Publication: 4-amino- 3,5- dimetilpirazolden türeyen sübstitüe üre, tiyoüre ve hidrazonların sentezi ve biyolojik aktivitelerinin incelenmesi
Abstract
Yapısında çeşitli sübstitüentler içeren pirazol türevlerinin antikonvulsan, antibakteriyal, hipoglisemik, analjezik, antiinflamatuvar ve antitümoral etki gösterdikleri bilinmektedir. Ayrıca literatürlerde hidrazon yapısı içeren maddelerin antimikrobiyal, tiyoüre ve ürelerin antikonvulsan, antihipertansif, antimikrobiyal, antiinflamatuvar, anti-HIV etkilerinin bulunduğu kaydedilmiştir. Hem pirazol ana yapısının hem de eklenecek grupların önemli farmakolojik aktivitelerin bulunması sentezlenecek bileşiklerin seçiminde önemli etken olmuştur. Bu çalışmada 4-amino-3,5-di/ 1,3,5-trimetilpirazolden hareketle yeni hidrazon, tiyoüre ve üre türevleri sentezlenmiştir. 4-Amino-3,5-dimetilpirazol (1) ve 4-amino-1,3,5-trimetilpirazol (2), 4-(fenilazo)-3,5-dimetilpirazol ve 4-(4-karbetoksifenilazo)-1,3,5-trimetilpirazol'ün etanollü ortamda hidrazin hidrat ile redüksiyonuyla elde edilmiştir. Madde 1 ve 2'nin diazonyum tuzlarının sodyum asetatlı ortamda asetilaseton, etil asetoasetat, 1-benzoilaseton, 6-metilheptan-2,4-dion ve metil 4-metoksiasetoasetat ile kenetlenmesiyle 3a-e, 6a-b maddeleri elde edilmiştir. Ayrıca madde 1 ve 2'nin sübstitüe izotiyosiyanatlar yada izosiyanatlar katımı sonucu tiyoüre türevi 4a-m, 7a-b ve üre türevi 5a-b, 8 maddeleri kazanılmıştır. Sentezlenen bileşiklerin yapıları elementel analiz, UV, IR, 1H-NMR, 13C-NMR ve Kütle spektral analizleri yardımıyla aydınlatılmıştır. Hidrazon türevlerinin (3a-e, 6a-b) 1H-NMR spektrumlarında hidrazon NH protonları 11.50-15.00 ppm arasında sinyal vermiştir. Ancak 3a, 3d ve 3e bileşiklerinde hidrazon protonlarının üç farklı alanda saptanması bileşiklerin izomerlerinin bulunduğunu göstermiştir. Tiyoüre türevlerinin (4a-m, 7a-b) 1H-NMR spektrumlarında da N1'de alkil grubu içeren bileşiklerde N1-H protonları 6.75-7.10 ppm, N2-H protonları 8.40-8.70 ppm arasında sinyal vermiştir. N1'de aril içeren bileşiklerde ise bu protonlar syn(Z) ve anti (E) izomerleri nedeniyle 8.40-10.05 ppm'ler arasında yaygın pikler halinde gözlenmiştir. Tüm bileşikler Mycobacterium tuberculosis H37Rv suşuna karşı 6.25mg/ ml konsantrasyonda test edilmiştir. Hidrazon türevlerinden etil 2-[(3,5-dimetilpirazol-4-il)hidrazono]-3-oksobütirat (3d) % 29 ve metil 2-[(3,5-dimetilpirazol-4-il)hidrazono]-4-metoksi-3-oksobütirat (3e) %28 inhibisyon göstermişlerdir. İncelenen tiyoüre ve üre türevlerinin ise belirgin bir inhibisyon göstermediği tespit edilmiştir. Antikonvulsan aktivite tarama kapsamında prototip olarak seçilen madde 4a, 4f, 4g, 4l ve 7b'nin Pentilentetrazol (PTZ) ile oluşturulan konvulsiyonlara karşı incelenmiştir. Test edilen bileşiklerden 25mg/ kg dozda 4a %40, 4l %30 ve 4f, 4g, 7b ise %50'lik bir koruma sağlamışlardır. Ayrıca madde 4l denenen 50 ve 100 mg/ kg dozlarda doza bağımlı koruma göstermiştir.
