Synthesis of New Derivatives Of Some Non-Steriodal Anti-inflammatory Drugs and Evaluation with Their Nanosystems


Thesis Type: Doctorate

Institution Of The Thesis: Hacettepe University, Fen Bilimleri Enstitüsü, Nanoteknoloji Ve Nanotıp A.B.D., Turkey

Approval Date: 2019

Thesis Language: Turkish

Student: Gülce Taşkor Önel

Consultant: Nezire Saygılı

Abstract:

NSAIDs, such as acetylsalicylic acid, ibuprofen, naproxen and flurbiprofen, are commonly used commercial drugs with weakly acidic structure. These types of drugs are well absorbed from the stomach and bowel mucosa. Treating pain by inhibiting COX-1 and COX-2 cyclooxygenase enzymes causes stomach discomfort.

In our study, pre-drug molecules were synthesized upon further reduction of acidity of various NSAIDs in order to reduce this side effect. Drugs were derivatized from the free carboxylic acid group which are the common functional group of NSAIDs.  In the synthesis step, the carboxylic acid group of NSAIDs was converted to acyl halides. After that the amide derivatives of NSAIDs were synthesized using amino acid ester and amino alcohol containing amino functional group with method of nucleophilic addition and elimination reactions. Chromatographic methods were used in purification studies (TLC and column chromatography) of synthesized molecules. 1H-NMR, 13C-NMR, HRMS, IR analysis methods were used in chemical structure characterization studies of prodrugs.

In the second step, the nanosystems of some of these novel drug derivatives were designed. Formulation of the structures of oil/water (o/w) nanoemulsion (NE) containing NSAIDs and prodrugs were studied. It was aimed to increasing the bioefficacy by preparing of nanoemulsions of both NSAIDs and some of the prodrugs. When preparing nanoemulsions, NSAIDs or the derivatives were first dissolved into oil phase. Then, by using the high pressure homogenization and the ultrasonic emulsification methods, the oil phase was added into the aqueous phase (o/w) and their colloidal dispersion systems with dimensions of 160-265 nm were prepared.  For the characterization studies of nanoemulsions were taken dimension and zeta potential measurements, for the morphologies of NE’s the TEM images were taken. In-vitro cell viability tests were performed by using cell culture techniques for the selected prodrug. The developed naproxen derivative prodrug was observed to be non-toxic on L929 mouse fibroblast cells at low concentration. In addition, when we examined the cytotoxicity of nanoemulsion of naproxen derivative prodrug, it was observed that the cell viability was higher than empty nanoemulsion in almost all concentrations. Anti-inflammatory and anti-oxidant tests were carried out for derivative molecules selected within the scope of biological activity studies.

According to the results obtained, novel prodrug molecules were synthesized by derivatization studies of NSAIDs. By converting the acidic carboxylic acid group to the amide group, the acidity of the NSAIDs were reduced. The nanoemulsion systems were formulated to increase the bioavailability of NSAIDs and prodrugs.