Synthesis, characterization and biological activity of carbamide, semicarbazide, carbazide and ester derivatives of amino acids and nonsteroidal antiinflammatory drugs

U okviru ovog doktorskog rada, koji je nastavak istraživanja o mogućnostima korištenja benzotriazola u sintetskoj kemiji na Zavodu za Farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta u Zagrebu, sintetizirano je nekoliko serija spojeva. Polazni spoj u sintezi svih prekursora bio je klorid 1- benzotriazolkarboksilne kiseline (BtcCl) koji daje vrlo reaktivne derivate. BtcCl vrlo lako reagira s nukleofilima dajući cijeli niz reaktivnih spojeva iz kojih je do sada pripravljen velik broj organskih spojeva. Derivati aminokiselina ureidoamidi 4a-o pripravljeni su reakcijom klorida N-(1-benzotriazolkarbonil)aminokiselina 3 i odgovarajućih aminoalkohola, a N- i O- supstituirane hidroksiuree 6a-l iz amida N-(1- benzotriazolkarbonil)aminokiselina i odgovarajućih hidroksilamina. Derivati nesteroidnih protuupalnih lijekova (NSAID, ibuprofena, fenoprofena i ketoprofena) sintetizirani su iz NSAID hidrazida 11 koji su dobiveni aminolizom NSAID benzotriazolida 10 i hidrazina. Hidrazidi 11 su u reakciji s 1-karbamoilbenzotriazolima (aktivne uree, 7) dali 1-acilsemikarbazidne derivate NSAID 13a-v, a u reakciji s 1-(1-benzotriazolkarbonil)-4- benziloksisemikarbazidom (9) 1-acil-5-benziloksikarbamoilkarbazide 14a-c. Reakcije u talini uz TEA bitno su skratile vrijeme reakcije. 4-Hidroksisemikarbazidni derivati NSAID 13w-y i 14d-f pripravljeni su katalitičkim hidrogeniranjem O-benzilnih derivata 13t-v i 14a-c uz Pd/C. Iz benzotriazolida ketoprofena (10d) i odgovarajućih ureidoamida (4b,i,j,m) pripravljeni su esteri s dvije molekule ketoprofena kovalentno povezane ureidoamidima u jednu molekulu („dvojni lijekovi“). Svi sintetizirani spojevi karakterizirani su uobičajenim analitičkim postupcima i spektroskopskim metodama te biološki ispitani in vitro na citostatsko, antivirusno, antimikrobno i antioksidativno djelovanje. Nadalje, ispitana je inhibicija lipooksigenaze i lipidne perkosidacije. Najbolje antitumorsko djelovanje pokazao je spoj 6l, antivirusno 13a,g,m, a antiooksidativno spoj 9. Najjači inhibitor lipooksigenaze bio je spoj 13s, a lipidne peroksidacije 13c,l,t. Uočeno je ponavljanje benzhidrilnog supstituenta u spojevima s istaknutom aktivnosti, što je dobar pokazatelj za daljnje usmjeravanje istraživanja.The research described in the thesis is a continuation of the previous work on the use of benzotriazole in the synthetic chemistry which has been carring out at Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry in Zagreb for many years. The thesis includes synthesis of several types of compounds. The initial compound for the synthesis of all the intermediates was benzotriazole carboxylic acid chloride (BtcCl), which upon the reaction with nucleophiles gives reactive products, useful in the preparation of various organic compounds. Amino acid derivatives ureidoamides 4a-o were syntehsized by aminolysis of N-(1- benzotriazolecarbonyl)amino acid chlorides 3 with corresponding aminoalcohols and N- i O- substituted hydroxyureas 6a-l were synthesizes from N-(1-benzotriazolecarbonyl)amino acid amides 5 and hydroxylamines. Nonsteroidal antiinflammatory drugs (NSAID, ibuprofen, fenoprofen and ketoprofen) derivatives were prepared from NSAID hydrazides 11 which were obtained by aminolysis of NSAID benzotriazolides 10 and hydrazine hydrate. The reaction of hydrazides 11 and 1-benzotriazole carboxylic acid amides 7 gave 1-acylsemicarbazides 13a-v, while with 1-(1-benzotriazolecarbonyl)-4-benzyloxysemicarbazide (9) gave 1-acyl-5- benzyloxycarbamoyl-carbazides 14a-c. Reactions in melted state in the presence of TEA significantly reduced the reaction time. 4-Hydroxysemicarbazide compounds 13w-y and 14d-f were prepared by catalytic hydrogenation of O-benzylated compounds 13t-v i 14a-c with Pd/C. Ketoprofen benzotriazolide (10d) reacted with several ureidoamides (4b,i,j,m) and gave esters with two molecules of ketoprofen combined covalently in one („twin drugs“). The compounds were evaluated for their biological activity in vitro: antitumor, antimicrobial, antiviral and antioxidant activity, inhibition of lipoxygenase and linoleic acid lipid peroxidation. The best antitumor activity was exerted by 6l, antiviral by 13a,g,m, antioxidant by compound 9. The strongest inhibitor of lipoxygenase was 13s. Compounds 13c,l,t showed the highest inhibition of linoleic acid lipid peroxidation. It is worth to note that compounds with the highest biological activity contained benzhydryl substituent

