Yeni 6-metilimizado[2,1-b]tiyazol-5-karbohidrazid türevlerinin sentezi ve yapılarının aydınlatılması
Synthesis and characterization of new 6-methylimidazo[2,1-b]thiazole-5-carbohydrazide derivatives
Yazar: FÜSUN UR GÖKTAŞ
Danışman: DOÇ.DR. NESRİN CESUR
İstanbul Üniversitesi / Sağlık Bilimleri Enstitüsü / Farmasötik Kimya Ana Bilim Dalı
Derece: Yüksek Lisans, 2001
Konu: Eczacılık ve Farmakoloji = Pharmacy and Pharmacology

Özet:
188 ÖZET Bu çalışmada imidazo[2,1-6]tiyazol halka sistemi taşıyan aşağıdaki bileşikler elde edilmiştir: 6-Metil-N2-(1-metiletiliden)imidazo[2,1-ö]tiyazol-5-karbohidrazid(lll) 6-Metil-N2-(1-metilpropiliden)imidazo[2,1-ö]tiyazol-5-karbohidrazid (IV) 6-Metil-N2-(1-etilpropiliden)imidazo[2,1-ö]tiyazol-5-karbohidrazid (V) 6-Metil-N2-(siklopentiliden)imidazo[2,1-ö]tiyazol-5-karbohidrazid(VI) 6-Metil-N2-(siklohekziliden)imidazo[2,1-ö]tiyazol-5-karbohidrazid(VII) 6-Metil-N2-(4-metilsiklohekziliden)imidazo[2,1-ö]tiyazol-5-karbohidrazid (VIII) 6-Metil-N2-(4-etilsiklohekziliden)imidazo[2, 1 -ö]tiyazol-5-karbohidrazid (IX) 2,2-Dimetil-3-[[(6-metilimidazo[2,1-ö]tiyazol-5-il)karbonil]amino]-4-tiyazolidinon(X) 2-Etil-2-metil-3-[[6-metilimidazo[2, 1 -ö]tiyazol-5-il)karbonil]amino]-4-tiyazolidinon (XI) 2, 2-Dietil-3-[[(6-metilimidazo[2,1-ö]tiyazol-5-il)karbonil]amino]-4-tiyazolidinon(XII) 2-Etil-3-[[(6-metilirnidazo{2,1-b]tiyazol-5-il)karboniI]amino]-2-pentil-4-tiyazolidinon(X!ll) 4-[[(6-Metilimidazo[2,1-ö]tiyazol-5-il)karbonil]amino]-1-tiya-4-azaspiro[4.4]nonan-3-on (XIV) 4-[[(6-Metilimidazo[2,1-ö]tiyazol-5-il)karbonil]amino]-1-tiya-4-azaspiro[4.5]dekan-3-on(XV) 8-MetiW-[[(6-metilimidazo[2,1-b]tiyazol-5-il)karborıil]amino]-1-tiya-4-azaspiro[4.5]dekan-3-orı (XVI). 8-Etil-4-[[(6-metilimidazo[2,1-ö]tiyazol-5-il)karbonil]amino]-1-tiya-4-azaspiro[4.5]dekan-3-on (XVII) Bu amaçla 2-aminotiyazol ve etil 2-kloroasetoasetatın reaksiyonu ile elde edilen etil 6-metilimidazo[2,1-b]tiyazol-5-karboksilat (I), hidrazin hidrat ile etkileştirilerek 6- metilimidazo[2,1-ö]tiyazol-5-karbohidrazid (II) kazanılmış; H'nin etanollü ortamda 2- propanon, 2-butanon, 3-pentanon, siklopentanon, siklohekzanon, 4-metilsiklohekzanon ve 4-etilsiklohekzanon ile kondensasyonundan literatürde yer almayan yedi yeni bileşik (III-IX) kazanılmıştır. III-IX susuz benzenli ortamda Dean-Stark tuzağı kullanılarak merkaptoasetik asid ile siklokondensasyona sokulmuş ve X-XII ile XIV-XVII bileşikleri; II, 3-oktanon ve merkaptoasetik asidin susuz benzenli ortamda Dean-Stark tuzağı kullanılarak birarada reaksiyona sokulmasıyla da XIII bileşiği kazanılmıştır. Bileşiklerin oluşum mekanizmaları tartışılmış ve sentez edilen bileşiklerin yapıları elementel analiz, UV, İR, 1H-NMR, HETCOR (13C-1H) ve kütle spektrumu verileri ile kanıtlanmıştır.189 Elde edilen tüm bileşiklerin Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella flexneri, Proteus mirabilis ATCC 14153 ve Candida albicans ATCC 10231'e karşı antimikrobiyel etkileri araştırılmış, XIII, XV ve XVI numaralı bileşiklerde S.epidermidis'e karşı değişen derecelerde etki saptanmıştır (MİK 19.5-78 jıg/ml).

