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İstanbul Üniversitesi / Sağlık Bilimleri Enstitüsü / Farmasötik Kimya Anabilim Dalı

2004

5-sübstitüe/nonsübstitüe 1H-indol-2-on-3-iliden türevlerinin sentezi ve yapılarının aydınlatılması

Synthesis and evaluation of structures of 5-substituted/nonsubstituted 1H-indole-2-one-3-ylidene derivatives

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Özet:

Facility (TAACF) Southern Research Institute'de antitüberküler, Fakültemiz Farmakoloji Anabilim Dalı'nda antikonvülsan aktiviteleri araştırılmıştır. Tüm maddelerimiz antifungal aktivite gösterirken, madde I-XII S.epidermidis'e, madde IV, VI, X-XII S.aureus'a karşı antibakteryel aktivite göstermiştir. Maddelerimizin antitüberküler etki araştırmasında, I-XX numaralı maddelerimiz Mycobacterium tuberculosis H37Rv suşuna karşı 6.25 ng/ml konsantrasyonda test edilmiş, ancak en fazla %12 inhibisyon gösterdiği saptanmıştır. Antikonvülsan etki araştırmasında ise prototip olarak seçilen I, IV, V, VI, VIII, XI, XIII, XVI, XVII ve XVIII numaralı maddelerimizden madde I ve VI hariç diğerlerinin nöbet latensinde istatistiksel olarak anlamlı bir artış gösterdiği ve PTZ nin nöbet eşiğini yükseltiği görülmüştür. Bu nedenle maddelerin antikonvülsan aktivite açısından umut verici bileşikler olabileceği ve daha ileri testlerde yüksek dozlarda çalışılmasına devam edilmesinin uygun olacağı düşünülmektedir. 225SUMMARY In this work, 20 novel compounds, 5-substituted/nonsubstituted 1H- indole-2-one-3-ylidene derivatives have been synthesized. 3-[2-[5-(p-methoxyphenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-1 H-indole-2-one (I) 3-[2-[5-(p-methoxyphenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-1-methyl-indole-2-one (II) 3-[2-[5-(p-methoxyphenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-5-methyl-1 H-indole-2-one (III) 3-[2-[5-(p-methoxyphenyl)-1,3,4-oxadiazol-2-yI]imino-4-thiazolidinon-5- ylidene]-5-nitro-1 H-indole-2-one (IV) 3-[2-[5-(p-methoxyphenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-5~bromo~1 H-indole-2-one (V) 3-[2-[5-(p-methoxyphenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazoIidinon-5- ylidene]-5-fluoro-1 H-indole-2-one (VI) 3-[2-[5-(p-methoxyphenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-5-trifIuoromethoxy-1 H-indole-2-one (VII) 3-[2-[5-(p-chlorophenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazoIidinon-5- ylidene]-1 H-indole-2-one (VIII) 3-[2-[5-(p-chlorophenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-1 -methyl-indoIe-2-one (IX) 3-[2-[5-(p-chlorophenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-5-nitro-1 H-indole-2-one (X) 3-[2-[5-(p-chlorophenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-5-bromo-1 H-indole-2-one (XI) 3-[2-[5-(p-chlorophenyl)-1,3,4-oxadiazol-2-yl]imino-4-thiazolidinon-5- ylidene]-5-fluoro-1 H-indole-2-one (XII) 3-[2-(4-carbethoxymethylthiazol-2-yl)imino-4-thiazolidinon-5-ylidene]- 1H-indole-2-one(XIII) 2263-[2-(4-carbethoxymethyIthiazol-2-yI)imino-4-thiazolidinon-5-ylidene]-1- methyI-indole-2-one (XIV) 3-[2-(4-carbethoxymethylthiazol-2-yl)imino-4-thiazolidinon-5-ylidene]-5- methyI-1H-indole-2-one (XV) 3-[2-(4-carbethoxymethylthiazol-2-yl)imino-4~thiazoIidinon-5-ylidene]-5~ nitro1H-indole-2-one (XVI) 3-[2-(4-carbethoxymethylthiazol-2-yl)imino-4-thiazolidinon-5-yIidene]-5- bromo-1H-indole-2-one (XVII) 3-[2-(4-carbethoxymethylthiazol-2-yl)imino-4-thiazolidinon-5-ylidene]-5- fluoro-1H-indole-2-one (XVIII) 3-[2-(4-carbethoxymethylthiazol-2-yl)imino-4-thiazolidinon-5-ylidene]-5- trifluoromethoxy-1 H-indole-2-one (XIX) 3-[2-(4-carbethoxymethylthiazol-2-yl)imino-4-thiazolidinon-5-ylidene]-5- sulfonic acid sodium salt -1 H-indole-2-one (XX) With this purpose, 2-amino-5-(p-methoxy/p-chlorophenyl)-1,3,4- oxadiazole or 2-amino-4-carbethoxymethylthiazole have been acylated by stirring with chloroacetyl chloride in benzene and pyridine at 20-30°C for 1 h. Compounds thus obtained have been reacted with ammonium thiocyanate in ethanol to yield thiazolidin-4-one ring which have been then refluxed in order to accomplish the condensation reaction with isatin or isatin derivatives and sodium acetate in acetic acid anhydride and glacial acetic acid at 150-160°C. Purity of the novel compounds were controlled by thin-layer chromatography and their structures were determined by elemental analyses, UV, IR, 1H-NMR, 13C-NMR and El Mass spectrometric data. In the 1H-NMR spectra, some of the protons appeared as double singlets or double doublets which led us to the conclusion that the partial restrictions of the rotations around the imino and ylidene bonds resulted in the presence of geometrical isomers (E and Z isomers) that are constantly converting to each other. On the other hand, the N-H proton of the thiazolidinone lactam group showed peaks at 1 1.73-14.04 ppm as expected proving that the structure of the compounds were 2-aminothiazolidin-4-one rather than 2-iminothiazolin-4-one. 227

Summary:

13C-NMR spectrum of Compound XVIII which was chosen as a prototype confirmed the structure. In the literature survey it was found that analogs of our compounds showed antimicrobial and anticonvulsant activities. All our compounds were tested for antibacterial activity at the Microbiology Department of our faculty, for antifungal activity at the Microbiology Department of Istanbul Medicine Faculty and for antituberculosis activity at Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) Southern Research Institute and their anticonvulsant activity was evaluated at the Pharmacology Department of our faculty. All compounds showed antifungal activity while Compounds l-XII showed antibacterial activity against S.epidermidis ATCC 12228 and Compounds IV, VI, X-XII against S.aureus ATCC 6538. All of the compounds were tested against M.tuberculosis H37Rv but the highest inhibition at 6.25 \xg/m\ was found to be 12%. Investigation of anticonvulsant activity which was carried on Compounds I, IV, V, VI, VIII, XI, XIII, XVI, XVII, XVIII that were chosen as prototypes revealed that all of the chosen compounds other than Compounds I and VI and have considerably increased the seizure latency statistically and that the same compounds have raised the seizure threshold induced by PTZ. As a result, they are expected prospectively to be compounds with anticonvulsant activity and it is worth carrying on further anticonvulsant activity testing higher doses. 228