Synthesis, characterization and biological activity of carbamide, semicarbazide, carbazide and ester derivatives of amino acids and nonsteroidal antiinflammatory drugs

U okviru ovog doktorskog rada, koji je nastavak istraživanja o mogućnostima korištenja benzotriazola u sintetskoj kemiji na Zavodu za Farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta u Zagrebu, sintetizirano je nekoliko serija spojeva. Polazni spoj u sintezi svih prekursora bio je klorid 1- benzotriazolkarboksilne kiseline (BtcCl) koji daje vrlo reaktivne derivate. BtcCl vrlo lako reagira s nukleofilima dajući cijeli niz reaktivnih spojeva iz kojih je do sada pripravljen velik broj organskih spojeva. Derivati aminokiselina ureidoamidi 4a-o pripravljeni su reakcijom klorida N-(1-benzotriazolkarbonil)aminokiselina 3 i odgovarajućih aminoalkohola, a N- i O- supstituirane hidroksiuree 6a-l iz amida N-(1- benzotriazolkarbonil)aminokiselina i odgovarajućih hidroksilamina. Derivati nesteroidnih protuupalnih lijekova (NSAID, ibuprofena, fenoprofena i ketoprofena) sintetizirani su iz NSAID hidrazida 11 koji su dobiveni aminolizom NSAID benzotriazolida 10 i hidrazina. Hidrazidi 11 su u reakciji s 1-karbamoilbenzotriazolima (aktivne uree, 7) dali 1-acilsemikarbazidne derivate NSAID 13a-v, a u reakciji s 1-(1-benzotriazolkarbonil)-4- benziloksisemikarbazidom (9) 1-acil-5-benziloksikarbamoilkarbazide 14a-c. Reakcije u talini uz TEA bitno su skratile vrijeme reakcije. 4-Hidroksisemikarbazidni derivati NSAID 13w-y i 14d-f pripravljeni su katalitičkim hidrogeniranjem O-benzilnih derivata 13t-v i 14a-c uz Pd/C. Iz benzotriazolida ketoprofena (10d) i odgovarajućih ureidoamida (4b,i,j,m) pripravljeni su esteri s dvije molekule ketoprofena kovalentno povezane ureidoamidima u jednu molekulu („dvojni lijekovi“). Svi sintetizirani spojevi karakterizirani su uobičajenim analitičkim postupcima i spektroskopskim metodama te biološki ispitani in vitro na citostatsko, antivirusno, antimikrobno i antioksidativno djelovanje. Nadalje, ispitana je inhibicija lipooksigenaze i lipidne perkosidacije. Najbolje antitumorsko djelovanje pokazao je spoj 6l, antivirusno 13a,g,m, a antiooksidativno spoj 9. Najjači inhibitor lipooksigenaze bio je spoj 13s, a lipidne peroksidacije 13c,l,t. Uočeno je ponavljanje benzhidrilnog supstituenta u spojevima s istaknutom aktivnosti, što je dobar pokazatelj za daljnje usmjeravanje istraživanja.The research described in the thesis is a continuation of the previous work on the use of benzotriazole in the synthetic chemistry which has been carring out at Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry