2-(aroilamino)-4-(metiltiyo)-bütirik asit hidrazidinden türeyen yeni açiltiyosemikarbazidler ve 1,3-tiyazolidin-4-on`ların sentezi ve yapılarının aydınlatılması
Synthesis and characterization of novel acylthiosemicarbazides and 1,3-thiazolidine-4-ones derived from 2-(aroylamino)-4-(methylthio) butyric acid hydrazide
Yazar: ESRA TATAR
Danışman: DOÇ.DR. İLKAY KÜÇÜKGÜZEL
Marmara Üniversitesi / Sağlık Bilimleri Enstitüsü / Farmasötik Kimya Ana Bilim Dalı
Derece: Yüksek Lisans, 2004
Konu: Eczacılık ve Farmakoloji = Pharmacy and Pharmacology

Özet:
1, 3-Tiyazolidin-4-onlar'ın, antibakteriyel, antifungal, anti-HIVl, antikonvülsan, antipsikotik, antienflamatuar, antidiyareik, antikanser ve kalsiyum antagonisti etki gösterdiği literatürlerde bildirilmiştir. Anabilim Dalımızda sentezlenen 2-(5-nitro-2- furil)-3-{[4-(4-metoksibenzoilarrımo)benzoil)annno}-4-tiyazolidinon'un Mycobacterium tuberculosis fD7J?'ye karşı 6.25 jig/ml konsantrasyonda yüksek inhibisyon göstermesi, l,3-tiyazolidin-4-on yapısmda yeni bileşikler sentezlemek konusunda bizi cesaretiendirmiştir. Tezimizde başlangıç maddesi olarak seçilen L-Metiyonin'in benzoillenmesiyle N- benzoil metiyonin [1], bu maddenin esterleştirilmesiyle 2-(benzoilamino)-4- (metiltiyo)butirik asit metil esteri [2], bileşik 2'nin hidrazin hidrat ile reaksiyonundan 2- (benzoilarnino)-4-(metiltiyo)butirik asit hidrazidi [3] elde edilmiştir. Bileşik 3 'ün, çeşitli isotiyosiyanatlara katımı sonucunda elde edilen l-[2-(benzoilamino)-4- (metiltiyo)butiril]-4-alkil/arilalkil tiyosemikarbazidler [4a-d], absolü etanolde, sodyum asetat varlığında etil bromoasetat ile reaksiyona sokularak N-{l-[[2-(3-alkil/arilalkil-4- okso-l,3-tiyazolidm-2-iliden)Wdrazmo]-karbonil]-3-(metiltiyo)-propil}benzamid'ler [5a-d] sentezlenmiştir. Bileşik [5a-d]'nin metanolde, sodyum metoksit varlığında aromatik aldehitlerle kondensasyonu sonucunda N-{l-[[2-[5-(nonsübstitüe/sübstitüe benziliden)-3-aMl/arilalMl-4-okso-l,3-tiyazolidm-2-iliden]Mdrazmo]karbonil]-3-(me- tiltiyo)propil}benzamid'ler [5a ı_ 4, 5b 1-4, 5c 1.4, 5d 1.4] kazamlmıştır. Sentezlenen bileşiklerin saflıkları ÎTK ve HPLC ile belirlenmiş, yapıları ; UV, İR, 'H-NMR, 13C- NMR, HR-EI ve HR-FAB kütle spektrumlan yardımıyla saptanmıştır. Sentezlenen bileşiklerden 1, 2, 3, 4a-d, 5a-d'nin antikonvülsan etkileri National Institute of Neurological Disorders and Stroke (NINDS/te, sentezlenen tüm bileşiklerin antimikrobiyal etkileri T.C. Atatürk Üniversitesi Biyoteknoloji Merkezfnde, antiviral etkileri Rega Institute for Medical Research (Katholieke Universiteit Leuvenfde incelenmiştir.Antimikrobiyal etki taramasında bileşik 5dı ve 5d3 Staphylococcus aureus ATCC 29213 susuna, bileşik 5dı ve Scfe Bacillus subtilis A57 susuna, Sdb ise Candida albicans A-l 77 susuna karşı vasat etkili bulunmuştur.

Abstract:
Synthesis and characterization of novel acylthiosemicarbazides and 1,3-thiazolidine- 4-ones derived from 2-(aroylamino)-4-methylthio)butyric acid hydrazide l,3-Thiazolidine-4-ones are known to possess antibacterial, antifungal, anti-HTVl, anticonvulsant, antipsychotic, antiinflammatory, antidiarrheal, anticancer, calcium antagonist activities. 2-(5-Nitro-2-furyl)-3-{ [4-(4-memoxy-benzoylamino)benzoyl)- amino}-4-thiazolidinone was synthesized previously in our laboratory and it exhibits high inhibition againist Mycobacterium tuberculosis H37Rv at a concentration of 6,25 fig/ml. All of these encouraged us to design new l,3-thiazolidine-4-ones. L-Methionine was chosen as a starting compound and N-benzoyl methionine [1] was prepared by benzoylation of methionine. 2-(Berizoylamino)-4-(methylthio)butyric acid methyl ester [2] was obtained by esterification of compound 1. 2-(Benzoylamino)- 4-(methylthio)butyric acid hydrazide [3] was prepared by heating compound 2 with hydrazine hydrate in methanol. By condensing compound [3] with various isothiocyanates in ethanol, l-[2-(Benzoylamino)-4-(methylthio)butyryl]-4-alkyl/- aıylalkylthiosemicarbazides [4a-d] were synthesized. N-{l-[[2-(3-alkyl/arylalkyl-4- oxo- 1,3 -thiazolidin-2-ylidene)hydrazino] carbonyl] -3 -(methylthio)propyl }benzamides [5a-d] were synthesized by refluxing the thiosemicarbazides [4a-d] and ethyl bromoacetate in the presence of sodium acetate in absolute ethanol. Synthesis of N-{ 1- [ [2- [5-(nonsubstituted/substituted benzylidene)-3 -alkyl/arylalkyl-4-oxo- 1,3 -thiazolidin- 2-ylidene]hydrazmo]carbonyl]-3-(memyl-thio)-propyl}benzamide derivatives [5ai-4, 5bı^, 5ci^t, 5di_4] were carried out by refluxing compounds 5a-d with aromatic aldehydes in the presence of sodium methoxide in methanolic medium. The purities of compounds were checked with TLC, HPLC. Their structures were elucidated by the use of their UV, IR, 'H-NMR, 13C-NMR, HR-EI and HR-FAB Mass spectral data. Anticonvulsant activity of the compounds 1, 2, 3, 4a-d and 5a-d was tested by National Institute of Neurological Disorders and Stroke (NINDS). Antimicrobial activity of all the synthesized compounds was screened by Biotechnology Application and Research Center, Atatürk University, Erzurum ; and, antiviral activity of allcompounds was examined by Rega Institute for Medical Research (Katholieke Universiteit Levy en). Compounds 5di, 5d3 exhibited activity against Staphylococcus aureus ATCC 29213, compound 5di, 5d2 showed activity against Bacillus subtilis A57 and compound 5d3 was observed to have positive response against Candida albicans A 177.