Publication: Diflunisal’den hareketle yeni hirdazit-hidrazonların sentezi ve yapılarının aydınlatılması
Abstract
Sübstitüe hidrazit-hidrazonların antitüberküler, antimikrobiyal, antikonvülsan, antiinflamatuvar ve antikanser etkiler gösterdiği literatürlerde bildirilmiştir. Ayrıca, izonikotinil hidrazonlarının antitüberküler, 4-hidroksibenzoik asit [(5-nitro-2-furil)metilen] hidrazidinin (Nifuroksazit) bağırsak antiseptiği olarak antibakteriyel; Anabilim Dalımızda sentezlenen bileşiklerden N1-[(4-metoksibenzamido)benzoil]-N2-[(5-nitro-2-furil)metilen] hidrazidinin antibakteriyel ve 4-fluorobenzoik asit [(5-nitro-2-furil)metilen] hidrazidinin de Staphylococcus aureus ATCC 29213 suşuna karşı 3,13 g/ ml'lik konsantrasyonda antibakteriyel etkinliğinin olduğunun bildirilmesiyle yeni hidrazit-hidrazonların sentezi konusunda bizi cesaretlendirmiştir. Hidrazit-hidrazonların sentezini gerçekleştirmemizde sentez başlangıç maddesi olarak analjezik, antiinflamatuvar etkili bir ilaç olan 2 ,4 -difluoro-4-hidroksibifenil -3- karboksilik asiti seçtik. Diflunisal'in metanol ile birkaç damla derişik sülfürik asitli ortamdaki tepkimesinden metil 2 ,4 -difluoro-4-hidroksibifenil -3- karboksilik asit metil esteri [1], bu maddenin hidrazin-hidrat ile metanollü ortamda ısıtılması ile 2'4'-difluoro-4-hidroksibifenil-3-karboksilik asit hidraziti [2], hidrazidin etanollü ortamda 5-nitro-2-furaldehit ve sübstitüe benzaldehitlerle kondensasyonu ile hidrazit-hidrazon yapısındaki 2'4'-difluoro-4-hidroksibifenil-3-karboksilik asit [(5-nitro-2-furil/ substitüefenil) metilen] hidrazitler [3a-o] sentezlenmiştir. Sentezlenen bileşiklerin saflıkları ince tabaka kromatografisi ve elementel analiz (CHNS) ile belirlenmiş, yapıları UV, IR, 1H-NMR ve EI-Kütle (Electron Impact Ionization) spektrumları yardımıyla saptanmıştır. Çalışma kapsamında sentezlenen bileşiklerin antimikrobiyal etkileri T.C. Atatürk Üniversitesi Biyoteknoloji Merkezinde ve antikonvülsan etkileri de National Institue of Neurological Disorders and Stroke (NINDS)'te incelenmiştir. Disk difüzyon ve mikrodilüsyon yöntemleri kullanılarak yapılan antimikrobiyal etki taramasında standart ilaç olarak 4. kuşak sefalosporin olan Sefepim'in az etkili olduğu Staphylococcus epidermis HE-5 suşuna ve Staphylococcus aureus HE-9 suşlarına karşı 2',4'-difluoro-4-hidroksibifenil-[(5-nitro-2-furil)metilen]-3-karboksilik asit hidrazidinin [3a] 18,75 g/ ml ve 37,5 g/ ml'lik konsantrasyonlarda ve ayrıca Acinetobacter calcoaceticus İÖ-16 suşuna da 2',4'-difluoro-4-hidroksibifenil-[(2,4,6-trimetilfenil) metilen]-3-karboksilik asit hidraziti [3o] 37,5 g/ ml'lik konsantrasyonlarda etkili olduğu tespit edilmiştir. 2.
