicarbazides, carbazides, sulfonylureas, sulfonylcarbazides, hydantoic acids, non-steroidal antiinflammatory drug (NSAID) and primaquine derivatives, polymer-drug and thiomer-drug conjugates. The results have been published in more than 30 papers and here we give an overview of all syntheses. (doi: 10.5562/cca2124

A convenient synthesis of new NSAID esters containing amino acid, urea and amide moieties

A convenient synthetic method for the preparation of novel NSAID twin esters 6a-i containing amino acid residue, urea and amide moieties has been developed. The synthetic pathway applied for the preparation of target compounds and key intermediates 1-benzotriazolecarboxylic acid chloride (1), NSAID benzotriazolides 2a-c and N-(1-benzotriazolecarbonyl)-amino acids 3a-d involved benzotriazole as a synthetic auxiliary. The final preparation step of esters 6a-i included the solvent-free reaction of compounds 2a-c with amino acid derivatives 5a-g, bearing two hydroxyl groups, one at each terminal, beside urea and amide functionalities

Late Eneolithic and Early Bronze Age graves at the site Osijek–Ciglana and Zeleno polje

na nalazištu Osijek – Ciglana i Zeleno polje 2015. godine pronađeni su ostaci višeslojnog naselja. Izdvaja se nalaz četiriju kosturnih grobova, od kojih se jedan nalazio izdvojeno na sjevernome dijelu istražene površine, a preostala su tri grupirana 260 m južnije. Svi su pokojnici bili pokopani u zgrčenom položaju na boku. S obzirom na činjenicu da u grobovima nisu nađeni prilozi ni dijelovi nošnje pokojnika, kao ni arheološki nalazi u njihovim zapunama, grobovi su datirani na osnovi rezultata radiokarbonskih analiza kostiju pokojnika. Grob smješten na sjevernom dijelu nalazišta (grob 1) datiran je u razdoblje kasnoga bakrenog doba i pripisan kasnoklasičnoj fazi vučedolske kulture. Tri groba evidentirana na južnome dijelu nalazišta (grobovi 2, 3 i 4) datirana su u rano brončano doba. Na temelju radiokarbonskog datuma i elemenata pogrebnog rituala, grobovi su pripisani Kisapostag kulturi. Spomenuti grobovi predstavljaju jedine kasnoeneolitičke i ranobrončanodobne nalaze s lokaliteta, a može se pretpostaviti postojanje istovremenih naselja u blizini. Analiza je ljudskih kosturnih ostataka pokazala da je u grobu 1 pokopana žena starija od 50 godina, u grobovima 2 i 4 muškarci u dobi od 35 do 50 godina, a u grobu 3 dijete u dobi od 10 do 15 godina.During the archaeological excavations at the site Osijek–Ciglana and Zeleno polje in 2015, the remains of a multi-layered settlement were found. Finds of four skeletal graves stand out, with one grave found isolated on the northern part of the excavated area, while the other three were grouped some 260 m to the south. All the bodies were laid in a crouched position on their side. Since no grave goods or parts of garment were registered in the graves and there were no archaeological finds in the grave fill, the graves are dated based on the results of the radiocarbon analysis of the inhumed bones. The grave situated on the northern part of the site (grave 1) is ascribed to the Late Eneolitihic and attributed to the late classical phase of the Vučedol Culture. The three graves recorded on the southern part of the site (graves 2, 3, and 4) were dated to the Early Bronze Age. On the basis of radiocarbon dates and elements of the burial practice, they are attributed to the Kisapostag Culture. The mentioned graves represent the only Late Eneolithic and Early Bronze Age finds from the site, and the existence of concurrent settlements nearby can be assumed. An analysis of human skeletal remains revealed the presence of a female over 50 years of age in grave 1, males 35 to 50 years of age in graves 2 and 4, as well as a juvenile aged 10 to 15 in grave 3