Sinteza i spektroskopska karakterizacija novih derivata imidazo[4,5-b]piridina kao potencijalnih optičkih pH senzora

master's thesis

• Title (english): Synthesis and spectroscopic characterization of novel imidazo[4,5-b]pyridine derivatives as potential optical pH sensors
• Author: Corina Šljubura
• Mentor: Marijana Hranjec (mentor)
• Committee member: Marijana Hranjec (predsjednik povjerenstva)
• Committee member: Dragana Vuk (član povjerenstva)
• Committee member: Dragana Mutavdžić Pavlović (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2023-07-13, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

U ovom radu provedena je sinteza i spektroskopska karakterizacija benzamidnih derivata imidazo[4,5-b]piridina koji se razlikuju prema položaju, odnosno redoslijedu kojim su supstituenti vezani na dušik amidne veze. Ciljani spojevi priređeni su klasičnim reakcijama organske sinteze. Korištenje polifosforne kiseline (PPA) katalizira reakciju kondenzacije iz odgovarajućih prekursora, 2,3-diaminopiridna 1 i p-aminobenzojeve kiseline 2 što rezultira stvaranjem 4-(3H-imidazo[4,5-b]piridin-2-il)anilina 3. Iz odgovarajućih benozil-klorida 4-5, te glavnog prekursora, amino derivata imidazo[4,5-b]piridina 3, reakcijom kondenzacije u apsolutnom toulenu uz trietilamin priređeni su konačni benzamidi 6-7. Reakcijom amidacije iz HATU i DIPEA aktivirane 4-nitrobenzojeve kiseline 10, te
4-(3H-imidazo[4,5-b]piridin-2-il)anilina 3 sintetiziran je benzamidni nitro derivat 11. Reakcija ciklokondenzacije 2,3-diaminopiridina 1 s 4-formilbenzojevom kiselinom 14 i natrijevim metabisulfitom u DMSO daje 4-(3H-imidazo[4,5-b]piridin-2-il)benzojevu kiselinu 15 koja potom u reakciji nukleofilne supstitucije s tionilkloridom u toulenu daje
4-(3H-imidazo[4,5-b]piridin-2-il)benzoil klorid 16. Reakcijom kondenzacije spoja 16 s odgovarajućim aromatskim aminima 17-19 u apsolutnom toulenu uz trietilamin priređena je druga vrsta benzamida 20-22. Amidino-supstituirani benzamidi 8-9 i 25-26 priređeni su iz nitrilnih benzmida 7, odnosno 22, Pinnerovom reakcijom u dva stupnja u kiselom mediju. Amino-supstituirani derivati 12 i 23 priređeni su reakcijom redukcije s SnCl2×2H2O, te su s klorovodičnom kiselinom prevedeni u hidrokloridne soli 13 i 24. Priređenim derivatima ispitana je i antiproliferativna aktivnost in vitro na nekoliko staničnih linija humanih karcinoma. Derivati 12 i 23 dodatno su spektroskopski okarakterizirani u nekoliko otapala različite polarnosti, te su provedene spektroskopske UV/Vis pH titracije kako bi se ispitala mogućnost primjene kao optičkih pH senzora. Strukture svih priređenih produkata potvrđene su
1H i 13C NMR spektroskopijom, a nekih i masenom spektrometrijom. Tijek Pinnerovih reakcija za pripravu amidino-supstituiranih benzamida praćen je IR spektroskopijom.

Abstract (english)

This work presents the synthesis and spectroscopic characterization of
imidazo[4,5-b]pyridine benzamides, which differ according to the position, or the order in which the substituents are attached to the nitrogen of the amide bond. Targeted compounds were prepared by conventional reactions of organic synthesis. The use of polyphosphoric acid (PPA) catalyzes a condensation reaction from the precursors, 2,3-diaminopyridine 1 and p-aminobenzoic acid 2 leading to the formation of 4-(3H-imidazo[4,5-b]pyridin-2-yl)aniline 3. From the corresponding benzoyl chlorides 4-5 and the main precursor, amino derivative of imidazo[4,5-b]pyridine 3 by a condensation in absolute toluene with triethylamine, target benzamides 6-7 were synthesized. Nitro benzamide derivative 11 was synthesized by the amidation using HATU and DIPEA activated 4-nitrobenzoic acid 10 and
4-(3H-imidazo[4,5-b]pyridin-2-yl)aniline 3. Cyclocondensation of 2,3-diaminopyridine 1, 4-formylbenzoic acid 14 and sodium metabisulfite in DMSO produces
4-(3H-imidazo[4,5-b]pyridin-2-yl)benzoic acid 15 which then in a nucleophilic substitution with thionyl chloride in toluene gives 4-(3H-imidazo[4,5-b]pyridin-2-yl)benzoyl chloride 16.
By condensation of compound 16 with the corresponding aromatic amines 17-19 in absolute toluene with triethylamine, another class of benzamide was prepared 20-22.
Amidino-substituted benzamides 8-9 and 25-26 were prepared starting from corresponding nitrile benzamides 7 and 22, by a two-step Pinner reaction in an acidic medium.
Amino-substituted derivatives 12 and 23 were prepared by a reduction with SnCl2×2H2O and converted into hydrochloride salts 13 and 24. All prepared benzamides were tested for their antiproliferative activity in vitro on several human cancer cells. In addition, the spectroscopic properties of derivatives 12 and 23 were studied by UV/Vis spectroscopy and pH titrations in order to determine the possibility of application as optical pH sensors. The structures of all prepared products were confirmed by 1H and 13C NMR spectroscopy, and some by mass spectrometry. The Pinner reaction for the preparation of amidino-substituted benzamides was monitored by IR spectroscopy.

• Keywords: antiproliferativna aktivnost in vitro; benzamidi; imidazo[4 5-b]piridin; kondenzacija; 1H i 13C NMR spektroskopija; Pinnerova reakcija; pH titracije
• Keywords (english): ntiproliferative activity in vitro; benzamides; imidazo[4 5-b]pyridine; condensation; 1H and 13C NMR spectroscopy; Pinner reaction; pH titrations
• Language: croatian
• URN:NBN: urn:nbn:hr:149:654844
• Project: Number: IP-2018-01-4379; Title: Istraživanje antioksidativnog djelovanja benzazolskog skeleta u dizajnu novih antitumorskih agensa; Acronym: AntioxPot; Leader: Marijana Hranjec; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Project: Number: IP-2020-02-8090; Title: Dizajn, sinteza i računalna analiza novih optičkih kemijskih pH osjetilnih derivata benzazola; Title: Design, Synthesis and Computational Analysis of Novel Optical Chemical pH Sensing Benzazole Derivatives; Acronym: BenzpHSens; Leader: Robert Vianello; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Applied Chemistry - Graduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Applied organic chemistry; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra primijenjene kemije (magistar/magistra primijenjene kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2024-06-30
• Created on: 2023-07-27 11:29:27