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Abstract
Quinoline, Isoquinoline with various heterocyclic ring derivatives occupy a wide space biologically active molecules in the fields of anti-inflammatory, analgesic, antioxidant, antimicrobial, antitumor, antiviral, antimalarial and antiparasitic activities.
<This fact motivated our interest in the present investigation to design and synthesize new compounds comprising quinoline and isoquinoline bearing variuos moieties through different linkage.
<The newly synthesized compounds were screened for their antibacterial, antifungal, anti-inflammatory and antioxidant activities.
<The work done in the present thesis can be classified as follows:
<Chapter 1:
<Introduction:
This chapter presented a brief literature survey on some biologically active quinoline, isoquinoline, isoxazole, pyrazole, diazepine, triazole, oxadiazole, thiadiazoles and thiazolidines and thiazolidinone isolated or combined compounds exhibiting antimicrobial, antioxidant and anti-inflammatory activities.
Chapter 2:
<Research objectives:Regarding the anti-inflammatory, antimicrobial and antioxidant activities of different quinoline and isoquinoline this chapter deals with the aim of the work and the rationale upon which the new compounds have been synthesized to study their antimicrobial, antioxidant and anti-inflammatory activities.
Chapter 3:
Discussion:
This section deals with the theoretical concept of the methods adopted for the synthesis of the designed compounds with reference to the knowledge available in the literature and structural elucidation by various spectral data.
<English Summary
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Discussion contained the following six schemes:
<Scheme 1:
This scheme outlined the synthesis of the following starting materials: a) 6-substituted-2-methylcinchoninic acid IIIa,b from 5-substitutedisatin IIa,b according to Pfitzinger reaction using acetone in potassium hydroxide solution.
<b) Ethyl 6-substituted-2-methylcinchoninate; IVa,b from IIIa,b.c) The reaction of ethyl 6-bromo-2-methylcinchoninate IVa with morpholine to give 6-bromo-2-methyl-4-(morpholin-4-yl)carbonylquinoline V which was oxidized subsequently by heating under reflux with selenium dioxide to yield 6-bromo-4-(morpholin-4-ylcarbonyl)quinoline-2-carbaldehyde VI.
<The latter aldehyde VI was then reacted substituted acetophenone undergoing condensation affording chalcones VIIa-c. Further compounds were produced from cyclization of VIIa-c with hydroxylamine hydrochloride afforded (6-bromo-2-(5-(4-substituted-phenyl) 4,5-dihydroisoxazol-3-yl)quinolin-4-yl)(morpholino)methanone VIIIa-c.
In addition further cyclization occurred also with reaction of VIIa-c with phenylhydrazine HCl giving (6-bromo-2-(3-(4-substituted-phenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl)quinolin-4-yl)(morpholino)methanone IXa-c. Moreover cyclization of VIIa-c with o-phenylenediamine produced (6-bromo-2-(4-(4-substituted-phenyl)-1H-benzo[b][1,4] diazepin-2-yl)quinolin-4-yl)(morpholino)methanone X.
<In addition 2-(benzylamino)-1-(4-substitutedphenyl)-2-oxoethyl 6-substituted-2-methyl quinoline-4-carboxylate XIa-c was synthesized by passerini method involving an oxo component, an isocyanide, and a nucleophile in a single step.
Scheme 2:
The prepared ester IVa,b was then reacted with 99% hydrazine hydrate to yield 6-substituted-2-methylquinoline-4-carbohydrazide XIIa,b then N-Aryl-2-(6-substituted-2-methylquinoline-4-carbonyl)hydrazine-1-carbothioamides XIIIa-e from the reaction of corresponding acid hydrazide 6-substituted-2-methlycinchoninic acid hydrazide XIIa,b in absolute ethanol with an equimolar amount of the appropriate aryl isothiocaynate. Cyclization of the prepared thiosemicarbazides XIIIa-e with NaOH afforded 5-(6-substituted-2-methylquinolin-4-yl)-4-(4-aryl)-4H-1,2,4-triazole-3-thiol XIVa-e while with H2SO4 / HOAC yielded 5-(6-bromo-2-methylquinolin-4-yl)-N-(4-aryl)-1,3,4-thiadiazol-2-amine XVa-c also with HgO produced 5-(6-substituted-2-methylquinolin-4-yl)-N-(4-aryl)-1,3,4-oxadiazol-2-amine XVIa-e and cycliztion with m-chloroacetic acid gave 6-bromo-N’-(3-(4-aryl)-4-oxothiazolidin-2-ylidene)-2-methylquinoline-4-carbohydrazide XVIIa-c.