in Zagreb for many years. The thesis includes synthesis of several types of compounds. The initial compound for the synthesis of all the intermediates was benzotriazole carboxylic acid chloride (BtcCl), which upon the reaction with nucleophiles gives reactive products, useful in the preparation of various organic compounds. Amino acid derivatives ureidoamides 4a-o were syntehsized by aminolysis of N-(1- benzotriazolecarbonyl)amino acid chlorides 3 with corresponding aminoalcohols and N- i O- substituted hydroxyureas 6a-l were synthesizes from N-(1-benzotriazolecarbonyl)amino acid amides 5 and hydroxylamines. Nonsteroidal antiinflammatory drugs (NSAID, ibuprofen, fenoprofen and ketoprofen) derivatives were prepared from NSAID hydrazides 11 which were obtained by aminolysis of NSAID benzotriazolides 10 and hydrazine hydrate. The reaction of hydrazides 11 and 1-benzotriazole carboxylic acid amides 7 gave 1-acylsemicarbazides 13a-v, while with 1-(1-benzotriazolecarbonyl)-4-benzyloxysemicarbazide (9) gave 1-acyl-5- benzyloxycarbamoyl-carbazides 14a-c. Reactions in melted state in the presence of TEA significantly reduced the reaction time. 4-Hydroxysemicarbazide compounds 13w-y and 14d-f were prepared by catalytic hydrogenation of O-benzylated compounds 13t-v i 14a-c with Pd/C. Ketoprofen benzotriazolide (10d) reacted with several ureidoamides (4b,i,j,m) and gave esters with two molecules of ketoprofen combined covalently in one („twin drugs“). The compounds were evaluated for their biological activity in vitro: antitumor, antimicrobial, antiviral and antioxidant activity, inhibition of lipoxygenase and linoleic acid lipid peroxidation. The best antitumor activity was exerted by 6l, antiviral by 13a,g,m, antioxidant by compound 9. The strongest inhibitor of lipoxygenase was 13s. Compounds 13c,l,t showed the highest inhibition of linoleic acid lipid peroxidation. It is worth to note that compounds with the highest biological activity contained benzhydryl substituent

Computational Research of Music Criticism between 1878 and 1941 in Serbian

The article deals with the critical writing on music in the digitized newspapers in the Svetozar Marković University Library in Belgrade. The multidisciplinary research aims to connect the quantitative and qualitative analysis of the musical critics in Serbian in the period between 1878 and 1941, and to explore how to combine both the computational and traditional musicological approaches

Istraživanje roditeljske percepcije digitalne tehnologije kod djece predškolske dobi u dvije točke mjerenja

