Publication: 2-(Aroilamino)-3-Metilbütirik Asit Hidrazidi’nden türeyen 1,3-Tiyazolidin-4-On’ların sentezi ve yapılarının aydınlatılması
Abstract
1. ÖZET 1,3-Tiyazolidin-4-onlar’ın, antibakteriyel, anti-HIV1, antikanser, antikonvülsan, antipsikotik, antienflamatuar etki gösterdiği literatürlerde bildirilmiştir. Anabilim dalımızda sentezlenen 2-(5-nitro-2-furil)-3-{[4-(4-metoksibenzoilamino)benzoil)-amino}-4-tiyazolidinon’un Mycobacterium tuberculosis H37R’ye karşı 6.25 µg/ ml konsantrasyonda yüksek inhibisyon göstermesi, 1,3-tiyazolidin-4-on yapısında yeni bileşikler sentezlemek konusunda bizi cesaretlendirmiştir. Tezimizde başlangıç maddesi olarak seçilen L-Valin’in benzoillenmesiyle N-benzoil valin [1], bu maddenin esterleştirilmesiyle 2-(benzoilamino)-3-metil bütirik asit metil esteri [2], bileşik 2’nin hidrazin hidrat ile tepkimesinden 2-(benzoilamino)-3-metil bütirik asit hidraziti [3] elde edilmiştir. Bileşik 3’ün, çeşitli isotiyosiyanatlara katımı sonucunda elde edilen 1-[2-(benzoilamino)-3-metilbütiril]-4-alkil/ arilalkil tiyosemikarbazitlerin [4a-e], mutlak etanolde, sodyum asetat varlığında etil bromoasetat/ etil 2-bromopropionat ile tepkimesi sonucunda 2-[2-(benzoilamino)-3-metilbütirilhidra-zono]-3-alkil/ arilalkil-1,3-tiyazolidin-4-on’lar [5a-e] 2-[2-(benzoilamino)-3-metilbütirilhidrazono]-3-alkil/ arilalkil-5-metil-1,3-tiyazolidin-4-on’lar [6a-e] sentez-lenmiştir. Bileşik 3’ün, çeşitli aromatik aldehitlerle kondensasyonu sonucunda elde edilen 2-(benzoilamino)-3-metil-N′-(arilmetilen)bütanohidrazit’ler [7a-j] kuru benzende, merkaptoasetik asit / 2-merkaptopropionik asit ile Dean-Stark su tutucusu varlığında ısıtılarak 3-[2-(benzoilamino)-3-metilbütanamido]-2-aril-1,3-tiyazolidin-4-on’lar [8a-j] ve 3-[2-(benzoilamino)-3-metilbütanamido]-2-aril-5-metil-1,3-tiyazo-lidin-4-on’lar [9a-j] sentezlenmiştir. Sentezlenen bileşiklerin saflıkları İTK ve HPLC ile belirlenmiş, yapıları ; UV, IR, 1H-NMR, 13C-NMR, HR-EI ve HR-FAB kütle spektrumları yardımıyla saptanmıştır. Sentezlenen bileşiklerden 2-(benzoilamino)-3-metil-N′-(2-fluorometilen)bütanohidrazit’in [7c], 2-(benzoilamino)-3-metil-N′-(2,6-difluorometilen)bütanohidrazit’in [7f] ve 2-(benzoilamino)-3-metil-N′-(2-fluoro-6-klorometilen)bütanohidrazit’in [7g] HIV-1 IIIB suşuna karşı aktif olduğu tespit edilmiştir. Anahtar Sözcükler: Antiviral, hidrazit-hidrazon, 1,3-tiyazolidin-4-on, tiyosemikarbazit, L-Valin. 2.
