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U ovom radu opisana je sinteza nekoliko klasa derivata benzimidazola i benzotiazola kojima je ispitana antiproliferativna i antioksidativna aktivnost. U linearnoj višestupanjskoj sintezi novih konjugata benzazola primijenjeni su klasični sintetski pristupi kao i neke suvremene sintetske metode, uključujući sintezu u ekološki prihvatljivim otapalima ili sintezu potpomognutu mikrovalovima. Novi akrilonitrilni derivati N-supstituiranih derivata benzazola 32‒71 i 77‒107 priređeni su aldolnom kondenzacijom odgovarajućih cijanometilbenzazola s benzaldehidima supstituirani promjenjivim brojem metoksi i hidroksi skupina te 4-N,N-dimetilamino i 4-N,N-dietilamino skupinom. Derivati Schiffovih baza supstituirani benzimidazolom 117‒132 priređeni su kondenzacijom N-supstituiranih 2-aminobenzimidazola 108‒115 s odgovarajućim 4-N,N-dimetilamino i 4-N,N-dietilamino supstituiranim benzaldehidima. Derivati iminokumarina i kumarina 134‒149 te amidino-supstituirani derivati kumarina 164‒175 priređeni su ciklokondenzacijom različito supstituiranih 2-hidroksibenzaldehida s odgovarajućim 2-cijanometilbenzimidazolima, te iz kumarinskih aldehida reakcijom kondenzacije s odgovarajućim 4-amidino-supstituiranim 1,2-fenilendiaminima uz korištenje p-benzokinona kao oksidansa. Amidino-supstituirani benzimidazoli 193‒216 priređeni su kondenzacijom 5-supstituiranih salicilaldehida s odgovarajućim 4-amidino-supstituiranim 1,2-fenilendiaminima. Amidino-supstituirani benzotiazoli 179‒181 i 216‒227 priređeni su iz različito supstituiranih 2-hidroksibenzaldehida i odgovarajućih zwitter iona u ledenoj octenoj kiselini. Metoksi-supstituirani karboksamidi 235‒262 priređeni su kondenzacijom benzoilnih klorida s N-supstituiranim derivatima 2-aminobenzimidazola. Hidroksi-supstituirani amidni derivati N-benzimidazola 263‒268 i 280‒286 priređeni su uklanjanjem zaštitnih metoksi skupina, korištenjem BBr3 na niskim temperaturama, te benzilnih zaštitnih skupina katalitičkim hidrogeniranjem uz Pd/C u metanolu. Amidino-supstituirani derivati benzamida 289‒293 priređeni su kiselo-kataliziranom Pinnerovom reakcijom iz odgovarajućih cijano-supstituiranih polaznih spojeva. Strukture novosintetiziranih spojeva potvrđene su 1H i 13C NMR spektroskopijom, a nekim je spojevima struktura dodatno okarakterizirana i masenom spektrometrijom. Svim priređenim spojevima ispitana je antiproliferativna aktivnost in vitro na niz staničnih linija humanih karcinoma i zdravih stanica, dok je ispitivanje antioksidativne aktivnosti in vitro provedeno primjenom spektroskopskih metoda DPPH, FRAP i ABTS. Amidino-supstituiranim derivatima 164‒175 i 179‒181 ispitana je antiviralna aktivnost in vitro na nekoliko sojeva virusa, te su neki od derivata pokazali jako dobru i selektivnu aktivnost prema pojedinim sojevima virusa. Derivatima Schiffovih baza 117‒132 te amidino-supstituiranim benzazolima 193‒216 i 217‒228 ispitana je i antibakterijska aktivnost prema Gram pozitivnim i Gram negativnim bakterijama. Iz dobivenih rezultata ispitivanja biološke aktivnosti i SAR studije, utvrđeno je da na antioksidativnu aktivnost značajno utječe broj metoksi i hidroksi skupina na fenilnom prstenu, te supstituent na dušikovom atomu benzimidazolne jezgre. Najizraženiji utjecaj na povećanje antiproliferativne aktivnosti pokazuje 4-N,N-dietilamino skupina smještena na položaju 7 kumarinskog prstena i fenilnom prstenu akrilonitrilnih derivata, te izobutilni supstituent na N atomu benzimidazolne jezgre. Nekima od najaktivnijih derivata benzazola dodatno su ispitani mehanizmi biološkog djelovanja, te je tako utvrđeno da neki derivati akrilonitrila i iminokumarina djeluju kao inhibitori polimerizacije tubulina, dok je amidnim derivatima ispitana i antioksidativna aktivnost u stanicama. Dokazano je i da najbolju antivirusnu aktivnost ima kumarinski derivat benzimidazola supstituiran nesupstituiranim amidinom koji inhibira ranu fazu replikacijskog ciklusa virusa, odnosno sintezu virusne RNK. This thesis describes the synthesis of several classes of benzimidazoles and