To get a better understanding of the parental perception of digital devices used by preschool children in Croatia, as well as their expectations and mediation strategies, we report the findings from a qualitative study with two measurement points. At the first point, five families with children aged 6 to 7 were interviewed at their homes, where they provided information on how their children engage with new technologies, how such technologies are perceived by different family members and how parents manage their children’s use of digital technology. A year and a half later, the same families were interviewed again, in a similar manner, focusing on the changes which happened in that period, as reported by the parents. Results show that parents find digital technology important and beneficial for children’s cognitive and emotional development, but they fear possible negative consequences of its use. Most often, they use restrictive mediation. A year and a half later, parents also express the need for more educational support when it comes to mediating their children’s interaction with digital technology.Kako bismo istražili kakva je percepcija digitalne tehnologije od strane roditelja predškolske djece u Hrvatskoj, kakva je roditeljska medijacija dječjih interakcija s digitalnim uređajima, proveli smo kvalitativno istraživanje s dva mjerenja. U prvom istraživanju provedeno je pet dubinskih intervjua s petero roditelja i njihove djece u dobi od 6 i 7 godina na temu upotrebe digitalne tehnologije. U ponovljenom istraživanju, godinu i pol dana kasnije, dubinskim intervjuima s istih pet obitelji, ispitali smo je li i u kojoj mjeri došlo do promjena u navedenim varijablama. Rezultati pokazuju kako roditelji digitalne medije često smatraju važnim za kognitivni i emocionalni razvoj djece, no istovremeno se pribojavaju mogućih negativnih posljedica njihova korištenja. Najčešće primjenjuju restriktivne oblike medijacije. Godinu i pol dana kasnije roditelji sve jasnije ističu kako im je potrebna potpora i daljnja edukacija o tome kako moderirati dječje interakcije s digitalnom tehnologijom

NON-MELANOMA SKIN CARCINOMAS OF THE HEAD AND NECK

Background: The aim of this study was to evaluate the incidence and clinical features of non-melanoma tumors of the head and neck, as well as the validity of surgical therapy in their treatment. Subjects and methods: The study included 530 patients who were operated in the Otorhinolaryngology department of the Livno County Hospital. Results: In 295 cases (65.1%), it was basal cell carcinoma of the skin and was followed by squamous cell carcinoma of the skin, in 119 cases (29.9%) while the remaining 5% of cases referred to other non-melanoma skin carcinomas. Statistically significant, the most common non-melanoma skin carcinoma was basal cell carcinoma (hi-kvadrat =625,67; df=4; p<0,01). The most co mmon localization was the skin of the nose (24,2%), which proved to be statistically significant (hi-kvadrat =290,824; df=5; p=0,00). All patient underwent classic surgery, and in 358 cases (89.5%) the tumor was completely removed, while in 40 cases (10.5%) the tumor was partially removed which proved to be statisticaly significant (hi-kvadrat =254,08; df=1; p=0,00). Conclusions: The results of the study fully confirm the assertion that classical surgery is the method of choice in the treatment of non-melanoma skin cancers and in the vast majority it is proven to be sufficient

NON-MELANOMA SKIN CARCINOMAS OF THE HEAD AND NECK

Background: The aim of this study was to evaluate the incidence and clinical features of non-melanoma tumors of the head and neck, as well as the validity of surgical therapy in their treatment. Subjects and methods: The study included 530 patients who were operated in the Otorhinolaryngology department of the Livno County Hospital. Results: In 295 cases (65.1%), it was basal cell carcinoma of the skin and was followed by squamous cell carcinoma of the skin, in 119 cases (29.9%) while the remaining 5% of cases referred to other non-melanoma skin carcinomas. Statistically significant, the most common non-melanoma skin carcinoma was basal cell carcinoma (hi-kvadrat =625,67; df=4; p<0,01). The most co mmon localization was the skin of the nose (24,2%), which proved to be statistically significant (hi-kvadrat =290,824; df=5; p=0,00). All patient underwent classic surgery, and in 358 cases (89.5%) the tumor was completely removed, while in 40 cases (10.5%) the tumor was partially removed which proved to be statisticaly significant (hi-kvadrat =254,08; df=1; p=0,00). Conclusions: The results of the study fully confirm the assertion that classical surgery is the method of choice in the treatment of non-melanoma skin cancers and in the vast majority it is proven to be sufficient

Stavovi učitelja prema darovitim učenicima i razlike u stavovima s obzirom na staž

