Bazı N-(2-metilimidazo [1,2-a] piridin-3-il)hidrazinkarboksamidlerin sentezleri ve biyolojik özelliklerinin incelenmesi
Synthesis of some N-(2methylimidazo[1,2-a]pyridin-3-yl) hydrazinecarboxamide and evaluatino of their biological activities
Yazar: BİRGÜL ÖZDEN KASIMOĞULLARI
Danışman: PROF.DR. ZAFER CESUR
İstanbul Üniversitesi / Sağlık Bilimleri Enstitüsü / Farmasötik Kimya Ana Bilim Dalı
Derece: Doktora, 2006
Konu: Eczacılık ve Farmakoloji = Pharmacy and Pharmacology ; Kimya = Chemistry

Özet:
ÖzetBu çalışmada imidazo[1,2-a]piridin halka sistemini taşıyan semikarbazon (VIa-f),tiyosemikarbazid (VIIa-j), 4-tiyazolidinon (VIIa-d) ve 2-hidrazono-4-tiyazolidinon (IXa-j)yapısında aşağıdaki bileşikler elde edilmiştir.2-Metilimidazo[1,2-a]piridin-3-karbonil azid, IIIEtil 2-Metilimidazo[1,2-a]piridin-3-ilkarbamat, IVN-(2-Metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VBenzaldehid N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon, VIa4-Klorobenzaldehid N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon, VIb4-Nitrobenzaldehid N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon, VIc4-Metilbenzaldehid N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon, VId4-Metoksibenzaldehid N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon, VIe5-Nitrofurfural N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon, VIf2-[(Metilamino)karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VIIa2-[(Etilamino)karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VIIb2-[(Allilamino)karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VIIc2-[(Siklohekzilamino)karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VIId2-(Anilinokarbonotiyoil)-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid , VIIe2-[[(4-Florofenil)amino]karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid,VIIf2-[[(4-Klorofenil)amino]karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VIIg2-[[(4-Bromofenil)amino]karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VIIh2-[[(4-Tolil)amino]karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VIIi2-[[(4-Nitrofenil)amino]karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid, VIIjN-(2-Metilimidazo[1,2-a]piridin-3-il)-N'-[4-okso-2-fenil-1,3-tiyazolidin-3-il]üre, VIIIaN-(2-Metilimidazo[1,2-a]piridin-3-il)-N'-[4-okso-2-(4-klorofenil)-1,3-tiyazolidin-3-il]üre, VIIIbN-(2-Metilimidazo[1,2-a]piridin-3-il)-N'-[4-okso-2-(4-metilfenil)-1,3-tiyazolidin-3-il]üre, VIIIcN-(2-Metilimidazo[1,2-a]piridin-3-il)-N'-[4-okso-2-(4-metoksifenil)-1,3-tiyazolidin-3-il]üre, VIIId3-Metil-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXa3-Etil-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXb3-Allil-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXc3-Siklohekzil-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikar bazon], IXd3-Fenil-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXe3-(4-Florofenil)-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXf3-(4-Klorofenil)-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXg3-(4-Bromofenil)-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXh3-(4-Tolil)-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXi3-(4-Nitrofenil)-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazon], IXjSentez çalışmalarının ilk aşamasında 2-metilimidazo[1,2-a]piridin-3-karbohidrazid' innitröz asidle reaksiyona sokulmasıyla 2-metilimidazo[1,2-a]piridin-3-karbonil azid (III) eldeedilmiştir. Madde III' ün absolu etanol ile ısıtılmasıyla etil 2-metilimidazo[1,2-a]piridin-3-ilkarbamat (IV) ve IV' ün hidrazin hidrat ile reaksiyonundan N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamid (V) kazanılmıştır. Madde V' in aromatik aldehitler ve alkil/arilisotiyosiyanatlarla muamele edilmesiyle sırasıyla aromatik aldehit N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazonlara (VIa-f) ve 2-[(alkil/arilamino)karbonotiyoil]-N-(2-metilimidazo[1,2-a]piridin-3-il)hidrazinkarboksamidlere (VIIa-j) geçilmiştir. Madde VIa,b,d,e' ninmerkaptoasetik asidle siklokondensasyon reaksiyonundan 4-tiyazolidinon türevi N-(2-aril-4-okso-1,3-tiyazolidin-3-il)-N'-(2-metilimidazo[1,2-a]piridin-3-il)üreler (VIIIa-d) ve maddeVIIa-j' nin etil bromoasetat ile reaksiyonundan yine 4-tiyazolidinon türevi 3-(alkil/aril)-1,3-tiyazolidin-2,4-dion 2-[N-(2-metilimidazo[1,2-a]piridin-3-il)semikarbazonlar (IXa-j) eldeedilmiştir.Bileşiklerin oluşum mekanizmaları tartışılmış ve sentez edilen bileşiklerin yapılarıelementel analiz, UV, IR, 1H-NMR, HETCOR, HMBC ve kütle spektrumları yardımıyladoğrulanmıştır.Elde edilen tüm bileşiklerin BACTEC 460 Radyometrik Hassasiyet Yöntemine göreantitüberküloz aktiviteleri araştırılmış, ancak 6.25 Âµg/ml konsantrasyonda VIc, VIIi, IXg veIXh maddelerinde zayıf etkinlik görülmesi dışında aktif olmadıkları tespit edilmiştir.Antifungal aktivite testlerinde sentez edilen bileşiklerin Microsporum gypseum (NCPF-580), M. canis, Trichophyton tonsurans NCPF 245, T. rubrum, Candida albicans (ATCC10231) ve C. parapsilosis (ATCC 22019) suşlarına karşı aktiviteleri araştırılmıştır. Bütünmaddeler için değişik konsantrasyonlarda aktivite gözlenirken; en yüksek aktivite VIIi,g,h veIXi maddelerinde M. canis ve IXi' de Trichophyton tonsurans (NCPF 245) suşlarına karşı tespitedilmiştir.Anahtar Kelimeler: İmidazo[1,2-a]piridin, 4-tiyazolidinon, antitüberküloz aktivite, antifungalaktivite.

