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Abstract In this study we reported the synthesis and reactivity of novel heterocyclic compounds containing both indole and oxindole moieties possessing significant biological activity. 1.Synthesis of key starting materials 1.1:Synthesis of 5-Substituted isatins. 5-Substituted isatin were synthesized using Sandemyer methodology starting from the corresponding amines [Scheme 1]. 1.2:Synthesis of Indole 3-carbinal. The formulation of commercially available indole with DMF/POCl3 by Vismeyer - Hack reaction is carried out to obtain indole 3-carbinal in good yield [Scheme 2]. Scheme 1. a) Cl3CCH(OH)2,H2NOH.HCl. ,b)H2SO4.,c)H2O.1.3:Synthesis of 1-(4-(2-Methoxybenzyl)-6-arylpyridazin-3-yl)hydrazine derivatives. 6-Aryl-4-(2-methoxyphenylmethyl)pyridazin-3(2H)-ones (2a-c) were synthesized via the base catalyzed condensation of 6-aryl-4,5-dihydropyridazin-3(2H) ones (1a-c) with 2-methoxybenzaldehyde.Reaction of (2a-c) with phosphorus oxychloride gave 3-chloropyridazines (3a-c), which on treatment with hydrazine hydrate gave 1-(4-(2-Methoxybenzyl)-6-arylpyridazin-3-yl)hydrazine derivatives (4a-c) in good yield [Scheme 3]. Scheme 3.Experimental protocol for the synthesis of 1-(4-(2-methoxybenzyl)-6- arylpyridazin-3-yl)hydrazines (4a- These 3-hydrazino pyridazine compounds (4a-c) were used as key starting materials for the preparation of new hydrazone derivatives of expected biological activity. 2.Synthesis of new hydrazones 2.1: Synthesis of new hydrazone derivatives based on oxindole moiety. Condensation reaction of 3-hydrazino pyridazine compounds (4a-c) with 5- substituted isatins to afford 6-aryl-3-{2-[4-(2-methoxybenzyl)pyridazin-3(2H)- ylidene]hydrazono}-5-substituted-indolin-2-ones (5a-r) [Scheme 4]. Scheme (4) 2.2: Synthesis of new hydrazone derivatives based on indole moiety. Also condensation reaction of 3-hydrazino pyridazine compounds (4a-c) with indole 3-carbinal in refluxing ethanol yielded the corresponding hydrazone derivatives 2-((1H-indol-3-yl) methylene)-1-(4-(2-methoxybenzyl)-6- arylpyridazin-3-yl) hydrazines (6a-c) [Scheme 5]. Comp. No R Ar 5(a,b,c)* H C6H5, C6H4CH3p, C6H4Clp 5(d,e,f)* CH3 C6H5, C6H4CH3p, C6H4Clp 5(g,h,i)* Cl C6H5, C6H4CH3p, C6H4Clp 5(j,k,l)* OCH3 C6H5, C6H4CH3p, C6H4Clp 5m,n,o NO2 C6H5, C6H4CH3p, C6H4Clp 5p,q,r F C6H5, C6H4CH3p, C6H4Clp N OCH3 (6a-c) Ar,a = C6H5, b = C6H4CH3p, c = C6H4Clp Scheme (5) 3. Synthesis of new bis Schiff bases The present study involved the synthesis of three different clases of bis Schiff base derivatives from condensation reaction of three different di-amines namely benzidine (4,4`-diamino-1,1`-biphenyl), 3,3’-dimethoxybenzidine and 2,6-diaminopyridine with 5-substituted isatins or indole 3-carbinal. Condensation of two moles of 5-substituted isatins and indole 3-carbinal with one mole of benzidine in ethanol at ambient temperature gave the desired bis Schiff bases named bis N-[(1,3-dihydro)-2H-indol-2-one] 4,4`-diamino-1,1`- biphenyl derivatives (7a-e) and bis-N-[(1H-indol-3yl)methylene]4,4`-diamino- 1,1`-biphenyl (9a) respectively. In the same manner condensation of two moles of 5-substituted isatins and indole 3-carbinal with one mole of 3,3’-dimethoxybenzidine in ethanol at ambient temperature gave the desired bis Schiff bases bis N-[(1,3-dihydro)-2H-indol-2- one]3,3’-dimethoxybenzidine derivatives (8a-e) and bis-N-[(1H-indol- 3yl)methylene]3,3’-dimethoxybenzidine (9b) respectively. Also reaction of two moles of 5-substituted isatins and indole 3-carbinal with one mole of 2,6-diaminopyridine yielded bis N-[(1,3-dihydro)-2H-indol-2- one]pyridine 2,6-diamine derivatives (10a-e) and bis N-[(1H-indol- 3yl)methylene]pyridine 2,6-diamine (11) [Scheme 6,7]. R, a = H, b = CH3, c = Cl, d = NO2, e = Scheme 7. (i) benzidine,(ii) 3,3’-dimethoxybenzidine,(iii) 2,6-diamino-pyridine OCH3 OCH3 (6a-c) (12a-c) 4. Synthesis of spiro and non spiro compounds This study was extended to investigate the synthesis of new compounds starting with the new hydrazones and bis Schiff bases. Three classes of spiro and non spiro compounds are synthesized :( i) thiazolodine-diones. (ii) 2-azetidinones .(iii) 1, 2, 4 triazoles. 4.1: Synthesis of new thiazolodine-dione derivatives. Condensation of the hydrazone derivatives (6a-c) and bis Schiff bases (7b),(8a), (9a,b) and (11) derivatives with mercaptoacetic acid under reflux using a Dean- Stark apparatus afforded the compounds (12a-c),(13a,b) and (14a-c) respectively [Scheme 8,9,10,11]. Ar,a = C6H5, b = C6H4CH3p, c = C6H4Clp Scheme 4.2: Synthesis of new 2- azetidinone derivatives. New bis 2-azetidinone were synthesized by cycloaddition reaction of chloroacetyl chloride with selected bis Schiff bases (7a),(8a) , (9a,b) and (11) in the molar ratio 2:1 in presence of triethylamine as base at 80oC afforded the corresponding bis 2-azetidinones (15a,b) and (16a-c) respectively [Scheme 12,13,14]. CH N CH Cl O O Cl (16a,b) ClCOCH2Cl/Et3N 5. Synthesis of bis Mannich bases Moreover, bis Mannich bases of the new hydrazones (6a,b) , bis schiff bases (10a,b) and (11) were synthesized via reaction of the acidic imino group of oxindole or indole with formaldehyde and secondary amine such as piperidine or morpholine to yield the corresponding bis N-Mannich base derivatives (7. Evaluation of the biological activity of the new compounds 7.1: In-vitro antimicrobial activity measurement. Some of the synthesized compounds were tested for their in vitro antimicrobial activity in terms of minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC). 7.2:In vitro cytotoxicity evaluation ”antiproliferative studies” 1-Antiproliferative effects of metal complexes (22a-k) ,(23a) and (24a) ,also starting ligands (5a,6a) against HCT116 (Colon), MCF7( Breast ) and HELA (Cervix) tumor cell lines were studied. 2- Antiproliferative effects of metal complexes (25a-c) ,(26a-f) and also bis Schiff base (11) were investigated only against HELA (Cervix) tumor cell line . All the structures of the new products were established using elemental analysis and spectral data, (Mass, IR, UV-Vis ,13C-NMR and 1HNMR spectra).In addition to previous instrumental analysis and for metal complexes, Magnetic susceptibilities ,ESR spectra and molar conductance measurement were used. The metal percentage was estimated using Inductively Coupled Argon Plasma (ICP) technique. |