benzothiazoles in order to investigate their antiproliferative and antioxidant activity. By using multi-step linear synthesis of new benzazole conjugates, classical synthetic approaches as well as some modern synthetic methods, including synthesis in environmentally friendly solvents or microwave-assisted synthesis, were applied. New acrylonitrile derivatives of N-substituted benzazoles 32‒71 and 77‒107 were prepared by aldol condensation of the corresponding cyanomethylbenzazoles with benzaldehydes with a variable number of methoxy and hydroxy groups and 4-N,N-dimethylamino and 4-N,N-diethylamino groups. Benzimidazole derived Schiff bases 117‒132 were prepared by condensation of N-substituted 2-aminobenzimidazoles 108‒115 with corresponding 4-N,N-dimethylamino and 4-N,N-diethylamino-substituted benzaldehydes. Iminocoumarin and coumarine derivatives 134‒149 and amidino-substituted coumarine derivatives 164‒175 obtained by cyclocondensation of substituted 2-hydroxybenzaldehydes with corresponding 2-cyanomethylbenzimidazoles as well as from coumarine aldehydes with corresponding 4-amidino-substituted 1,2-phenylenediamines using p-benzoquinone as an oxidant. Amidino-substituted benzimidazoles 193‒216 were synthesized within the condensation of 5-substituted salicylaldehydes with corresponding 4-amidino-substituted 1,2-phenylenediamines. Amidino-substituted benzothiazoles 179‒181 i 216‒227 were prepared by condensation of differently substituted 2-hydroxybenzaldehydes and corresponding zwitter ions in glacial acetic acid. Methoxy-substituted carboxamides 235‒262 were prepared by condensation of benzoyl chlorides with N-substituted 2-aminobenzimidazole derivatives. Hydroxy-substituted amide derivatives of N-benzimidazole 263‒268 and 280‒286 obtained by removing protective methoxy groups, using BBr3 at low temperatures, and benzyl protective groups by catalytic hydrogenation with Pd/C in methanol. Amidino-substituted benzamide derivatives 289‒293 were synthesized via acid-catalyzed Pinner reaction from the corresponding cyano-substituted starting precursors. Structures of all newly prepared compounds were confirmed by 1H and 13C NMR spectroscopy while some of them were additionally characterized by mass spectrometry. All prepared compounds were tested for their antiproliferative activity in vitro on a number of human cancer cell lines as well as normal fibroblasts, while antioxidant activity in vitro was performed using spectroscopic DPPH, FRAP and ABTS methods. Amidino-substituted derivatives 164‒175 and 179‒181 were tested for antiviral activity in vitro on several virus strains, and some compounds have shown pronounced and selective activity against some viruses. Schiff base derived benzazoles 117‒132 and amidino-substituted benzazoles 193‒216 and 217‒228 were tested for antibacterial activity against Gram positive and Gram negative bacteria. Results obtained from evaluation of biological activity and SAR studies, revealed that the antioxidant activity is affected by the number of methoxy and hydroxy groups on the phenyl ring as well as the substituent on the nitrogen atom of the benzimidazole nucleus. The strongest impact on the enhancement of antiproliferative activity was observed by 4-N,N-diethylamino group placed at the position 7 on coumarin ring and phenyl ring of acrylonitrile derivatives. The isobutyl substituent on the N atom of the benzimidazole core has the greatest influence on increasing the activity of the synthesized compounds. Some of the most active benzazole derivatives were additionally evaluated to study their mechanisms of biological action and it was confirmed that some of the acrylonitrile and iminocoumarin derivatives have proven to be tubuline polymerization inhibitors, while for amide derivatives the antioxidative activity was tested also in the cells. It has been proven that the most promising antiviral activity has been possessed by coumarine derived benzimidazole substituted with amidine group, being inhibitor of an early step in the replication cycle of virus, respectively the synthesis of viral RNA.