<>English Summary
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Scheme 3:
<The synthesis of 6-bromo-N-(2,5-dioxopyrrolidin-1-yl)-2-methylquinoline-4-carboxamide XVIII,N-(1,3-dioxoisoindolin-2-yl)-6-substituted-2-methylquinoline-4-carboxamide XIXa,b, 6-bromo-N’-(5-substituted-2-oxoindolin-3-ylidene)-2-methylquinoline-4-carbohydrazide XXa-c and 6-bromo-N’-(4-substitutedbenzylidene)-2-methylquinoline-4-carbohydrazide XXIa-d by reaction of the acid hydrazides with succinic anhydride, phthalic anhydride, isatins and aromatic aldehydes forming amide linkage with the corresponding rings respectively.
Scheme 4:
<It shows the synthesis of 6-bromo-N’-formyl-2-methylquinoline-4-carbohydrazide XXII from the acid hydrazide VIIa through reacting with formic acid which was then cyclized with phosphorous oxychloride to give 2-(6-bromo-2-methylquinolin-4-yl)-1,3,4-oxadiazole XXIII. Moreover a novel 2-(6-bromo-2-methylquinoline-4-carbonyl)hydrazine-1-carbodithioate XXIV formed through the reaction of the acid hydrazide VIIa with CS2 in the presence of KOH and undergoes several cyclization reactions with phenacyl bromide or p-bromophenacyl bromide, H2SO4 and hydrazine hydrate affording 6-bromo-N-(4-(4-substitutedphenyl)-2-thioxothiazol-3(2H)-yl)-2-methylquinoline-4-carboxamide XXVa,b, 5-(6-bromo-2-methylquinolin-4-yl)-1,3,4-thiadiazole-2(3H)-thione XXVI and 4-amino-5-(6-bromo-2-methylquinolin-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione XXVII respectively.
<Scheme 5:
Several derivatives from key intermediate 4-amino-5-(6-bromo-2-methyl quinolin-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione XXVII which reactes with phenacyl bromide and p-bromo phenacyl bromide, ethyl bromoacetate, various aromatic aldehydes, methyl chloroformate and aryl isothiocaynates afforded 3-(6-bromo-2-methylquinolin-4-yl)-6-(4-substitutedphenyl)-1,8a-dihydro-7H- [1,2,4]triazolo [3,4-b][1,3,4]thiadiazine XXVIIIa,b, 3-(6-bromo-2-methylquinolin-4-yl)-1,8a- dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6(7H)-one XXIX, 5-(6-bromo-2- methylquinolin-4-yl)-4-((4-substitutedbenzylidene)amino)-2,4-dihydro-3H-1,2,4-triazole-3-thione XXXa,b, methyl (3-(6-bromo-2-methylquinolin-4-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl) carbamate XXXI and 1-(3-(6-bromo-2-methylquinolin-4-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3-substitutedthiourea XXXIIa,b.
Scheme 6:
It illustrates new efforts to synthesis ethyl 4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylate XXXIV from refluxing the corresponding ethyl 2-(1,3-dioxoisoindolin-2-yl)acetate XXXIII with sodium ethoxide. Furthur reaction of XXXIV with hydrazine hydrate to give 4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carbohydrazide XXXV which
English Summary
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aided in forming the 2-(1,4-dihydroxyisoquinoline-3-carbonyl)-N-(p-substituted)hydrazine-1-carbothioamide XXXVIa,b.
The cyclization of the prepared thiosemicarbazides XXXVIa,b with NaOH afforded 4-hydroxy-3-(5-mercapto-4-(substituted)-4H-1,2,4-triazol-3-yl)isoquinolin-1(2H)-one XXXVIIa,b while with H2SO4 / HOAC yielded 4-hydroxy-3-(5-(p-substitutedamino)-1,3,4-thiadiazol-2-yl)isoquinolin-1(2H)-one XXXVIIIa,b and with HgO produced 4-hydroxy-3-(5-(p-substitutedamino)-1,3,4-oxadiazol-2-yl)isoquinolin-1(2H)-one XXXIXa,b.
