| Sažetak | U okviru doktorskog rada opisana je sinteza, strukturna karakterizacija i biološka aktivnost novih derivata imidazo[4,5-b]piridina. Za sintezu novih spojeva korištene su klasične metode organske sinteze, sinteza potpomognuta mikrovalovima, paralelna sinteza i organometalna sinteza. Akrilonitrilni derivati 21–40 i 58–89 priređeni su aldolnom kondenzacijom 2-cijanometilimidazo[4,5-b]piridina s različitim benzaldehidima. Ispitan je utjecaj supstitucije u položaju N3 imidazo[4,5-b]piridinske jezgre, broj i položaj metoksi i hidroksi skupina, te prisutnost N,N-dialkilnog supstituenta u para-položaju fenilne jezgre na biološku aktivnost i spektroskopske karakteristike. Nadalje, reakcijom ciklokondenzacije
2-cijanometilimidazo[4,5-b]piridina i salicilbenzaldehida priređeni su iminokumarinski derivati 97–119 supstituirani u položajima 6 i 7 iminokumarinske jezgre, te na N3 dušikovom atomu imidazo[4,5-b]piridinske jezgre. 2-fenilamidino-supstituirani derivati imidazo[4,5-b]piridina 126–133 priređeni su iz cijano-supstituiranih prekursora 122–125, dok su reakcijom metiliranja priređeni derivati 134–136. Pinnerovom reakcijom u dva stupnja, priređeni su svi derivati supstituirani cikličkim amidinima, a one-pot reakcijom s reagensom LiHMDS derivati supstituirani nesupstituiranim amidinom. Suzukijevom reakcijom priređeni su derivati 142–146 i 149–154 supstituirani u položaju 6 imidazo[4,5-b]piridinske jezgre, a ovisno o korištenoj bornoj kiselini, u para-položaju fenilnog prstena supstituirani su različitim skupinama. N3-metil-supstituirani amidini imidazo[4,5-b]piridina 163–171 priređeni su iz cijano-supstituiranih prekursora 152, 161 i 162 Pinnerovom reakcijom. Serija konjugata imidazo[4,5-b]piridina i amidino-supstituiranih benzazola 182–190 priređena je kondenzacijom amidino-supstituiranih prekursora 173–181, odnosno
4-amidino-1,2-fenilendiamin-hidroklorida ili 5-amidino-2-aminobenzentiola s
imidazo[4,5-b]piridin-6-karbaldehidom 172. Schiffove baze imidazo[4,5-b]piridina 194–197 priređene su iz imidazo[4,5-b]piridina-karbaldehida 172 s anilinima, a Schiffove baze 202–214 iz 2-aminofenil-supstituiranih imidazo[4,5-b]piridina s benzaldehidima. Priređene su i dvije klase amidnih derivata imidazo[4,5-b]piridina koje se međusobno razlikuju prema položaju amidne veze. Derivati 217, 218, 230, 231 i 234 priređeni su iz benzoilnog klorida i amino-supstituiranih derivata, dok je derivat 222 priređen katalitički. Amidino-supstituirani derivati 219, 220, 232 i 233 priređeni su Pinnerovom reakcijom u dva stupnja.
