الفهرس 
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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.