Iskanje novih učinkovin za zaviranje rasti Candida albicans iz knjižnice spojin Fakultete za farmacijo Univerze v Ljubljani

Škufca, Nastja (avtor), Hrast Rambaher, Martina (mentor), Golob, Majda (komentor)

Rod Candida predstavlja kvasovke iz kraljestva gliv (Fungi), med katerimi je klinično pomembna tudi vrsta Candida albicans, saj povzroča sistemske kandidozne okužbe po vsem svetu. Zaradi naraščajoče odpornosti na obstoječa protiglivična zdravila ter njene izjemne sposobnosti preživetja v različnih okoljih, predstavlja ta kvasovka vse večji izziv v sodobni medicini. Na resnost problema opozarja tudi Svetovna zdravstvena organizacija (SZO), ki je kvasovko C. albicans uvrstila v kritično pomembno skupino patogenov. To dodatno poudarja potrebo po razvoju novih, učinkovitih protiglivičnih učinkovin. Ena izmed ključnih strategij pri odkrivanju novih potencialnih učinkovin je rešetanje knjižnice spojin. V okviru magistrske naloge smo glede protiglivičnega delovanja testirali 1629 spojin iz knjižnice spojin Fakultete za farmacijo Univerze v Ljubljani, ki so bile prvotno sintetizirane ali kupljene za potrebe različnih raziskovalnih projektov, usmerjenih predvsem v protitumorsko in protimikrobno delovanje ter v razvoj inhibitorjev določenih encimov. V presejalnem testiranju smo identificirali 12 spojin, ki so izkazale zaviralno delovanje na kvasovko C. albicans. V nadaljevanju smo tem potencialnim spojinam z mikrodilucijsko metodo določili minimalno inhibitorno koncentracijo (MIK) – najnižjo koncentracijo, ki še zavira rast mikroorganizmov. Na podlagi dobljenih rezultatov smo za 8 spojin z gotovostjo potrdili jasno zaviralno delovanje na kvasovko C. albicans. Največ aktivnih spojin je pripadalo derivatom pirido [4,3-b] karbazolov, ki so že znani po protitumorski aktivnosti in tudi protiglivičnem delovanju na kvasovko C. albicans. Velik potencial za razvoj novih protiglivičnih učinkovin pa predstavljajo spojine s cianotiofensko osnovo, naftamidno osnovo in derivati 6-(trifluorometil) pirimidin-2-amina. Rezultati te magistrske naloge predstavljajo pomembno izhodišče za nadaljnji razvoj potencialnih protiglivičnih učinkovin, vključno z analizo odnosa med strukturo in delovanjem (SAR), določitvijo mehanizmov delovanja in optimizacijo fizikalno-kemijskih lastnosti.

• Jezik: Slovenski jezik
• Ključne besede: knjižnica spojin, Candida albicans, mikrodilucijska metoda, minmalna inhibitorna koncentracija, protiglivične učinkovine
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2025
• PID: 20.500.12556/RUL-172732
• Datum objave v RUL: 11.09.2025

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Identification of novel compounds for inhibition of Candida albicans growth from the compound library of the Faculty of Pharmacy University of Ljubljana

Izvleček

The genus Candida belongs to the fungal kingdom (Fungi), among which the species Candida albicans is clinically important, as it is responsible for systemic candidiasis worldwide. Due to its increasing resistance to currently available antifungal agents and its remarkable ability to survive in diverse environments, this yeast represents an ever-growing challenge in modern medicine. The severity of the problem has also been highlighted by the World Health Organization (WHO), which has classified C. albicans as a critical priority pathogen. This further underscores the urgent need for the development of novel and effective antifungal agents. One of the key strategies in discovering new potential active compounds is the screening of compound libraries. As part of this master's thesis, a total of 1629 compounds from the compound library of the Faculty of Pharmacy, University of Ljubljana, were tested. These compounds had originally been synthesized or purchased for various research projects primarily focused on antitumor and antimicrobial activity, as well as on the development of specific enzyme inhibitors. In the initial screening, 12 compounds were identified as exhibiting inhibitory activity against C. albicans. Furthermore, the minimum inhibitory concentrations (MICs) of the potential compounds identified in the initial screening were determined using the microdilution method. Based on these results, 8 compounds were conclusively confirmed to exhibit clear inhibitory activity against C. albicans. The majority of active compounds belonged to derivatives of pyrido[4,3-b]carbazoles, which are known for their antitumor activity and have been previously associated with antifungal effects against C. albicans. Compounds with a cyanothiophene core, a naphthamide core, and derivatives of 6-(trifluoromethyl) pyrimidin-2-amine also demonstrated significant potential for the development of new antifungal agents. The results of this thesis therefore provide an important basis for the further development of potential antifungal agents, including structure–activity relationship (SAR) analysis, elucidation of mechanisms of action, and optimization of physicochemical properties.

• Ključne besede: compound library, Candida albicans, microdilution method, minimum inhibitory concentration, antifungal agents