Attitudes help us understand teachers’ relationship towards gifted students and they influence teachers’ practice, which can eventually determine the development of the gifted. The aim of this study was to examine the teachers\u27 attitudes towards gifted students and some forms of work with gifted children in school, such as acceleration and ability grouping; as well as to determine whether teachers differ in their attitudes depending on the years of experience. The study was conducted on a sample of 209 class teachers in the area of Brod-Posavina county. The results showed that primary school teachers have positive attitudes towards the needs, support and social value of gifted students but express ambivalent attitudes towards the acceleration, ability grouping and concern that the special treatment of the gifted could have negative consequences. Statistically significant differences were established for certain statements among teachers depending on their years of teaching.Stavovi nam pomažu u razumijevanju odnosa učitelja prema darovitim učenicima te utječu na njihovu nastavnu praksu, što u konačnici može odrediti njihov razvoj. Cilj je ovog istraživanja bio ispitati stavove učitelja razredne nastave prema darovitim učenicima i nekim oblicima rada s darovitima u školi poput akceleracije i grupiranja prema sposobnostima, te utvrditi razlikuju li se učitelji u svojim stavovima s obzirom na godine radnog staža. Istraživanje je provedeno na uzorku od 209 učitelja razredne nastave s područja Brodsko-posavske županije. Rezultati su pokazali da učitelji imaju pozitivne stavove prema potrebama, podršci i društvenoj vrijednosti darovitih, no iskazuju neutralne stavove prema akceleraciji, grupiranju prema sposobnostima i bojazni da bi poseban tretman darovitih mogao imati negativne posljedice. Utvrđene su statistički značajne razlike na pojedinim tvrdnjama između učitelja s najmanje radnog staža u odnosu na starije kolege

TEACHERS’ ASSESSMENTS TOWARD OUT-OF-CLASSROOM RESEARCH TEACHING IN NATURAL AND SOCIAL SCIENCES

Izvanučionička istraživačka nastava temelji se na učenju otkrivanjem, u neposrednoj stvarnosti, ostvarivanju iskustvenog učenja koje vodi do trajnog znanja, rasterećenju učenika te interdisciplinarnom pristupu sadržajima nastave. Takvo poučavanje podrazumijeva uporabu primarnih izvora znanja, poticanje promatranja, samostalna istraživanja, zaključivanje te praktično djelovanje učenika u neposrednoj stvarnosti. Planiranje i provođenje izvanučioničke istraživačke nastave zahtijeva veliki angažman učitelja stoga nas je zanimalo provode li učitelji takvu nastavu i koliko često. Cilj je provedenog istraživanja bio ispitati samoprocjenu učitelja o kompetencijama i motivaciji za planiranje i provođenje izvanučioničke istraživačke nastave, učestalost provođenja te prednosti i nedostatke iste. U istraživanju je sudjelovalo 146 učitelja voditelja županijskih vijeća s područja cijele Republike Hrvatske. Rezultati su ukazali da učitelji visoko procjenjuju svoje kompetencije planiranja i provođenja ovakve nastave te da su svjesni njezinih prednosti i nedostataka.Teaching using out-of-classroom research is based on learning through discovery in the immediate reality, and on the achievement of experiential learning that results in permanent knowledge, disburdening of students and in a interdisciplinary approach to teaching contents. Student oriented teaching is a basic element of the educational and teaching process and it implies the use of primary knowledge sources and the need to encourage observation, independent research, reaching autonomous conclusions as well as students’ practical work in the immediate reality. The planning and implementation of out-of-classroom research teaching requires much effort from the teachers. That is why we were interested in teachers’ attitudes toward it. The goal of the implemented research was to inquire into teachers’ attitudes toward competencies and motivation needed for planning and implementing out-of-classroom research teaching, but also how frequently it is implemented and what are its advantages and disadvantages. 146 teachers, heads of county boards, from the whole country participated in the research. The results have shown that teachers highly assess their competencies in planning and implementing such a teaching form and that they are well aware of its advantages and disadvantages