On the other hand, cyclization of XXXV with bis (carboxymethyl)trithiocarbonate, yielded 4-hydroxy-1-oxo-N-(4-oxo-2-thioxothiazolidin-3-yl)-1,2-dihydroisoquinoline-3-carboxamide XL.
Furthermore, condensation of the active methylene of compound XLI with the appropriate aromatic aldehyde in absolute ethanol containing anhydrous sodium acetate afforded N-(5-(4-substitutedbenzylidene)-4-oxo-2-thioxothiazolidin-3-yl)-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxamide XLIa,b.
Chapter 4:
Experimental:
This section described the detailed experimental procedures adopted for the synthesis of the starting materials, intermediates and final compounds. The structures of the synthesized compounds were confirmed by elemental microanalyses, IR, 1H-NMR spectra for all compounds as well as 13C-NMR and mass spectra for some representative examples.
<The compounds prepared in this section were listed as follows:
Scheme 1:
It described the synthesis of the following compounds.
• Isonitrosoacetanilide; (I).
• 5-substitutedisatin; (IIa,b).
• 6-substituted-2-methylcinchoninic acid; (IIIa,b).
• Ethyl 6-substituted-2-methylcinchoninate; (IVa,b).
• 6-Bromo-2-methyl-4-(morpholin-4-yl)carbonylquinoline; (V).
• 6-Bromo-2-formyl-4-(morpholin-4-yl)carbonylquinoline; (VI).
• 3-(6-bromo-4-(morpholine-4-carbonyl)quinolin-2-yl)-1-(4-substituted-phenyl)prop-2-en-1-one; (VIIa-c)
•
(6-bromo-2-(5-(4-substituted-phenyl) 4,5-dihydroisoxazol-3-yl)quinolin-4-yl)(morpholino)methanone; (VIIIa-c)
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• (6-bromo-2-(3-(4-substituted-phenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl)quinolin-4-yl)(morpholino)methanone; (IXa-c)
• (6-bromo-2-(4-(4-substituted-phenyl)-1H-benzo[b][1,4]diazepin-2-yl)quinolin-4-yl)(morpholino)methanone; Xa-c
• 2-(benzylamino)-1-(4-substitutedphenyl)-2-oxoethyl 6-substituted-2-methylquinoline-4-carboxylate; (XIa-c).
Scheme 2:
It illustrated the synthesis of the following compounds.
• 6-substituted-2-methylcinchoninic acid hydrazide; (XIIa,b).
• N-Aryl-2-(6-substituted-2-methylquinoline-4-carbonyl)hydrazine-1-carbothioamides; (XIIIa-e).
• 5-(6-bromo-2-methylquinolin-4-yl)-4-(4-aryl)-4H-1,2,4-triazole-3-thiol; (XIVa-e).
• 5-(6-bromo-2-methylquinolin-4-yl)-N-(4-aryl)-1,3,4-thiadiazol-2-amine; (XVa-c).
• 5-(6-bromo-2-methylquinolin-4-yl)-N-(4-aryl)-1,3,4-oxadiazol-2-amine; (XVIa-e).
• 6-bromo-N’-(3-(4-aryl)-4-oxothiazolidin-2-ylidene)-2-methylquinoline-4-carbohydrazide; (XVIIa-c).
Scheme 3:
It demonstrates the synthesis of the following compounds.
• 6-bromo-N-(2,5-dioxopyrrolidin-1-yl)-2-methylquinoline-4-carboxamide; (XVIII)
• N-(1,3-dioxoisoindolin-2-yl)-6-substituted-2-methylquinoline-4-carboxamide; (XIXa,b)
• 6-bromo-N’-(5-substituted-2-oxoindolin-3-ylidene)-2-methylquinoline-4-carbohydrazide; (XXa-c).
• 6-bromo-N’-(4-substitutedbenzylidene)-2-methylquinoline-4-carbohydrazide; (XXIa-d).