Ubikvintin-proteasomski sistem je pomemben za zagotavljanje homeostaze proteinov v celicah, saj je odgovoren za razgradnjo napačno zvitih in poškodovanih proteinov. Raziskave so pokazale, da se pri avtoimunskih boleznih, raku in nevrodegenerativnih spremembah pod vplivom vnetnih citokinov poveča izražanje imunoproteasoma, zaradi česar se je v zadnjem desetletju povečal obseg raziskav na področju selektivnih zaviralcev imunoproteasoma, ki imajo, v primerjavi z neselektivnimi zaviralci, manj neželenih učinkov. V okviru magistrske naloge smo se osredotočili na sintezo 2-cianobenzimidazolov in 2-cianobenzoksazolov, ki so heterobicikli z elektrofilno bojno glavo – nitrilom. Ciano skupina lahko tvori kovalentno vez s Cys48 v 5i podenoti imunoproteasoma, kar omogoča selektivno zaviranje 5i podenote imunoproteasoma, saj 5c konstitutivna podenota proteasoma na tem mestu nima cisteinskega aminokislinskega preostanka. Pri sintezi smo izhajali iz substituiranih orto-fenilendiaminov oziroma 2-aminofenolov, kjer je v prvi stopnji potekala ciklizacija med dinukleofilom in Appelovo soljo. Sintetizirane 2-cianobenzimidazole smo v drugem koraku z uporabo metil jodida pretvorili do dveh položajnih izomerov 2-ciano-N-metilbenzimidazola, ki smo ju očistiti in ločiti s kolonsko kromatografijo, strukturo posameznega položajnega izomera pa smo potrdil z 2-dimenzionalnimi eksperimenti jedrske magnetne resonance. Metil karboksilate 2-cianobenzoksazolov smo pretvorili do karboksilnih kislin z in situ pripravljeno Lewisovo kislino aluminijev trijodid (AlI3) v brezvodnih pogojih, da smo se izognili hidrolizi aktiviranega nitrila. Rezultati biokemijskega testiranja spojin na 5i podenoti imunoproteasoma so razkrili, da spojine 1, 2, 4B, 7–10 zavirajo imunoproteasom, najmočnejši zaviralec pa je bila spojina 7 z IC50 vrednostjo 12 ± 1 µM. 2-Cianobenzoksazoli so v splošnem močnejši zaviralci kot 2-cianobenzimidazoli, vendar so slednji zaradi boljše stabilnosti in manjše reaktivnosti lahko boljša osnova za nadaljnjo optimizacijo nizkomolekularnih zaviralcev 5i podenote imunoproteasoma. The ubiquintin-proteasome system is central to protein homeostasis in cells, and is responsible for the degradation of misfolded and damaged proteins. Research has shown that in autoimmune diseases, cancer, and neurodegenerative disorders, immunoproteasome expression is increased under the influence of inflammatory cytokines. As a result, the scope of research in the field of selective immunoproteasome inhibitors, which have fewer adverse side effects compared to non-selective inhibitors, has increased in the last decade. In the master thesis, we focused on the synthesis of 2-cyanobenzimidazoles and 2-cyanobenzoxazoles, which are heterobicycles with an electrophilic warhead – nitrile. The nitrile group can form a covalent bond with Cys48 of immunoproteasome subunit 5i, which allows selective inhibition of the immunoproteasome, since the constitutive subunit 5c lacks a cysteine amino acid at this sub-site. Substituted ortho-phenylenediamines or 2-aminophenols were used for the first step – the cyclization reaction of dinucleophile and Appel's salt. The synthesized 2-cyanobenzimidazoles were then methylated with methyl iodide to give two positional isomers of 2-cyano-N-methylbenzimidazole, which were separated and purified by column chromatography. The structures of the positional isomers were confirmed by 2-D nuclear magnetic resonance experiments. Methyl carboxylates of 2-cyanobenzoxazoles were converted to carboxylic acids using the Lewis acid aluminum triiodide (AlI3) generated in situ under anhydrous conditions to avoid hydrolysis of the activated nitrile. The results of the biochemical assay on the 5i subunit of immunoproteasome showed that compounds 1, 2, 4B, 7–10 inhibited the immunoproteasome, with compound 7 beeing the most potent inhibitor with an IC50 value of 12 ± 1 µM. 2-Cyanobenzoxazoles were generally more potent inhibitors than 2-cyanobenzimidazoles, but the latter may be a better starting point for further optimization of small molecule inhibitors of the immunoproteasome 5i subunit due to their better stability and lower reactivity.