Abstract:
190 SUMMARY in this study the synthesis of the following compounds bearing the imidazo- [2,1-6]thiazole ring system has been described: 6-Methyl-N2-(1-methyIethylidene)imidazo[2,1-ö]thiazol-5-carbohydrazide(lll) 6-Methyl-N2-(1-methylpropylidene)imidazo[2,1-ö]thiazol-5-carbohydrazide(IV) 6-MethyI-N2-(1-ethylpropylidene)imidazo[2,1-ö]thiazol-5-carbohydrazide(V) 6-Methyl-N2-(cyclopentylidene)imidazo[2, 1 -6]thiazol-5-carbohydrazide (VI) 6-Methyl-N2-(cyclohexylidene)imidazo[2,1-6]thiazol-5-carbohydrazide(VII) 6-Methyl-N2-(4-methylcyclohexylidene)imidazo[2,1-ö]thiazol-5-carbohydrazide(VIII) 6-Methyl-N2-(4-ethylcyclohexylidene)imidazo[2, 1 -6]thiazol-5-carbohydrazide (IX) 2l2-Dimethyl-3-[[(6-methylimidazo[2)1-ö]thiazol-5-il)carbonyl]amino]-4-thiazolidinone(X) 2-Ethyl-2-methyl-3-[[6-methylimidazo[2,1-ö]trıiazol-5-yl)carbonyl]amino]-4-thiazolidinone(XI) 2,2-Diethyl-3-[[(6-methylimidazo[2,1-ö]thiazol-5-yl)carbonyl]amino]-4-thiazolidinone(XII) 2-Ethyl-3-[[(6-methylimidazo{2,1-ö]thiazol-5-yl)carbonyl]amino]-2-pentyl-4-thiazolidinone(XIII) 4-[[(6-Methylimidazo[2,1-ö]thiazol-5-yl)carbonyl]amino]-1-thia-4-azaspiro[4.4]norıan-3-one(XIV) 4-[[(6-Methylimidazo[2,1-ö]thiazol-5-yl)carbonyl]amino]-1-thia-4-azaspiro[4.5]decan-3-one(XV) 8-MethyM^[(6-methylimidazo[2,1-ö]thiazol-5-il)carbonyl]amino]-1-thia-4-azaspiro[4.5]decan-3- one (XVI) 8-Ethyl-4-[[(6-methylimidazo[2, 1 -ö]thiazol-5-il)carbonyl]amino]-1 -thia-4-azaspiro[4.5]decan-3- one (XVII) Thus ethyl 6-methylimidazo[2,1-ö]thiazol-5-carboxylate (I), obtained from the reaction of 2-aminothiazole with ethyl 2-chloroacetoacetate, was reacted with hydrazine hydrate to yield 6-methylimidazo[2,1-6]thiazol-5-carbohydrazide (II). II was converted to hitherto unknown hydrazide-hydrazones on treatment with 2-propanone, 2-butanone, 3-pentanone, cyclopentanone, cyclohexanone, 4-metylcyclohexanone and 4-ethylcyclohexanone, respectively. Cyclocondensation of hydrazide-hydrazones with mercaptoacetic acid in dry benzene using a Dean-Stark water trap yielded compounds X-XVII. The synthesis of XIII could be achieved reacting II, 3-octanone and mercaptoacetic acid under the above reaction conditions.191 The mechanisms of the reaction involved in the formation starting materials and the end products have been discussed in the appropriate sections and the structures of the new compounds (lll-XVII) have been confirmed on the basis of elemantal analysis and data obtained from UV, IR,1H-NMR, 13C-NMR, HETCOR (13C-1H) and mass spectra. All the compounds were tested for antimicrobial activity against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella flexneri, Proteus mirabilis ATCC 14153 and Candida albicans ATCC 10231. Compound XIII, XV and XVI demonstrated varying degrees of antimicrobial activity against S. epidermidis (MIC 19.5-78 ng/ml'1).