Sinteza novih 5-amidino benzimidazola s potencijalnim antitripanosomskim djelovanjem

master's thesis

• Title (english): Synthesis of novel 5-amidino benzimidazoles with potential antitrypanosomal activity
• Author: Rebeka Štulić
• Mentor: Silvana Raić-Malić (mentor)
• Committee member: Silvana Raić-Malić (predsjednik povjerenstva)
• Committee member: Silvija Maračić (član povjerenstva)
• Committee member: Svjetlana Krištafor (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2020-09-30, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

U okviru ovog rada provedena je sinteza, spektroskopska karakterizacija i in silico analiza novih 5-amidino-supstituiranih derivata benzimidazola s potencijalnom antitripanosomskom aktivnošću. Za pripravu ciljanih spojeva korištene su klasične metode organske sinteze i mikrovalovima potpomognuta sinteza. Amidino-benzimidazolni hibridi (37-60) pripravljeni su kondenzacijom bisulfitnih adukata odgovarajućih benzaldehidnih prekursora (4-18, 26-34) s 4-amidino-1,2-fenilendiaminom 36. Sinteza derivata 39, 45, 46, 48, 58 i 59 provedena je klasičnim pristupom i primjenom mikrovalova. Arilni (4-9), morfolinski (10-15) i dietilaminski (16-18) benzaldehidni intermedijari su dobiveni reakcijom O-alkiliranja potpomognutom mikrovalnim zračenjem iz 4-hidroksibenzaldehida (1-3). Sinteza 4-((1,2,3-triazol-4-il)metoksi)benzaldehida (26-34) provedena je regioselektivnom Cu(I)-kataliziranom cikloadicijom iz priređenih 4-(prop-2-iniloksi)benzaldehida (19-21) i odgovarajućih azida. Click reakcija je izvedena u mikrovalnom reaktoru i pri konvencionalnim uvjetima za nesupstituirane 1,2,3-triazolilne produkte (26-28). Amidinski prekursor 4-(1,4,5,6-tetrahidropirimidin-2-il)benzen-1,2-diamin hidroklorid 36 sintetiziran je Pinnerovom metodom iz 3,4-diaminobenzonitrila 35. Strukturna i spektroskopska karakterizacija novopripravljenih spojeva provedena je 1H i 13C NMR spektroskopijom. Tijek Pinnerove reakcije kod priprave amidina 36 praćen je IR spektroskopijom. ADME i farmakokinetička svojstva te istraživanje parametara sličnosti s lijekovima za novopripravljene spojeve predviđeno je in silico pristupom.

Abstract (english)

This paper describes synthesis, spectroscopic characterization and in silico analysis of novel 5-amidinobenzimidazole derivatives designed with the aim to evaluate their antitrypanosomal activity. For the synthesis of target compounds classical methods of organic synthesis, and microwave-assisted synthesis were used. Amidinobenzimidazole hybrids (37-60) were prepared by condensation of the bisulfite adducts of the corresponding benzaldehyde derivatives (4-18, 26-34) with 4-amidino-1,2-phenylenediamine 36. Synthesis of compounds 39, 45, 46, 48, 58 i 59 was carried out under classic conditions and applying microwave irradiation. Benzaldehyde intermediates containing aryl (4-9), morpholino (10-15) and diethylamino (16-18) substituents were synthesized in microwave-assisted O-alkylation reactions from the corresponding 4-hydroxybenzaldehydes (1-3). Regioselective Cu(I)-catalysed 1,3-dipolar cycloaddition from the 4-(prop-2-ynyloxy)benzaldehydes (19-21) was used to obtain the 4-((1,2,3-triazol-4-yl)methoxy)benzaldehyde derivatives (26-34). Synthesis of unsubstituted 1,2,3-triazole derivatives (26-28) was executed by classic and microwave-assisted syntheses. 4-(1,4,5,6-Tetrahydropyrimidin-2-yl)benzene-1,2-diamine hydrochloride 36 was synthesised from the diaminobenzonitrile 35 by the Pinner method. The structures of all newly synthesized compounds were confirmed by means of 1H NMR and 13C NMR. The course of Pinner reaction preparation of amidine 36 was monitored by IR spectroscopy. ADME and pharmacokinetic properties as well as druglike nature of novel compounds were predicted by in silico approach.

• Keywords: amidino-benzimidazoli; 1 2 3-triazoli; click kemija; Pinnerova reakcija; sinteza potpomognuta mikrovalovima
• Keywords (english): amidinobenzimidazoles; 1 2 3-triazoles; click chemistry; Pinner reaction; microwave assisted synthesis
• Language: croatian
• URN:NBN: urn:nbn:hr:149:608046
• Project: Number: IP-2018-01-4682; Title: Novi spojevi temeljeni na bioizosterima purina za ispitivanje njihovih antitumorskih i antipatogenih djelovanja; Acronym: PurBioCaPa; Leader: Silvana Raić-Malić; 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: Access restricted to students and staff of home institution
• Created on: 2022-04-19 13:09:37