Sinteza i strukturna karakterizacija novih 2-hidroksi supstituiranih amidina benzimidazola i benzotiazola kao biološki aktivnih spojeva

master's thesis

• Title (english): Synthesis and and structural characterization of novel 2-hydroxy substituted benzimidazole and benzothiazole amidines as biologically active compounds
• Author: Teo Tomić
• Mentor: Marijana Hranjec (mentor)
• Committee member: Marijana Hranjec (predsjednik povjerenstva)
• Committee member: Svjetlana Krištafor (član povjerenstva)
• Committee member: Dragana Mutavdžić Pavlović (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2022-07-01, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

U okviru ovog rada provedena je sinteza novih i potencijalno biološki aktivnih amidino supstituiranih benzimidazola 20-29, amidino supstituiranih N-metil-benzimidazola 30-34 te amidino supstituiranih benzotiazola 37-46. Navedeni spojevi priređeni su klasičnim reakcijama organske sinteze te mikrovalovima potpomognutom sintezom. Amidino supstituirani 1,2-fenilendiamini 8 i 9 kao glavni prekursori za sintezu amidino supstituiranih derivata benzimidazola 20-29 priređeni su u nekoliko sintetskih koraka iz 4-aminobenzonitrila 1. Acetiliranjem, a zatim nitriranjem 4-aminobenzonitrila 1 priređen je 4-amino-3-nitrobenzonitril 4. Pinnerovom reakcijom 4-amino-3-nitrobenzonitrila 4 u kiselom mediju, a zatim katalitičkim hidrogeniranjem dobivenog spoja 6 i 7 priređeni su ciljani prekursori 8 i 9. 4-(2-imidazolinil)-N-metil-1,2-fenilendiamin 14 kao glavni prekursor za sintezu N-metil-benzimidazola 30-34, priređen je iz 4-klor-3-nitrobenzonitrila 10. Reakcijom aminacije priređen je 4-N-metilamino-3-nitrobenzonitril 11 iz kojeg je Pinnerovom reakcijom u kiselom mediju, a zatim kataličkim hidrogeniranjem priređen ciljani prekursor 14. Ciljani spojevi 20-29 i 30-34 priređeni su reakcijom kondenzacije njihovih prekursora 8, 9 ili 11 s odgovarajućim aldehidima 15-19 uz prisustvo p-benzokinona kao oksidansa. Amidino supstituirani benzotiazoli 37-46 priređeni su reakcijom kondenzacije amidino supstituiranih benzentiolata 35 ili 36 i odgovarajućih aldehida 15-19. Ciljani spojevi priređeni su u obliku slobodne baze te su s HCl-om u vodenom mediju prevedeni u njihove hidroklorne soli. Strukture svih priređenih spojeva potvrđene su 1H i 13C NMR spektroskopijom. Tijek Pinnerovih reakcija kod priprave amidino supstituiranih prekursora, praćen je IR spektroskopijom. Svim priređenim derivatima ispitana je antiproliferativna aktivnost in vitro na osam staničnih linija humanih karcinoma. Svi ispitani spojevi pokazali su umjerenu do jaku aktivnost. Najizraženiju aktivnost pokazao je derivat benzotiazola 45 supstituiran fluorom i nesupstituiranim amidinom.

Abstract (english)

This work presents the synthesis and spectroscopic caracterization of novel and potentially biologially active amidine substituted benzimidazoles 20-29, amidine substituted N-methyl-benzimidazoles 30-34 and amidine substituted benzothiazoles 37-46. These compounds were prepared by classical methods of organic synthesis and by microwave assisted reactions. Amidine substituted 1,2-phenylenediamines 8 and 9 as main precursors for the synthesis of amidine substituted benzimidazoles 20-29, were prepared in several synthetic steps starting from 4-aminobenzonitrile 1. 4-amino-3-nitrobenzotrile 4 was prepared by acetylation followed by nitration of aminobenzonitrile 1. Precursors 8 i 9 were prepared by Pinner reaction from 4-amino-3-nitrobenzotrile 4 in acidic solution, which first gave compounds 6 and 7 that were then catalytically hydrogenated to the targeted precursors. 4-(2-imidazolinyl)-N-methyl-1,2-phenylenediamine 14 as a main precursor for the synthesis of N-methyl-benzimidazoles 30-34 was prepared starting from 4-chloro-3-nitrobenzonitrile 10. By microwave assisted amination of compound 10, 4-N-methylamino-3-nitrobenzonitrile 11 was obtained, which gave by Pinner reaction and catalytic hidrogenation the targeted compound 14. Amidino substituted benzimidazoles 20-29 and 30-34 were prepared by condensation of 8, 9 or 11 with the corresponding aldehydes 15-19 using p-benzoquinone as an oxidant. Amidine substituted benzothiazoles 37-46 were prepared by condensation of amidine substituted benzenthiolates 35 or 36 with corresponding aldehydes 15-19. The targeted compounds were obtained as free bases which were then converted into hydrochloric salts with HCl in aqueous solution. The structures of all prepared compounds were confirmed by 1H and 13C NMR spectroscopy. The Pinner reaction in the preparation of amidino substituited precursors was monitored by IR spectroscopy. All prepared compounds were tested for their antiproliferative activity in vitro on eight human cancer cells. Tested compounds showed moderate to strong activity. The most significant activity was displayed by benzothiazole derivative substituted with fluorine and unsubstituted amidine group 45.

• Keywords: amidini; aminacija; antiproliferativna aktivnost; benzimidazoli; benzotiazoli; Pinnerova reakcija; 1H i 13C NMR spektroskopija
• Keywords (english): amidines; amination; antiproliferative activity; benzimidazoles; benzothiazoles; Pinner reaction; 1H and 13C NMR spectroscopy
• Language: croatian
• URN:NBN: urn:nbn:hr:149:094502
• Project: Number: 125-0982464-1356; Title: Novi heterocikli kao antitumorski i antivirusni (pametni) lijekovi; Title: New heterocycles as antitumor and antiviral (smart) drugs; Leader: Marijana Hranjec; Jurisdiction: Croatia; Funder: MZOS; Funding stream: ZP
• Study programme: Title: Applied Chemistry - Graduate study; specializations in: Environmental chemistry and green technologies, Advanced materials and technologies, Applied organic chemistry; Course: Environmental chemistry and green technologies; 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: Access restricted to students and staff of home institution
• Created on: 2023-02-26 15:33:20