Scheme 4:
• 6-bromo-N’-formyl-2-methylquinoline-4-carbohydrazide; (XXII)
• 2-(6-bromo-2-methylquinolin-4-yl)-1,3,4-oxadiazole; (XXIII)
• 2-(6-bromo-2-methylquinoline-4-carbonyl)hydrazine-1-carbodithioate; (XXIV)
• 6-bromo-N-(4-(4-substitutedphenyl)-2-thioxothiazol-3(2H)-yl)-2-methylquinoline-4-carboxamide; (XXVa,b)
• 5-(6-bromo-2-methylquinolin-4-yl)-1,3,4-thiadiazole-2(3H)-thione; (XXVI)
• 4-amino-5-(6-bromo-2-methylquinolin-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione; (XXVII)
English Summary
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Scheme 5:
• 3-(6-bromo-2-methylquinolin-4-yl)-6-(4-substitutedphenyl)-1,8a-dihydro-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine; (XXVIIIa,b)
• 3-(6-bromo-2-methylquinolin-4-yl)-1,8a-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6(7H)-one; (XXIX)
• 5-(6-bromo-2-methylquinolin-4-yl)-4-((4-substitutedbenzylidene)amino)-2,4-dihydro-3H-1,2,4-triazole-3-thione; (XXXa,b)
• methyl (3-(6-bromo-2-methylquinolin-4-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)carbamate; (XXXI)
• 1-(3-(6-bromo-2-methylquinolin-4-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3-substitutedthiourea; (XXXIIa,b)Scheme 6:
It involved the synthesis of the following compounds.
• 6-substituted-2-methlycinchoninic acid hydrazide; (XIIa,b)
• ethyl 2-(1,3-dioxoisoindolin-2-yl)acetate; (XXXIII)
• ethyl 4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylate; (XXXIV)
• 4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carbohydrazide; (XXXV)
• 2-(1,4-dihydroxyisoquinoline-3-carbonyl)-N-(p-substituted)hydrazine-1-carbothioamide; (XXXVIa,b)
• 4-hydroxy-3-(5-mercapto-4-(substituted)-4H-1,2,4-triazol-3-yl)isoquinolin-1(2H)-one; (XXXVIIa,b)
• 4-hydroxy-3-(5-(p-substitutedamino)-1,3,4-thiadiazol-2-yl)isoquinolin-1(2H)-one; (XXXVIIIa,b)
• 4-hydroxy-3-(5-(p-substitutedamino)-1,3,4-oxadiazol-2-yl)isoquinolin-1(2H)-one; (XXXIXa,b)
• 4-hydroxy-1-oxo-N-(4-oxo-2-thioxothiazolidin-3-yl)-1,2-dihydroisoquinoline-3-carboxamide; (XL)
• N-(5-(4-substitutedbenzylidene)-4-oxo-2-thioxothiazolidin-3-yl)-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; (XLIa,b)
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Chapter 5:
Biological screening:
In vitro antimicrobial screening
All the newly synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus and Bacillus subtilis as representatives of Gram-positive bacteria, Escherichia coli and Pseudomonas aeruginosa as representatives of Gram-negative bacteria. These compounds were also evaluated for their in vitro antifungal activity against Candida albicans. The results showed that all the tested compounds lacked any significant antibacterial or antifungal activity against the tested pathological strains except compounds VIIIa, VIIIb, VIIIc, XVb, XXIX, XXXa, XXXI and XXXIIb exhibited potential antibacterial activity against E. coli.
In vitro antioxidant screening
All the newly synthesized compounds were screened for their in vitro antioxidant activity using DPPH free radical scavenging assay. The results showed that in general, all tested compounds with antioxidant activity contained NH function which might explain their activity by hydrogen atom donating ability. Compounds XIIIa-e showed antioxidant activity higher than that of standard, trolox. Compounds XXXV and XLa showed moderate activity while compounds XVc showed weak antioxidant activity.
<Anti-inflammatory screening:
<All the newly synthesized compounds were screened for their invitro anti-inflammatory activity. Interpretation of the anti-inflammatory activity of the tested compounds indicated that among the tested compounds; XIIIb, XIVb, XIVe, XVIb and XXII showed remarkable invivo anti-inflammatory models.
<Molecular modeling:
<This part explained the docking procedure of the most active anti-inflammatory compounds namely; XIIIb, XIVb, XIVe, XVIb and XXII within the binding site of the target enzyme in order to understand the mode of interaction of these compounds using Molecular Operating Environment (MOE Dock 2014.0901) software.
<Chapter 6:
<References:
In this section, 199 references were used for planning and accomplishing the work done.
These references have been listed in the order of their appearance in the text.