Sinteza, karakterizacija i derivatizacija polisupstituiranog piperidino-morfolinskog spiro gradivnog bloka

master's thesis

• Title (english): Synthesis, characterization and derivatization of a polysubstituted piperidino-morpholine spiro building block
• Author: Rea Klarić-Kukuz
• Mentor: Zrinka Rajić (mentor)
• Mentor: Ivaylo Jivkov Elenkov (mentor)
• Committee member: Zrinka Rajić (predsjednik povjerenstva)
• Committee member: Kristina Pavić (član povjerenstva)
• Committee member: Ivaylo Jivkov Elenkov (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2024-09-11, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Male molekule s novim mehanizmima djelovanja neophodne su u rješavanju izazovnih biomedicinskih problema današnjice poput rezistencije na postojeće lijekove za liječenje raka i zaraznih bolesti. Jedan od pristupa otkriću novih biološki aktivnih molekula uključuje sintezu usmjerenu na raznolikost (engl. diversity-oriented synthesis, DOS), koja primarno podrazumijeva razlike u strukturnoj okosnici, supstituentima i stereokemiji. Različiti lijekovi koji u svojoj strukturi sadrže morfolinski prsten imaju široku terapijsku primjenu. Privilegirani je farmakofor s mogućnošću stvaranja molekulskih interakcija s raznovrsnim biološkim metama i modificiranja farmakokinetičkih svojstava. Stoga je morfolin strukturni motiv od posebnog interesa za dizajniranje i razvoj lijekova. Istodobno je povećan interes za sintezu manje planarnih biološki aktivnih spojeva što rezultira uvođenjem spiro spojeva u nova istraživanja.
Slijedom navedenih spoznaja, cilj ovog diplomskog rada bila je sinteza i karakterizacija polisupstituiranog piperidino-morfolinskog spiro gradivnog bloka te njegova derivatizacija u svrhu dobivanja novih spojeva s različitim svojstvima, korištenjem principa sinteze usmjerene na raznolikost. Osnovna strukturna okosnica sintetizirana je preko dva sintetska puta, u šest odnosno četiri reakcijska koraka, od kojih je zadnji korak intramolekulska ciklizacija u bazičnim uvjetima. U nekoliko sljedećih sintetskih koraka, iz glavnog intermedijara 6, pripravljeni su odgovarajući prekursori. Šest novih derivata 9a-c i 13a-c dobiveno je iz spojeva 8 i 12 s dvije slobodne amino-skupine, završnim reakcijama N-acetiliranja, sulfonamidacije i Eschweiler-Clarke reakcijom. Strukturna raznolikost postignuta je supstituiranjem osnovne strukturne okosnice u tri različita položaja, a strukture novosintetiziranih spojeva potvrđene su uobičajenim spektroskopskim metodama (1D i 2D NMR, MS). Dokazana je izražena trodimenzionalnost struktura finalnih spojeva 9a-c i 13a-c pomoću NOESY NMR spektara. Finalnim spojevima određena su i fizikalno-kemijska svojstva in silico.

Abstract (english)

Small molecules with novel mechanisms of action are necessary in addressing today’s challenging biomedical problems such as resistance to existing drugs for the treatment of cancer and infectious diseases. One of the approaches to the discovery of new bioactive molecules includes diversity-oriented synthesis (DOS), which primarily implies differences in the molecular scaffold, substituents and stereochemistry. Various drugs containing a morpholine ring in their structure are widely used for the treatment of numerous diseases. It is a privileged pharmacophore with the possibility of forming molecular interactions with diverse biological targets and modifying pharmacokinetic properties. Therefore, morpholine is a structural motif of special interest for the drug design and development. At the same time, interest for the synthesis of less planar bioactive compounds increases, resulting in the introduction of spiro compounds into new studies.
Following the stated facts, the aim of this thesis was to synthesize and characterize polysubstituted piperidino-morpholine spiro building block. Furthermore, this scaffold was derivatized in order to obtain novel compounds with different properties, using the diversity-oriented synthesis approach. The scaffold was synthesized via two synthetic routes, in six or four reaction steps, with the last step of intramolecular cyclization under basic conditions. In several subsequent chemical reactions, the corresponding precursors were prepared from the main intermediate 6. Six novel derivatives 9a-c and 13a-c were obtained from compounds 8 and 12 with two free amino groups by N-acetylation, sulfonamidation and Eschweiler-Clarke reaction respectively. Structural diversity was achieved by substituting the scaffold at three different positions. The structures of the novel compounds were confirmed by standard spectroscopic methods (1D and 2D NMR, MS). Noticeable three-dimensionality of the structures of the final compounds 9a-c and 13a-c was proved by means of NOESY NMR spectra. Additionally, the physicochemical properties of final compounds were calculated in silico.

• Keywords: sinteza; sinteza usmjerena na raznolikost; morfolin; piperidin; spiro spoj
• Keywords (english): synthesis; diversity-oriented synthesis; morpholine; piperidine; spiro compound
• Language: croatian
• URN:NBN: urn:nbn:hr:163:804148
• Study programme: Title: Pharmacy - integrated undergraduate and graduate - university study; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: sveučilišni magistar farmacije (sveučilišni magistar farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2026-09-11
• Created on: 2024-10-11 10:38:45