Tese (doutorado) — Universidade de Brasília, Instituto de Química, Programa de Pós-Graduação em Química, 2022. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) e Fundação de Apoio à Pesquisa do Distrito Federal (FAP/DF). Os íons lantanídeos (Ln3+) possuem propriedades espectroscópicas e magnéticas únicas, as quais lhes proporcionam um amplo potencial de aplicação, como por exemplo: agentes antitumorais, catálise, sondas luminescentes, entre outras. Nas sondas luminescentes, os íons Ln3+ , quando coordenados a agentes complexantes cromóforos, como o ácido picolínico, podem intensificar suas propriedades luminescentes através do efeito antena. Compostos benzimidazóis normalmente são encontrados em produtos naturais, e são amplamente conhecidos por possuírem uma gama de atividades biológicas. Assim como o benzimidazol, as bases de Schiff apresentam extensa aplicação terapêutica, destacando-se em ambos a atividade anticancerígena. Este trabalho é dividido em duas etapas: a primeira etapa consiste na síntese e caracterização de complexos de íons Ln3+ obtidos a partir do ligante ácido picolínico. A segunda etapa mostra a síntese do Cloridrato de 2-(4-metoxifenil)-1H-benzimidazol (BenzHCl) a partir da base de Schiff N,N’-bis-(4-metoxibenzilideno)-benzeno-1,2-diamina (Anisalofeno) mediado por cloreto de Ln (Gd3+, Tb3+ ou Eu3+). Na primeira etapa, foram sintetizados 3 complexos inéditos com os íons: Gd (1), Eu (2) e Tb (3). Os complexos foram caracterizados por IV, TG/DTA, DRX de monocristal e pó. Ainda, realizou-se estudos de luminescência e estudo teórico de modelagem computacional. Diante das análises realizadas, foi possível obter as estruturas moleculares dos complexos 1-3, referindo-se a três complexos poliméricos e isoestruturais, onde a unidade assimétrica consiste em um cátion Ln3+ , um cátion Na+ , quatro ligantes pic e duas moléculas e meia de água, correspondendo à fórmula molecular Na[Ln(pic)4]⸱2,5H2O. Os estudos de luminescência dos complexos 1–3 demonstraram as bandas estreitas e características dos íons Ln3+ observando o efeito antena do ligante. Os estudos teóricos mostraram correspondência com os dados estruturais e luminescentes adquiridos experimentalmente. Já na segunda etapa deste trabalho, o mecanismo de reação do composto BenzHCl foi proposto a partir de diferentes estratégias sintéticas. A estrutura cristalina de BenzHCl revela duas unidades assimétricas semelhantes estabilizadas por ligações hidrogênio em moléculas de água, íons cloreto e átomos de nitrogênio protonados. O BenzHCl e a Anisalofeno foram caracterizados por IV, TG/DTA, DRX de monocristal, RMN de 1H e RMN de 13C. A viabilidade celular frente aos compostos BenzHCl e Anisalofeno (ensaio de MTT) foi testada em linhagem de célula saudável (fibroblasto) e em células de adenocarcinoma mamário humano (endenocarcinoma metastático MCF-7 e endenocarcinoma MDA-MB-231), onde ambos os compostos apresentaram maior toxicidade contra células doentes quando comparadas à célula saudável. Lanthanide ions (Ln3+) have unique spectroscopic and magnetic properties which provide them a wide application potential, such as antitumor agents, catalysis, luminescent probes, among others. As luminescent probes, Ln3+ ions, when coordinated to chromophore complexing agents, such as picolinic acid, can intensify their luminescent properties through the antenna effect. Benzimidazole compounds are commonly found on natural products and are widely known by having a range of biological activities. Just like benzimidazole, Schiff’s bases also have an extensive therapeutic application, with anticancer activity being highlighted in both. This work is divided in two steps: the first step consists in the synthesis and characterization of Ln3+ ion coordination compounds obtained from the picolinic acid. The second step shows the synthesis of 2-(4-methoxyphenyl)-1H-benzimidazole hydrochloride (BenzHCl) from the Schiff base N,N’-bis-(4-methoxybenzylidene)-benzene-1,2-diamine (Anisalofen) mediated by the lanthanide chloride (Gd3+, Tb3+ or Eu3+). In the first step, 3 new complexes with ions Gd (1), Eu (2) and Tb (3) were synthetized. These complexes were characterized by FT-IR, thermogravimetric analysis, powder XRD, and single crystal XRD. Moreover, luminescence studies and theoretical studies of computational modeling were carried out. From the analysis results, it was possible to obtain the molecular structures of complexes 1–3, which are polymeric and isostructural complexes, where the asymmetric unit consists of 1 Ln3+ cation, 1 Na+ cation, 4 pic deprotonated ligands and 2.5 molecules of water, corresponding to the molecular formula Na[Ln(pic)4]⸱2.5H2O. Luminescence studies of complexes 1–3 demonstrated the characteristics narrow bands of Ln3+ ions and the antenna effect of the ligand. Theoretical studies showed correspondence with experimentally acquired structural and luminescent data. In the second step of this work, the reaction mechanism of BenzHCl compound was proposed from different synthetic strategies. The crystal structure of BenzHCl revealed two similar asymmetric units stabilized by hydrogen bonds in water molecules, chlorine ions and protonated nitrogen atoms. Both BenzHCl and Anisalofen were characterized by FT-IR, thermogravimetric analysis, single crystal DRX, 1H NMR, and 13C NMR. The cell viability of BenzHCl and Anisalofen was tested through the MTT cytotoxicity assay in a healthy cell line (fibroblast) and in human mammary adenocarcinoma cells (MCF-7 and MDA-MB-231), where both compounds showed greater toxicity against diseased cells when comparted to the healthy cell.