Abstract:
SummarySynthesis of some N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide andevaluation of their biological activitiesIn this research, following the compounds which are semicarbazone (VIa-f),thiosemicarbazide (VIIa-j), 4-thiazolidinone (VIIIa-d) and 2-hydrazono-4-thiazolidinone (IXa-j) derivatives containing an imidazo[1,2-a]pyridine ring system were synthesized.2-Methylimidazo[1,2-a]pyridine-3-carbonyl azide, IIIEthyl (2-methylimidazo[1,2-a]pyridin-3-yl)carbamate, IVN-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VBenzaldehyde N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone, VIa4-Chlorobenzaldehyde N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone, VIb4-Nitrobenzaldehyde N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone, VIc4-Methylbenzaldehyde N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone, VId4-Methoxybenzaldehyde N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone, VIe5-Nitro-2-furaldehyde N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone, VIf2-[(Methyllamino)carbonothioyl]-N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-a2-[(Ethylamino)carbonothioyl]-N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-b2-[(Allylamino)carbonothioyl]-N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-c2-[(Cyclohexylamino)carbonothioyl]-N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-d2-[(Anilino)carbonothioyl]-N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-e2-{[(4-Fluorophenyl)amino]carbonothioyl}- N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-f2-{[(4-Chlorophenyl)amino]carbonothioyl}- N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-g2-{[(4-Bromophenyl)amino]carbonothioyl}-N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-h2-{[(4-Methylphenyl)amino]carbonothioyl}- N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-i2-{[(4-Nitrophenyl)amino]carbonothioyl}- N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide, VII-j1-(2-Mmethylimidazo[1,2-a]pyridin-3-yl)-3-(4-okso-2-phenyl-1,3-thiazolidin-3-yl)urea, VIIIa1-(2-Methylimidazo[1,2-a]pyridin-3-yl))-3-[4-okso-2-(4-chlorophenyl)-1,3-thiazolidin-3-yl]urea, VIIIb1-(2-Methylimidazo[1,2-a]pyridin-3-yl))-3-[4-okso-2-(4-methylphenyl)-1,3-thiazolidin-3-yl]urea, VIIIc1-(2-Methylimidazo[1,2-a]pyridin-3-yl))-3-[4-okso-2-(4-methoxyphenyl)-1,3-thiazolidin-3-yl]urea, VIIId3-Methyl-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXa3-Ethyl-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXb3-Allyl-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXc3-Cyclohexyl-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXd3-Phenyl-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXe3-(4-Fluorophenyl)-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXf3-(4-Chlorophenyl)-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXg3-(4-Bromophenyl)-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXh3-(4-Methylphenyl)-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXi3-(4-Nitrophenyl)-1,3-thiazolidinone-2,4-dione 2-[ N-(2-methylimidazo[1,2-a]pyridin-3-yl)semicarbazone], IXjIn the first stage of the study 2-methylimidazo[1,2-a]pyridine-3-carbonyl azide (III)was obtained by reacting 2-methylimidazo[1,2-a]pyridine-3-carbohydrazide with nitrous acide.Compound III was refluxed in absolute ethanol to gain ethyl 2-methylimidazo[1,2-a]pyridin-3-ylcarbamate (IV) which was then reacted with hydrazine hydrate to give N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazine carboxamide (V). Compound V was treated witharomatic aldehydes and alkyl/aryl isothiocyanates to give aromatic aldehyde N-(2-methylimidazo[1,2-a]pyridin-3-yl) semicarbazones (VIa-f) and 2-[(alkyl/arylamino)carbono-thioyl]-N-(2-methylimidazo[1,2-a]pyridin-3-yl)hydrazinecarboxamide derivatives (VIIa-j),respectively. By the cyclocondensation reaction of compounds VIa,b,d,e with mercaptoaceticacid, the 4-thiazolidinone derivatives, N-(2-aryl-4-oxo-1,3-thiazolidin-3-yl-N'-(2-methylimidazo[1,2-a]pyridin-3-yl)ureas (VIIIa-d), and by the reaction of compounds VIIa-j with ethylbromoacetate, the 4-thiazolidinone derivatives, 3-(alkyl/aryl)-1,3-thiazolidin-2,4-dione 2-[N-(2-methylimidazo[1,2-a]pyridin-3-yl)]semicarbazones (IXa-j) were obtained.The formation of the compounds were discussed and the structures of the synthesizedcompounds were confirmed by elementel analysis, UV, IR, 1H-NMR, HETCOR, HMBC andmass spectrometry.All the compounds were evaluated for antituberculosis activity using the BACTECmethod, but none of the compounds (except VIc, VIIi, IXg and IXh, that have weak activity)showed activity at 6.25 Âµg/ml.In antifungal activity screening, the activities of synthesized compounds wereinvestigated against Microsporum gypseum (NCPF-580), M. canis, Trichophyton tonsuransNCPF 245, T. rubrum, Candida albicans (ATCC 10231) ve C. parapsilosis (ATCC 22019). Forall compounds, activity was found at varying concentrations while the highest activities weredetermined with compounds VIIi,g,h and IXi against M. canis and with compound IXi againstTrichophyton tonsurans NCPF 245.Keywords= Imidazo[1,2-a]pyridine, 4-thiazolidinone, antituberculosis activity, antifungalactivity.