Amino-supstituirani imidazo[4,5-b]piridini 102, 111, 147, 155, 233 i 235 priređeni su redukcijom iz odgovarajućih nitro-supstituiranih derivata. Radi bolje topljivosti derivati 103, 112, 119, 148, 156, 224 i 236 su pripravljeni kao amonijeve hidrokloridne soli. Strukture svih priređenih ciljanih spojeva i prekursora potvrđene su 1H i 13C NMR spektroskopijom, a za pojedine spojeve i dodatno masenom spektrometrijom. Detaljna spektroskopska karakterizacija u svrhu pronalaženja novih potencijalnih optičkih pH-senzora, provedena je za odabrane spojeve iz klasa akrilonitrila, iminokumarina i Schiffovih baza, a pKa vrijednosti određene su eksperimentalno i računalnim metodama. Svim ciljanim novopriređenim spojevima ispitana je antiproliferativna aktivnost in vitro na nekoliko staničnih linija humanih karcinoma. Za najaktivnije derivate istražen je mehanizam biološkog djelovanja koji je dodatno potvrđen, za neke derivate, i računalnom analizom. Antioksidativna aktivnost in vitro ispitana je spektroskopskim metodama DPPH, FRAP i ABTS, te elektrokemijski, dok je mehanizam antioksidativnog djelovanja potvrđen i računalnom analizom. Najaktivnijim amidinskim derivatima ispitana je interakcija s ct-DNK. Odabranim derivatima ispitana je antibakterijska aktivnost in vitro na nekoliko sojeva Gram-pozitivnih i Gram-negativnih bakterija, te antivirusna aktivnost in vitro prema odabranim vrstama virusa. |
| Sažetak (engleski) | Within this work, the synthesis, structural characterization and biological activity of novel imidazo[4,5-b]pyridine derivatives was described. For the synthesis of targeted compounds, classical methods of organic chemistry, parallel synthesis, and microwave assisted synthesis as well as organometal chemistry were used. Acrylonitrile derivatives 21–40 and 58–89 were prepared in the aldol condensation from 2-cyanomethylimidazo[4,5-b]pyridines and various benzaldehydes. Influence of N3 substitution on imidazo[4,5-b]pyridine core, the number and the position of hydroxy and methoxy groups as well as presence of N,N-dialkyl substituent placed at para-position of the phenyl ring on biological activity and spectroscopic characteristics was investigated. In the cyclocondensation reaction from 2-cyanomethylimidazo[4,5-b]pyridines and salicyl benzaldehydes, iminocoumarin derivatives 97–119 substituted at positions 6 and 7 of iminocoumarin core as well as at the position N3 of imidazo[4,5-b]pyridine nucleus were prepared. 2-phenylamidino-substituted
imidazo[4,5-b]pyridine derivatives 126–133 were prepared from cyano-substituted precursors 122–125, while derivatives 134–136 were prepared in the reaction of methylation. Two step Pinner reaction was used to prepare compounds substituted with cyclic amidines, while one pot reaction with LiHMDS was used to prepare derivatives with unsubstituted amidines. Suzuki coupling was used to prepare derivatives 142–146 and 149–154 substituted at the postition 6 of imidazo[4,5-b]pyridine core, depending on used boronic acid, substituted at the p–position of the phenyl ring with different substituents.
N3-methyl-substituted amidine derivatives 163–171 were prepared from cyano-substituted precursors 152, 161 and 162 in Pinner reaction and one pot reaction with LiHMDS. Benzazole conjugates of imidazo[4,5-b]pyridine with amidino-substituted benzazoles 182–190 were synthesized by condensation amidino-substituted precursors 173–181, respectively from 4-amidino-1,2-phenylenediamines hydrochlorides or 5-amidino-2-amino-substituted benzenthiolates with imidazo[4,5-b]pyridine-6-carbaldehyde 172. Imidazo[4,5-b]pyridine derived Schiff bases 194–197 were prepared from imidazo[4,5-b]pyridine-6-carbaldehyde 172 with various anilines, while Schiff bases 202–214 obtained from
2-aminophenyl-substituted imidazo[4,5-b]pyridines with benzaldehydes. Two series of amide derivatives were prepared which differ from position of amide bond. Derivatives 217, 218, 230, 231 and 234 were prepared by reactions between benzoil chlorides and
amino-substituted derivatives, while derivative 222 was prepared catalytically.
Amidino-substituted derivatives 219, 220, 232 and 233 were prepared by Pinner reaction.
All amino-substituted imidazo[4,5-b]pyridines 102, 111, 147, 155, 233 i 235 were prepared by reduction of corresponding nitro-substituted compounds. Some derivatives 103, 112, 119, 148, 156, 224 and 236 were prepared as ammonium hydrochloride salts in order to achieve better solubility. Structures of targeted compounds and precursors were analysed by means of 1H and 13C NMR spectroscopy, and were further confirmed by mass spectrometry for selected compounds. Thorough spectroscopic characterization was conducted for selected acrylonitrile, iminocoumarin and Schiff base derivatives, while pKa values were determined experimentally and computationally. All targeted compounds were evaluated for their antiproliferative activity in vitro on several human cancer cell lines. Mechanism of action was further investigated for the most active compounds and for some chosen derivatives confirmed also by computational analysis. Antioxidative activity in vitro was determined by using spectroscopic methods DPPH, FRAP and ABTS as well as electrochemically, while their mechanism of antioxidative action was explained by computational analysis. The most active amidine compounds were chosen for studying their interaction with ct-DNA. Selected compounds were tested also for their antibacterial activity in vitro against some Gram positive and Gram negative bacterial strains, as well as antiviral activity in vitro against selected viruses. |