Çalışmamızda yeni antikanser ilaçlar geliştirmek üzere bazı benzimidazol-tiyadiazol türevi bileşikler tasarlanmış ve yapıları 1H-NMR,13C-NMR ve elemental analiz spektral verileriyle kanıtlanmıştır. Bileşiklerin sitotoksik aktiviteleri HT29 hücre hattı üzerinde MTT yöntemi kullanılarak referans bileşik florourasilile kıyaslanarak değerlendirilmiştir. Ayrıca, bileşiklerin seçiciliklerini tespit etmek amacıyla L929 (sağlıklı fare fibroblast hücresi) hücre hattına karşı sitotoksik etkisi değerlendirilmiştir. Bileşiklerin IC50 değerleri incelendiğinde, 5-(2-(2,6-dimetoksifenil)-1H-benz[d]imidazol-5(6)-il)-N-siklohekzil-1,3,4-tiyadiazol-2-amin yapısına sahip BT-2 bileşiği 34,13±2,48 µM IC50 değeri ile referans ilaç fluorourasil (12,84 ± 3,66 µM) ile kıyaslanabilir etki göstermiştir. BT-2 bileşiğinin L929 sağlıklı hücre hattı üzerindeki sitotoksik etkisinin referans ilaçtan daha düşük olduğu tespit edilmiştir. Bu sonuçlar, BT-2 bileşiğinin antikanser etkisinin geliştirilebilmesi konusunda umut vericidir. Ayrıca, TAS ve TOS ile bileşiklerin antioksidan özellikleri değerlendirilmiştir. BT-2 bileşiğinin TOS değerinin kontrol ilaçla karşılaştırılabilir düzeyde olduğu görülmüştür., In our study, some benzimidazole-thiadiazole derivative compounds were designed to develop new anticancer drugs, and their structures were proven by 1H-NMR, 13C-NMR, and elemental analysis spectral data. The cytotoxic activities of the compounds were evaluated by comparing the reference compound fluorouracil using the MTT method on the HT29 cell line. In addition, the cytotoxic effect of the compounds against the L929 (healthy mouse fibroblast cell) cell line was evaluated in order to determine the selectivity of the compounds. When the IC50 values of the compounds are examined, the structure of 5-(2-(2,6-dimethoxyphenyl)-1H-benz[d]imidazol-5(6)-yl)-N-cyclohexyl-1,3,4-thiadiazol-2-amine (BT-2) compound with an IC50 value of 34.13±2.48 µM showed comparable efficacy to the reference drug fluorouracil (12.84 ± 3.66 µM). It was determined that the cytotoxic effect of BT-2 compound on L929 healthy cell line was lower than the reference drug. These results are promising in terms of improving the anticancer effect of BT-2 compound. In addition, TAS and TOS of the compounds and antioxidant properties of the compounds were evaluated. The TOS value of the BT-2 compound appears to be comparable to the control drug.

Benzimidazol je važan farmakofor i smatra se povlaštenom strukturom u medicinskoj kemiji.1 Derivati benzimidazola pokazuju brojne farmakološke aktivnosti poput antituberkulostatske, antimalarijske, antimikrobne, antivirusne, antitumorske i protuupalne.2 1, 2, 3-triazolni prsten kao dušiikov heterociklički gradivni blok ima značajnu ulogu u dizajnu i sintezi lijekova budući da ne predstavlja samo pasivnu poveznicu. nego je i farmakofor jer se lako povezuje s biološkim metama putem vodikovih veza i dipolnih interakcija.3 U ovom radu je prikazana sinteza i biološka ispitivanja novih derivata 2- arilbenzimidazola premoštenih 1, 2, 3-triazolnim prstenom. Ultrazvukom potpomognutom reakcijom ciklizacije O- alkiliranih benzaldehida s različito supstituiranim 1, 2-diaminobenzenom sintetizirani su 2-arilbenzimidazoli. 1, 2, 3-triazolni derivati benzimidazola pripravljeni su Huisgenovom 1, 3- dipolarnom cikloadicijom s odgovarajućim azidima. Antitumorska ispitivanja derivata benzimidazola su pokazala da derivat 2-arilbenzimidazola s N, N- dietilnim supstituentom ima najizraženiju antitumorsku aktivnost protiv tumorskih staničnih linija porijeklom iz čovjeka: adenokarcinom gušterače (Capan-1, IC50=2, 2 μM), karcinom pluća (NCI-H46, IC50=2, 2 μM), akutna limfoblastična leukemija (DND-41, IC50=2, 6 μM), kronična mijeloična leukemija (K-562, IC50=2, 0 μM) i non- Hodgkinov limfom (Z-138, IC50= 2, 0 μM). Ispitano je i antibakterijsko djelovanje novopripravljenih spojeva na bakterijskim stanicama Escherichia coli, Enterococcus Faecalis, Klebsiella Pneumonia, Pseudomonas aeruginosa, Staphylococcus aureus. Najizraženiju inhibiciju (MIC> 88-98%) je pokazao 6-klor-benzimidazolni derivat s morfolinskim supstituentom na bakteriju Enterococcus Faecalis pri svim ispitanim koncetracijama (256-0, 25 mg/L).