Synthesis And Characterization of Novel 1,3-Thiazolidine-4-Ones Derived from 2-(Aroylamino)-3-Methyl Butyric Acid Hydrazide. 1,3-Thiazolidine-4-ones are known to possess antibacterial, anti-HIV1, anticancer, anticonvulsant, antipsychotic, and antiinflammatory activities. 2-(5-Nitro-2-furyl)-3-{[4-(4-methoxybenzoylamino)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 g/ ml. All of these encouraged us to design new 1,3-thiazolidine-4-ones. L-Valine was chosen as a starting compound and N-benzoyl valine [1] was prepared by benzoylation of valine. 2-(Benzoylamino)-3-methylbutyric acid methyl ester [2] was obtained by esterification of compound 1. 2-(Benzoylamino)-3-methylbutyric acid hydrazide [3] was prepared by heating compound 2 with hydrazine hydrate in methanol. By condensing compound [3] with various isothiocyanates in ethanol, 1-[2-(benzoylamino)-3-methylbutyryl]-4-alkyl/ arylalkyl thiosemicarbazides [4a-e] were synthesized. 2-[2-(Benzoylamino)-3-methylbutyrylhydrazono]-3-alkyl/ arylalkyl-1,3-thiazolidine-4-ones [5a-e] were synthesized by refluxing 1-[2-(benzoylamino)-3-methylbutyryl]-4-alkyl/ arylalkyl thiosemicarbazides [4a-e] and ethyl bromoacetate in the presence of sodium acetate in absolute ethanol. 2-[2-(Benzoylamino)-3-methylbutyrylyhydrazono]-3-alkyll/ arylalkyl-5-methyl-1,3-thiazolidine-4-ones [6a-e] were synthesized by compounds [4a-e] and ethyl bromopropionate in the presence of sodium acetate in absolute ethanol. 2-(Benzoylamino)-3-methyl-N′-(arylmethylene)butanohydrazides [7a-j] were carried out by refluxing compound [3] with various aromatic aldehyde in ethanolic medium. 3-[2-(Benzoylamino)-3-methylbutanamido]-2-aryl-1,3-thiazolidine-4-ones [8a-j] were synthesized by refluxing compounds [7a-j] with mercaptoacetic acid in dry benzene under Dean-Stark apparatus. 3-[2-(Benzoylamino)-3-methylbutanamido]-2-aryl-5-methyl-1,3-thiazolidine-4-ones [9a-j] were synthesized by refluxing compounds [7a-j] with mercaptopropionic acid in dry benzene under Dean-Stark apparatus. The purities of compounds were checked with TLC, HPLC. Their structures were elucidated by the use of their UV, IR, 1H-NMR, 13C-NMR, HR-EI and HR-FAB Mass spectral data. 2-(Benzoylamino)-3-methyl-N′-(2-fluoromethylene)butanohydrazide [7c], 2-(benzoylamino)-3-methyl-N′-(2,6-difluoromethylene)butanohydrazide [7f], 2-(benzoylamino)-3-methyl-N′-(2-fluoro-6-chloromethylene)butanohydrazide [7g] were found to be active againist HIV-1 strain IIIB . Antiviral, hydrazide-hydrazone, 1,3-thiazolidin-4-one, thiosemicarbazide, L-Valine.
Synthesis And Characterization of Novel 1,3-Thiazolidine-4-Ones Derived from 2-(Aroylamino)-3-Methyl Butyric Acid Hydrazide. 1,3-Thiazolidine-4-ones are known to possess antibacterial, anti-HIV1, anticancer, anticonvulsant, antipsychotic, and antiinflammatory activities. 2-(5-Nitro-2-furyl)-3-{[4-(4-methoxybenzoylamino)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 g/ ml. All of these encouraged us to design new 1,3-thiazolidine-4-ones. L-Valine was chosen as a starting compound and N-benzoyl valine [1] was prepared by benzoylation of valine. 2-(Benzoylamino)-3-methylbutyric acid methyl ester [2] was obtained by esterification of compound 1. 2-(Benzoylamino)-3-methylbutyric acid hydrazide [3] was prepared by heating compound 2 with hydrazine hydrate in methanol. By condensing compound [3] with various isothiocyanates in ethanol, 1-[2-(benzoylamino)-3-methylbutyryl]-4-alkyl/ arylalkyl thiosemicarbazides [4a-e] were synthesized. 2-[2-(Benzoylamino)-3-methylbutyrylhydrazono]-3-alkyl/ arylalkyl-1,3-thiazolidine-4-ones [5a-e] were synthesized by refluxing 1-[2-(benzoylamino)-3-methylbutyryl]-4-alkyl/ arylalkyl thiosemicarbazides [4a-e] and ethyl bromoacetate in the presence of sodium acetate in absolute ethanol. 2-[2-(Benzoylamino)-3-methylbutyrylyhydrazono]-3-alkyll/ arylalkyl-5-methyl-1,3-thiazolidine-4-ones [6a-e] were synthesized by compounds [4a-e] and ethyl bromopropionate in the presence of sodium acetate in absolute ethanol. 2-(Benzoylamino)-3-methyl-N′-(arylmethylene)butanohydrazides [7a-j] were carried out by refluxing compound [3] with various aromatic aldehyde in ethanolic medium. 3-[2-(Benzoylamino)-3-methylbutanamido]-2-aryl-1,3-thiazolidine-4-ones [8a-j] were synthesized by refluxing compounds [7a-j] with mercaptoacetic acid in dry benzene under Dean-Stark apparatus. 3-[2-(Benzoylamino)-3-methylbutanamido]-2-aryl-5-methyl-1,3-thiazolidine-4-ones [9a-j] were synthesized by refluxing compounds [7a-j] with mercaptopropionic acid in dry benzene under Dean-Stark apparatus. The purities of compounds were checked with TLC, HPLC. Their structures were elucidated by the use of their UV, IR, 1H-NMR, 13C-NMR, HR-EI and HR-FAB Mass spectral data. 2-(Benzoylamino)-3-methyl-N′-(2-fluoromethylene)butanohydrazide [7c], 2-(benzoylamino)-3-methyl-N′-(2,6-difluoromethylene)butanohydrazide [7f], 2-(benzoylamino)-3-methyl-N′-(2-fluoro-6-chloromethylene)butanohydrazide [7g] were found to be active againist HIV-1 strain IIIB . Antiviral, hydrazide-hydrazone, 1,3-thiazolidin-4-one, thiosemicarbazide, L-Valine.