Sinteza ustrezno substituiranih tiazolo[4,5-c]kinolinov kot potencialnih protituberkoloznih učinkovin : [diplomska naloga]

Božič, Dane (author), Anderluh, Marko (mentor)

Tuberkuloza je danes ena najbolj razširjenih bakterijskih bolezni, za katero letno umre približno 2 milijona ljudi po celem svetu. Število novoobolelih se iz leta v leto drastično povečuje in bo po ocenah Svetovne zdravstvene organizacije kmalu doseglo 10 milijonov. Stanje še poslabšuje pojav rezistentnih sevov Mycobacterium tuberculosis na do sedaj odkrite antibiotike, kar narekuje nujo po odkrivanju novih protituberkuloznih učinkovin. Tega se zavedajo tudi v originatorskih farmacevtskih podjetjih, saj je opaziti vedno več publikacij s področja protituberkuloznih učinkovin ravno iz originatorskih laboratorijev. Katedra za farmacevtsko kemijo na Fakulteti za farmacijo sodeluje v skupnem evropskem projektu »Open Collaborative Model for Tuberculosis Lead Optimisation« (akronim »ORCHID«) z madridskim laboratorijem Tres Cantos Medicines Development Campus podjetja GlaxoSmithKline pri razvoju novih protituberkuloznih učinkovin. Razvili so več derivatov tiazolo[4,5-c]kinolinov in nekateri med njimi so izkazovali zelo dobro učinkovitost proti sevom Mycobacterium tuberculosis. Žal pa vse učinkovine kažejo tendenco k slabi vodotopnosti.Med diplomskim delom smo v laboratoriju želeli izdelati nove analoge spojine vodnice z namenom ohraniti ali izboljšati protimikobakterijski učinek ter izboljšati vodotopnost spojin, s čimer bi posledično povečali obseg absorpcije in biološko uporabnost. Sintetizirali smo dve spojini, ki imata skupen tiazolo[4,5-c]kinolinski skelet, razlikujeta pa se v substituentu na mestu 6 na kinolinskem ter mestu 2' na tiazolnem obroču. Pri sintezi prve končne spojine smo kot reagent uporabili p-nitrofenilocetno kislino, ki bi po našem mnenju lahko prispevala k boljšemu protimikobakterijskemu delovanju, k izboljšanju farmakokinetičnih lastnosti pa verjetno ne tako bistveno. Za sintezo druge končne spojine smo uporabili BOC-fenilglicin, ki bi lahko pripomogel k enakemu ali celo izboljšanemu protimikobakterijskemu učinku, drastično pa bi pripomogel k izboljšanju farmakokinetičnih lastnosti. Druga spojina za razliko od prve na mestu 6 nima klorovega atoma, kar bi lahko vplivalo na jakost in spekter delovanja. Sinteza tretje končne spojine, pri kateri smo kot kislino uporabili 2-amino-4-tiazolocetno kislino, ni uspela zaradi porabe izhodne spojine. Obe končni spojini smo poslali na določanje protimikobakterijskega učinka.

• Language: Slovenian
• Keywords: sintezni postopki tuberkoloza zdravljenje 6-kloro-2-metil-4-kinolinol reakcijske sheme
• Work type: Undergraduate thesis
• Typology: 2.11 - Undergraduate Thesis
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [D. Božič]
• Year: 2011
• Number of pages: VIII, 62 f.
• PID: 20.500.12556/RUL-71262
• UDC: 54.057
• COBISS.SI-ID: 3149425
• Publication date in RUL: 10.07.2015

Secondary language

• Language: English
• Title: Synthesis of suitable subsituted thiazolo[4,5-c]quinolines as potential antitubercular drugs

Abstract

Nowadays tuberculosis is one of the most widely spread diseases, which annually takes 2 million human lives worldwide. The number of new cases is drastically rising and will soon reach 10 million according to the World Health Organisation. To make it worse the emergence of drug resistant strains of Mycobacterium tuberculosis to current regimen makes the researching for novel drugs an urgent priority. More and more publications about antitubercular drugs come from originator pharmaceutical companies that are aware of the severity of the situation. Department for Pharmaceutical Chemistry from Faculty of Pharmacy, University of Ljubljana participates in the development of new antitubercular drugs in the European project »Open Collaborative Model of Tuberculosis Lead Optimisation« (acronime »ORCHID«) with Madrid laboratory Tres Cantos Medicines Development Campus of GlaxoSmithKline company. The latter developed derivatives of thiazolo[4,5-c]quinolines and some of them were very effective against Mycobacterium tuberculosis strains. Unfortunately, all of them showed tendency toward poor solubility in water During thesis we have tried to synthesize new analogues of a lead compound aiming to retaining or improving antimicobacterial activity and improve water solubility, which will further lead to greater extent of absorption and bioavailability. We synthesized two compounds, which both had a common thiazolo[4,5-c]quinoline scaffold, the only differences were the substituents at place 6 in quinoline and place 2' in thiazolo ring. In the synthesis of the first final compound we used p-nitrophenylacetic acid, which in our opinion may improve the antimicobacterial activity but not the pharmacokinetic properties. BOC-phenylglycin was used to synthesize the second final compound. We think it might possess an equal or better antitubercular activity and contribute to superior pharmacokinetic properties. Because of the missing chlorine atom at the place 6 this compound might slightly differ in its potency and antibacterial spectrum. Synthesis of the third final compound with 2-amino-4-thiazoloacetic acid never could not be accomplished because we have run out of the parent compound. Both final compounds will be further evaluated for antimicobacterial activity.