U ovom radu opisana je sinteza novih 1,2,3-triazolom premoštenih arilimidamidnih derivata benzimidazola, poznatih i kao reverzni amidini benzimidazola, s potencijalnim antitripanosomskim djelovanjem. Za pripravu ciljanih spojeva korištene su klasične metode organske sinteze. Arilimidamidni derivati benzimidazola (23a–23c, 24a–24c, 25a–25c) pripravljeni su iz odgovarajućih 5(6)-aminobenzimidazolnih prekursora (20a–20c, 21a–21c, 22a–22c) i priređenog S-(2-naftilmetil)tiobenzimidatnog hidrobromida 4. 5(6)-aminobenzimidazolni prekursori dobiveni su reakcijom redukcije iz 5(6)-nitrobenzimidazolnih prekursora (17a–17c, 18a–18c, 19a–19c) pripravljenih kondenzacijom bisulfitnih adukata benzaldehidnih prekursora (13a–13c, 14a–14c, 15a–15c) s 4-nitro-o-fenilendiaminom 16. Benzil- (13a–13c), pikolil- (14a–14c) i etinilmorfolin- (15a–15c) 1,2,3-triazolni derivati benzaldehida pripravljeni su regioselektivnom Cu(I)-kataliziranom cikloadicijom iz priređenih 4-(prop-2-iniloksi)benzaldehida (6a–6c) i odgovarajućih azida. Strukturna i spektroskopska karakterizacija novopripravljenih spojeva provedena je 1H i 13C NMR spektroskopijom. In this work the synthesis of new 1,2,3-triazolyl bridged arylimidazole benzimidazole derivatives, also known as benzimidazole reversed amidines with potential antitrypanosomal activity is described. For the synthesis of target compounds classical methods of organic sythesis were used. Arylimidamide benzimidazole derivatives (23a–23c, 24a–24c, 25a–25c) were prepared from the corresponding 5(6)-aminobenzimidazole precursors (20a–20c, 21a–21c, 22a–22c) and prepared S-(2-naphtylmethyl)thiobenzimidate hydrobromide 4. 5(6)-Aminobenzimidazole precursors were obtained by a reduction reaction from 5(6)-nitrobenzimidazoles (17a–17c, 18a–18c, 19a–19c) prepared by condensation of bisulfite aducts of the corresponding benzaldehyde precursors (13a–13c, 14a–14c, 15a–15c) with 4-nitro-o-phenylenediamine 16. Benzyl- (13a–13c), picolyl- (14a–14c) and ethynylmorpholine- (15a–15c) 1,2,3-triazole derivatives of benzaldehyde were prepared by regioselective Cu(I)-catalyzed cycloaddition from the prepared 4-(prop-2-ynyloxy)benzaldehydes (6a–6c) and the corresponding azides. The structures of all newly synthesized compounds were confirmed by the means of 1H NMR and 13C NMR spectroscopy.

Four different benzimidazolium salts (1-4) were prepared in three steps at 80 oC and their structures were elucidated using spectroscopic methods. The compounds (1-4) obtained were tested in in situ medium as catalyst in the carbon-carbon (C-C) bond formation reactions of two different boronic acid derivatives with various aryl halides in the presence of palladium acetate (PdOAc)2 and sodium tertiarybutoxide (NaOBut) as a base. With this reaction, four coupling products (5-8) were synthesized in different yields ranging from 11 to 93%. Compound 2 from the carbene precursors tested in the Suzuki-Miyaura cross-coupling reaction was found to be a more effective catalyst candidate than others.

