Doctoral Dissertation Abstracts
SYNTIIESIS, STRUCTURAL ELUCIDATION AND ENANTIOSEP ARATION OF SOME BIOLOG!CAL ACT!VE OCTAHYDROQUINAZOLINE
DERIVATIVES
Mine YARIM, Supervisor: Assoc. Prof. Dr. Selma SARAÇ, Department of Pharrnaceutical Chernistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, TURKEY.
Date of Defense: June 21, 2000.
In l:his study, twenty five 4-arylocta-hydroquinazoline -2,5-dione derivatives were synthesized and screened in vitro far their calciwn antagonistic activities. The cornpounds were prepared by reacting 5,5-dirnethyl- 1,3-cyc!ohexanedione with appropriate arornatic alde- hydes and urea/N-rnethylurea under rnodified Big- inelli reaction conditions.
The physical properties, Rı values on thin layer chrornatography and the UV absorption properties of the cornpounds were determined. The structure of the cornpounds were proved by IR, lH-NMR, 13C-NMR, mass spectroscopy, X-ray crystallography and elernantal analysis data.
The cornpounds were resolved into their enantiomers by high perforrnance liquid chromatography (HPLC) using cellulose tris- (3,5-dimethylphenylcarbamate) (Chiralcel OD) and amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD) as chiral stationary phase.
The calcium antagonistic activities of the compounds were determined by the tests performed on iso]ated rat ileum and lamb carotid artery. 4- (3-Chlorophenyl)-1,7,7-trimethyl-1, 2, 3, 4, 5, 6, 7, 8, -octahydroquinazdine-2, 5-dione (compound XVI) and 4-(3-bromophenyl)-1,7,7-trimethyl-l, 2, 3, 4, 5, 6, 7, 8-octahydroquinazdine-2,5-dione (compounds XIX) exerted a weak inhibitory effect on barium chloride-induced contractions in rat ileum. On lamb carotid artery stimulated with potassium ch!oride, compound XVI showed a contraction inhibition of 38.83 % and this compound was found rnore active than nicardipine (35.50 %).
STUDIES ON SUBSTITUTED 4(1H)-PYRID!NONE AND 4(1H)-PYRIDINTHIONE DERIV AT!VES
Mutlu DİLSİZ-AYTEMİR, Supervisor: Prof.Dr.Dilek Demir EROL, Cosupervisor: Prof. Dr. Robert C.
Hider, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara-Turkey.
Date of Defense: June 26, 2000.
In !his study, fortytwo new substituted 4(JH)- pyridinone and 4(1H)-pyridinthione derivatives were synthesized and their antimicrobial activity were tested in vitro.
3 / 5-Benzyloxy-2 / 6-methy l-N-substituted-4(1H)- pyridinone derivatives were prepared using AN- RORC mechanisrn in acidic condition. In addition to these compounds, 4(JH)-pyridinthione derivatives were synthesized from 4(1H)- pyridinone by using Lawesson's reagent. Hydroxy-4(JH)-pyridinone.HBr salts were prepared by hydrobromic acid. O- Benzotriazol-1-yl-N ,N,N' ,N'-tetramethyluronium tetrafluoroborate (TBTU) was used to synthesize the
substituted amid derivatives from 2 position of 4- pyrone ring.
The physical properties, Rı values on thin layer chromatography, melting points and the UV absorp- tion properties of the compounds were determined.
The structure of the compounds were c!arified by IR, lH-NMR, 13C-NMR, mass spectroscopy and el- emantal analysis data.
Antimicrobial activities of the synthesized com- pounds were investigated against to sorne Gram positive (Staphylcoccus aureus and Enterococcus facealis), Gram negative (Eschericia coli and Pseudo- monas aeroginosa) bacteria and yeast like fungi such as Candida albicans, C. krusei and C. par- apsilosis using microdilution method. Ceftazidime and fluconazole were used as reference drugs in an- tibacterial and antifungal activity studies re- spectively.
Particularly, Compounds 24, 28, 33 and 35 showed higher antibacterial and antifungal activity than the other compounds. Moreover, Compounds 28 (MIC: 8 µg/ıhl), 35 (MIC: 8 µg/ml) consist of hy- droxy-4(1H)-pyridinone structure and Compound 42 (MIC: 4 µg/ml), consists of 3-hydroxy-4-pyrone structure had higher activity !han fluconazole (MIC: 16-64 µg/ml), againts C. krusei.
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Doctoral Dissertation Abstracts
STIJDIES ON FORMULATION; DEGRADATION;
IN VITRO AND IN VIVO EVALUATION OF TERBUTALINE SULFATE LOADED
BIODEGRADABLE MICROP ARTICULAR SYSTEMS
Handan SELEK, Supervisor: Prof. Dr. Süheyla KAŞ,
Deparbnent of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, TURKEY
Date of Defense : June 26, 2000
Terbutaline sulfate (IBS), is a direct!y acting
~-adrenoreseptor sympatomimetic amine. It is used in the treabnent of bronchial astluna, chronic bronchitis and emphysema involving bronchospasm.
The objective of this study was to prepare microsphere formulations using natura! and synthetic biodegradable polymers in order to prolong the biological half-life (3-4 hrs), to control its release, to increase the patient compliance and to investigate the degradation of the microsphere formulations.
The TBS loaded microspheres were prepared by natura! biodegradable polymers, being starch and BSA and synthetic biodegradable polymers being two different mo!ecular weighed PLGA (75:25) (68900 Da and 14740 Da) L-PLA (48720 Da) and their rnixhıres
being, Mixtrıre I and Mixtrıre II.
Partide size, drug yield, encapsulation efficiency, release studies, swelling properties, visual degradation and microvolume degradation in the presence of enzymes and changes in pH of the medium and in vivo biodistribution of the prepared formulations were realized. The accumulation of the radiolabeled and passively targeted microspheres in the lungs were evaluated in vivo.
Among the in vitro and in vivo evaluated microspheres, TBS loaded BSA microspheres seem to fit the set objectives of the study.
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