SYNTHESIS OF SUBSTITUTED UREA, THIOUREA AND HYDRAZONES FROM 4-AMINO-3,5-DIMETHYLPYRAZOLE AND STUDYING THE BIOLOGICAL ACTIVITIES The anticonvulsant, antibacterial, hypoglycemic, analgesic, antiiflammatory and antitumoral effects of substituent form of pyrazole derivatives is known. It was recorded that the compounds containing hydrazone, thiourea and urea groups have antimicrobial, antihypertensive, antiinflammatory and anti-HIV effects. Identification of pyrazole main structure and pharmacological activity of substituents is an important factor to decide synthesis of new compounds. In this search, compounds containing hydrazone, thiourea and urea substituents were synthesized from the 4-amino 3,5-di/ 1,3,5-trimethylpyrazoles. 4-amino-3,5-dimethylpyrazole (1) and 4-amino-1,3,5-trimethylpyrazole (2) were obtained from the reduction of 4-(phenylazo)-3,5-dimethylpyrazole and 4-(4-carbetoxyphenylazo)-1,3,5-trimethylpyrazole with hydrazine hydrate in ethanolic medium. Aryldiazonium salts of the compounds 1 and 2 coupled with acetylacetone, 1-benzoylacetone, ethyl acetoacetate, 6-methyl heptane-2,4-dione and methyl 4-methoxyacetoacetate in the presence of sodium acetate to give 3a-e and 6a-b. Furthermore thiourea (4a-m, 7a-b) and urea (5a-b, 8) derivatives were obtained by the addition of compounds 1 and 2 to substituted isothiocyanates or isocyanates. The synhesized compounds were elucidated using elemental analysis and UV, IR, 1H-NMR, 13C-NMR and Mass spectroscopy. 1H-NMR spectra of the coupling products (3a-e, 6a-b) exhibited a hydrazone NH group at 11.00-15.00 ppm. Observing hydrazone protons of compounds 3a, 3d and 3e in three different fields proves the existance of isomers of 3a, 3d and 3e. In the 1H-NMR spectra of the thiourea derivatives, the compounds containing alkyl groups attached to N1 showed the N1-H and N2-H protons at 6.75-7.10 and 8.40-8.70 ppm respectively. The same protons of the compounds containing aryl group at N1 position were observed by wide spread peak at 8.40-10.05 ppm, because of the syn or anti isomers. The synthesized molecules were tested to antituberculosis activity against Mycobacterium tuberculosis at 6.25 mg/ ml concentration. Both hydrazone products, ethyl 2-[(3,5-dimethylpyrazole-4-yl)hydrazono]-3-oxobutyrate (3d) and methyl 2-[(3,5-dimethylpyrazole-4-yl)hydrazono]-4-methoxy-3-oxobutyrate (3e) showed activity towards Mycobacterium tuberculosis at 29% and 28% respectively. Thiourea and urea derivatives were also searched for antituberculosis activity but no remarkable activity was obseved. The compounds 4a, 4f, 4g, 4l and 7b were chosen as prototypes searched the anticonvulsant activity against PTZ induced seizures. For 25 mg/ kg dose, anticonvulsan protection of examined compounds are as following: 4a 40%, 4l 30% and 4f, 4g, 7b 50%. Compound 4l showed dose-dependent anticonvulsan protection at 50 and 100 mg/ kg doses.
SYNTHESIS OF SUBSTITUTED UREA, THIOUREA AND HYDRAZONES FROM 4-AMINO-3,5-DIMETHYLPYRAZOLE AND STUDYING THE BIOLOGICAL ACTIVITIES The anticonvulsant, antibacterial, hypoglycemic, analgesic, antiiflammatory and antitumoral effects of substituent form of pyrazole derivatives is known. It was recorded that the compounds containing hydrazone, thiourea and urea groups have antimicrobial, antihypertensive, antiinflammatory and anti-HIV effects. Identification of pyrazole main structure and pharmacological activity of substituents is an important factor to decide synthesis of new compounds. In this search, compounds containing hydrazone, thiourea and urea substituents were synthesized from the 4-amino 3,5-di/ 1,3,5-trimethylpyrazoles. 4-amino-3,5-dimethylpyrazole (1) and 4-amino-1,3,5-trimethylpyrazole (2) were obtained from the reduction of 4-(phenylazo)-3,5-dimethylpyrazole and 4-(4-carbetoxyphenylazo)-1,3,5-trimethylpyrazole with hydrazine hydrate in ethanolic medium. Aryldiazonium salts of the compounds 1 and 2 coupled with acetylacetone, 1-benzoylacetone, ethyl acetoacetate, 6-methyl heptane-2,4-dione and methyl 4-methoxyacetoacetate in the presence of sodium acetate to give 3a-e and 6a-b. Furthermore thiourea (4a-m, 7a-b) and urea (5a-b, 8) derivatives were obtained by the addition of compounds 1 and 2 to substituted isothiocyanates or isocyanates. The synhesized compounds were elucidated using elemental analysis and UV, IR, 1H-NMR, 13C-NMR and Mass spectroscopy. 1H-NMR spectra of the coupling products (3a-e, 6a-b) exhibited a hydrazone NH group at 11.00-15.00 ppm. Observing hydrazone protons of compounds 3a, 3d and 3e in three different fields proves the existance of isomers of 3a, 3d and 3e. In the 1H-NMR spectra of the thiourea derivatives, the compounds containing alkyl groups attached to N1 showed the N1-H and N2-H protons at 6.75-7.10 and 8.40-8.70 ppm respectively. The same protons of the compounds containing aryl group at N1 position were observed by wide spread peak at 8.40-10.05 ppm, because of the syn or anti isomers. The synthesized molecules were tested to antituberculosis activity against Mycobacterium tuberculosis at 6.25 mg/ ml concentration. Both hydrazone products, ethyl 2-[(3,5-dimethylpyrazole-4-yl)hydrazono]-3-oxobutyrate (3d) and methyl 2-[(3,5-dimethylpyrazole-4-yl)hydrazono]-4-methoxy-3-oxobutyrate (3e) showed activity towards Mycobacterium tuberculosis at 29% and 28% respectively. Thiourea and urea derivatives were also searched for antituberculosis activity but no remarkable activity was obseved. The compounds 4a, 4f, 4g, 4l and 7b were chosen as prototypes searched the anticonvulsant activity against PTZ induced seizures. For 25 mg/ kg dose, anticonvulsan protection of examined compounds are as following: 4a 40%, 4l 30% and 4f, 4g, 7b 50%. Compound 4l showed dose-dependent anticonvulsan protection at 50 and 100 mg/ kg doses.