Giriş ve Amaç: Benzimidazol türevi bileşikler günümüzde çeşitli hastalıkların tedavisinde kullanılmaktadır. Bunların başında Alzheimer hastalığı da gelmektedir. Alzheimer hastalığı dünya genelinde sıklıkla görülen hastalıklardan biridir. Bu çalışmada 1-benzil-2- sübstitüefenil-benzimidazol-5-sülfonamid türevi bileşiklerin kolinesteraz enzimleri üzerindeki etkileri araştırması amaçlanmıştır. Materyal ve Metot: Bu çalışmada 10 yeni bileşiğin sentezi yapılmıştır. Bu yeni bileşiklerin yapıları spektral analiz yöntemleriyle aydınlatılmıştır. Sentezlenen bileşiklerin kolinesteraz aktiviteleri incelenmiştir. Bulgular: Sentezlenen bileşiklerin kolinesteraz enzimlerine karşı IC50 değerleri tespit edilmiş ve bileşiklerin çoğu inhbitör etkili bulunmuştur. En etliki bileşiğin aktivitesinin takrine göre yaklaşık 5 kat daha yüksek olduğu tespit edilmiştir. Sonuç: 10 yeni bileşiğin sentezi yapılmıştır. Kolinesteraz enzimlerine karşı aktiviteleri incelenmiştir. Sonuçlara göre kolinesteraz enzimlerine karşı aktivitesi yüksek daha etkili bileşikler tasarlanacaktır.

Inhibitors based on nitrogen heteroatoms have been shown to be one of the effective chemicals in inhibiting metal corrosion. This study was carried out with the density functional theory (DFT), using different levels of calculation. Several proposals were evaluated to estimate the energy levels of the frontier molecular orbitals (HOMO-LUMO) and their isodensity. These parameters were considered to determine the nucleophilic and electrophilic part of the molecules. Finally, an analysis of the chemical reactivity parameters was carried out with electronic affinity, ionization potential, chemical hardness and electrophilicity index; the objective was to determine the effect about chemical hardness by changing the position of the substituents.

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Compostos heterocíclicos são moléculas orgânicas que possuem no anel um átomo diferente do carbono, como enxofre, oxigênio ou nitrogênio, podendo este anel ser aromático ou não. A química de compostos heterocíclicos é uma importante área da química orgânica que vem recebendo grande atenção da comunidade científica ao longo dos anos, por serem compostos amplamente distribuídos pela natureza e serem essenciais para a vida, desempenhando um papel vital no metabolismo das células. As julolidinas e os benzimidazóis são duas classes de compostos heterocíclicos que vem recebendo destaque nos últimos anos, devido às suas diversas aplicações e atividades biológicas reportadas na literatura. Outra área da química que vem recebendo atenção da comunidade científica nos últimos anos é a de sensores químicos fluorogênicos ou cromogênicos, que se baseiam no desenvolvimento de sistemas de detecção de espécies químicas, mediante mudança espontânea de cor ou emissão de radiação (fluorescência). Neste trabalho foram sintetizados oito derivados de julolidinas – quatro delas inéditas – que serão avaliados como sensores químicos fluorogênicos e/ou cromogênicos em diversas análises, como na detecção de fosfatase alcalina, detecção de espécies reativas de oxigênio como peróxido de hidrogênio e ácido hipocloroso e na detecção de íons metálicos em solução. Quatro das moléculas sintetizadas tiveram sua capacidade de complexação com diferentes metais avaliada e uma delas se mostrou seletiva para a complexação de Cu(II) em meio básico. Com isso, foram avaliados diversos parâmetros – concentração ótima de NaOH e ligante, cinética reacional, razão estequiométrica metal/ligante, seletividade, recuperação e precisão – e foi desenvolvida uma metodologia rápida, de baixo custo e de fácil acesso para determinação do teor de cobre em cachaças, que apresentou boa exatidão e precisão (CV = 4,5%). Palavras-chave: Benzimidazois. Benzotiazois. Sondas fluorescentes. Heterocyclic compounds are organic molecules that have another atom in their ring instead of carbon, such as sulfur, oxygen, or nitrogen. Besides, this molecules ring may be aromatic or not. The chemistry of heterocyclic compounds is an important area of organic chemistry that has received great attention from the scientific community over the years, since these compounds are widely available in nature and they are essential for life, providing a vital role in the metabolism of cells. Julolidines and benzimidazoles are two classes of heterocyclic compounds that are in the spotlight in recent years, due to their various applications and biological activities, which were reported in the literature. There is another area of chemistry receiving attention from the scientific community in recent years, which is fluorogenic or chromogenic chemical sensors. These sensors are based on the development of chemical species detection systems, through spontaneous color change or radiation emission (fluorescence). In this work, eight derivatives of julolidines were synthesized – four of them unpublished – and will be evaluated as fluorogenic and/or chromogenic chemical sensors in some analyzes, such as in the detection of alkaline phosphatase, detection of reactive oxygen species such as hydrogen peroxide and hypochlorous acid, and in the detection of metal ions in solution. We evaluated four of the synthesized molecules in their ability to complex with different metals. Furthermore, we proved that one of them is selective in complexing Cu(II) in an alkaline solution. Moreover, several parameters of these molecules were evaluated – optimal concentration of NaOH and ligand, reaction kinetics, stoichiometric metal/ligand ratio, selectivity, recovery, and precision – and a fast, low cost, and easily accessible methodology was developed for copper determination in cachaças, which presented good accuracy and precision (CV = 4.5%). Keywords: Benzimidazoles. Benzothiazoles. Fluorescent probes.