SYNTHESIS AND CHARACTERIZATION OF NOVEL HYDRAZIDE-HYDROZONES STARTING FROM DIFLUNISAL Substituted hydrazide-hydrazones are known to possess antitubercular, antimicrobial, anticonvulsant, antiinflamatuar and anticancer properties. Besides this, 4-hydroxybenzoic acid [(5-nitro-2-furyl)methylene] hydrazide (nifuroxazide) and isonicotinoyl hydrozones have exhibited antibacterial properties as intestine antiseptic and antitubercular properties respectively. N1-(4-methoxy benzamido) benzoyl]-N2-[(5-nitro-2-furyl)methylene] hydrazide and 4-fluorobenzoic acid [(5-nitro-2-furyl)methylene] hydrazide synthesized in our laboratory have been shown to posses antibacterial activity. The latter possess antibacterial property towards Staphylococcus aureus ATCC 29213 concentration of at a 3,13 µg/ ml. All of these encouraged us to design new hydrazide-hydrazones. 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid (Diflunisal) which possess analgesic and antiinflamatuar activity was chosen as a starting compound to design new hydrazide-hydrazones. 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid methyl ester was prepared by the reaction of diflunisal and methanol in a few drops of concentrated sulfuric acid. 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid hydrazide was synthesized by heating hydrazine hydrate and 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid methyl ester in methanol. After condensing hydrazine hydrate with 5-nitro-furalaldehyde and substituted benzaldehydes, 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid[(5-nitro-2-furyl/ substitue phenyl) methylene] hydrazides [3a-o] was obtained. The purities of the synthesized compounds were checked with thin layer chromotography and elemental analysis. Their structures were elucidated with UV, IR, 1H-NMR and EI-mass spectroscopic methods. Antimicrobial activity of the products was tested by T.C. Atatürk University, Biotechnology and Research Center and anticonvulsant activity was tested [National Institue of Neurological Disorders and Stroke (NINDS)]. Microdilution and disc diffusion methods were used for determination of antimicrobial activity. 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid[(5-nitro-2-furyl)methylene] hydrazide [3a] have shown activity against Staphylococcus epidermis HE-5 and Staphylococcus aureus HE-9 at a concentration of 18.75 µg/ ml and 37.5 µg/ ml, respectively. In addition, 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid[(2,4,6-trimethyl phenyl) methylene] hydrazide [3o] have exhibited activity against Acinetobacter calcoaceticus İÖ-16 at a concentration of 37.5 µg/ ml, whereas Cefepime, the drug used as standart, have been found less active against the microorganisms mentioned above.
SYNTHESIS AND CHARACTERIZATION OF NOVEL HYDRAZIDE-HYDROZONES STARTING FROM DIFLUNISAL Substituted hydrazide-hydrazones are known to possess antitubercular, antimicrobial, anticonvulsant, antiinflamatuar and anticancer properties. Besides this, 4-hydroxybenzoic acid [(5-nitro-2-furyl)methylene] hydrazide (nifuroxazide) and isonicotinoyl hydrozones have exhibited antibacterial properties as intestine antiseptic and antitubercular properties respectively. N1-(4-methoxy benzamido) benzoyl]-N2-[(5-nitro-2-furyl)methylene] hydrazide and 4-fluorobenzoic acid [(5-nitro-2-furyl)methylene] hydrazide synthesized in our laboratory have been shown to posses antibacterial activity. The latter possess antibacterial property towards Staphylococcus aureus ATCC 29213 concentration of at a 3,13 µg/ ml. All of these encouraged us to design new hydrazide-hydrazones. 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid (Diflunisal) which possess analgesic and antiinflamatuar activity was chosen as a starting compound to design new hydrazide-hydrazones. 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid methyl ester was prepared by the reaction of diflunisal and methanol in a few drops of concentrated sulfuric acid. 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid hydrazide was synthesized by heating hydrazine hydrate and 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid methyl ester in methanol. After condensing hydrazine hydrate with 5-nitro-furalaldehyde and substituted benzaldehydes, 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid[(5-nitro-2-furyl/ substitue phenyl) methylene] hydrazides [3a-o] was obtained. The purities of the synthesized compounds were checked with thin layer chromotography and elemental analysis. Their structures were elucidated with UV, IR, 1H-NMR and EI-mass spectroscopic methods. Antimicrobial activity of the products was tested by T.C. Atatürk University, Biotechnology and Research Center and anticonvulsant activity was tested [National Institue of Neurological Disorders and Stroke (NINDS)]. Microdilution and disc diffusion methods were used for determination of antimicrobial activity. 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid[(5-nitro-2-furyl)methylene] hydrazide [3a] have shown activity against Staphylococcus epidermis HE-5 and Staphylococcus aureus HE-9 at a concentration of 18.75 µg/ ml and 37.5 µg/ ml, respectively. In addition, 2´,4´-difluoro-4-hydroxybiphenyl-3-carboxylic acid[(2,4,6-trimethyl phenyl) methylene] hydrazide [3o] have exhibited activity against Acinetobacter calcoaceticus İÖ-16 at a concentration of 37.5 µg/ ml, whereas Cefepime, the drug used as standart, have been found less active against the microorganisms mentioned above.