Locker is a fungicide used in different crops for biological control, affecting both insect pests and pollinators, such as bees. This study aimed to evaluate toxicity and establish the lethal concentration (LC50) of the fungicide Locker in stingless bees Scaptotrigona bipunctata, investigating changes in brain cells chromatin structure and in midgut morphology. This agrochemical is a combined fungicide that contains three active ingredients: benzimidazole, triazole and strobilurin. Adult forage bees were orally exposed to the following concentrations: 1.7 mg a.i./L; 2.55 mg a.i./L; 3.4 mg a.i./L and 4.25 mg a.i./L of fungicide, and submitted to histochemical and morphological analysis 24, 48 and 72 hours after ingestion. The analysis of S. bipunctata brain cells showed changes in chromatin condensation in all treatments. There were also several morphological changes in the midgut at all concentrations and exposure times. Thus, the fungicide Locker significantly affected bee survival, inducing changes in their internal morphology, which can lead to alterations in their activities, directly interfering in their foraging behavior and survival. Locker es un fungicida utilizado en diferentes cultivos para el control biológico, que afecta tanto a insectos plagas como a polinizadores, como las abejas. Este estudio tuvo como objetivo evaluar la toxicidad y establecer la concentración letal (CL50) del fungicida Locker en abejas sin aguijón Scaptotrigona bipunctata, investigando cambios en la estructura de la cromatina de las células cerebrales y en la morfología del intestino de la abeja. El producto utilizado es un fungicida combinado que contiene tres principios activos: benzimidazol, triazol y estrobilurina. Las abejas forrajeras adultas fueron expuestas por vía oral a concentraciones de 1,7 mg a.i./L; 2,55 mg a.i./L; 3,4 mg a.i./L y 4,25 mg a.i./L de fungicida, y sometidos a análisis histoquímico y morfológico 24, 48 y 72 horas después de la ingestión del producto. El análisis de células cerebrales de S. bipunctata mostró cambios en la condensación de cromatina en todos los tratamientos. También hubo varios cambios morfológicos en el intestino medio en todas las concentraciones y tiempos de exposición. Así, el fungicida Locker afectó significativamente la supervivencia de las abejas, induciendo cambios en su morfología interna, lo que puede conducir a cambios en sus actividades, interfiriendo directamente en su comportamiento de forrajeo y supervivencia. Locker é um fungicida utilizado em diferentes culturas para controle biológico, afetando tanto insetos pragas quanto polinizadores, como as abelhas. Este estudo teve como objetivo avaliar a toxicidade e estabelecer a concentração letal (CL50) do fungicida Locker em abelhas sem ferrão Scaptotrigona bipunctata, investigando alterações na estrutura da cromatina das células cerebrais e na morfologia do intestino médio das abelhas. O produto utilizado é um fungicida combinado que contém três ingredientes ativos: benzimidazol, triazol e estrobilurina. Abelhas forrageiras adultas foram expostas via oral às concentrações de 1,7 mg i.a./L; 2,55 mg a.i./L; 3,4 mg i.a./L e 4,25 mg i.a./L de fungicida, e submetidas à análises histoquímicas e morfológicas após 24, 48 e 72 horas da ingestão do produto. A análise das células cerebrais de S. bipunctata mostrou alterações na condensação da cromatina em todos os tratamentos. Houve também várias mudanças morfológicas no intestino médio em todas as concentrações e tempos de exposição. Dessa forma, o fungicida Locker afetou significativamente a sobrevivência das abelhas, induzindo alterações em sua morfologia interna, que podem levar a alterações em suas atividades, interferindo diretamente em seu comportamento de forrageamento e sobrevivência.