الفهرس 
Chemistry of PyridinesOnly 14 pages are availabe for public view
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Abstract
Summary
The original work of this thesis can be classified into two parts:
Part (I):
Multicomponent reactions, solvent-free synthesis of pyrido[2,3-d]pyrimidine-4(1H) dione derivatives and evaluation the pharmaceutical activity for new synthesized compounds.
Part (II):
Synthesis of some new substituted imidazoles carrying pyrazole moiety.
Part (I)
In resumption of our work aiming to synthesize polyfunctional substituted heterocyclic compounds of potential biological activity, the synthesis of poly-functionalized 7-amino-5-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d]pyrimidine-6-carbonitrile (1a) and 2-amino-4-(4-methoxyphenyl)-5-oxo-5H-dipyrido[1,2-a:3’,2’-e]pyrimidine-3-carbonitrile (1b) was achieved via one-pot multicomponent reactions of the barbituric acid and/or 3H-pyrido [1,2-a]pyrimidine-2,4-dione, anisaldehyde, ammonium acetate and malononitrile or three-component reactions of barbituric acid and/or 3H-pyrido[1,2-a]pyrimidine-2,4-dione, arylidine of malononitrile and ammonium acetate in presencse of drops of triethylamine (TEA), under fusion at 150 oC (Scheme 1).
Presence of cyano group in ortho location relative to an amino group is considered as a flexible site for the synthesis of different polycyclic structures. Condensation of 7-amino-pyridopyrimidine-6-carbonitrile derivative 1a with ethyl acetoacetate and/or ethyl cyanoacetate in ethanol afforded N-(6-cyano-5-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)-3-oxo -butanamide 2 and 6-amino-8-hydroxy-5-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimido-[4,5-b][1,8]naphthayridine-7-carbonitrile 3.
On the other hand the pyridopyrimidine derivatives 1a and 1b were acetylated by using acetic anhydride to give the monoacetyl derivatives 1-Acetyl-7-amino-5-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile 4a, N-(3-cyano-4-(4-methoxyphenyl)-5-oxo-5H-dipyrido[1,2-a:3’,2’-e]pyrimidin-2-yl) acetamide 4b. acetylation of 1a occurred on NH group of pyrimidine but acetylation of 1b occurred on NH2 group which was revealed from elemental analysis and spectral data.
However acid hydrolysis of 7-amino-pyridopyrimidine-6-carbonitrile derivatives 1a,b with sulfuric acid (70%) gave the pyrido[2,3-d]pyrimidine-6-carboxylic acids 7-Amino-5-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine -6-carboxylic acid 5a, 2-Amino-4-(4-methoxyphenyl)-5-oxo-5H-dipyrido[1,2-a:3’, 2’-e]pyrimidine-3-carboxylic acid 5b.
Sulfurization of derivative 1a by using one mole of phosphorous pentasulfide gave 7-amino-5-(4-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbo nitrile 6 while using two mole of phosphorous pentasulfide gave 7-amino-5-(4-methoxyphenyl)-2,4-dithioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile 7. Upon refluxing an alcoholic solution of derivative 7 with hydrazine hydrate (75%), 7-amino-4-hydrazinyl-5-(4-methoxyphenyl)-2-thioxo-1,2-dihydro pyrido[2,3-d] pyrimidine-6-carbonitrile 8 was afforded. (Scheme 2).
Additionally, Reaction of pyridopyrimidine derivative 1a with phenyl isothiocyanate and/or carbon disulphide gave 1-(6-Cyano-5-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)-3-phenylthiourea 9 and 5-(4-Methoxyphenyl)-6,8-dithioxo-6,7,8,9-tetrahydropyrido[2,3-d:6,5-d’]dipyrimidine -2,4(1H,3H)-dione 10, respectively.
In the same context, Cyclocondensation of pyridopyrimidine derivatives 1a, b with formamide afforded 6-Amino-5-(4-methoxyphenyl)pyrido[2,3-d:6,5-d’] dipyrimidine-2,4(1H,3H)-dione 11a and 6-Amino-5-(4-methoxyphenyl)-5-oxo-5H-dipyrido[1,2-a:3’,2’-e]dipyrimidine 11b, respectively.
On the other hand reaction of pyridopyrimidine derivatives 1a, b with triethyl orthoacetate under refluxing for 24 h Ethyl-N-(6-cyano-5-(4-methoxyphenyl)-2,4-di-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)acetimidate 12a, Ethyl-N-(3-cyano-4-(4-methoxyphenyl)-5-oxo-5H-dipyrido[1,2-a:3’,2’-e]pyrimidin-2-yl)aceti- midate 12b (Scheme 3).
To create new heterocyclic moieties, the oxazolopyridopyrimidine-3-carbonitrile derivatives 13 and 14 were achieved when pyridopyrimidine derivative 1a was treated with oxalyl chloride and bromoacetyl bromide it gives 2-Amino-4-(4-methoxyphenyl)-5,8,9-trioxo-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[3,2-e] pyrimidine-3-carbonitrile 13 and 2-Amino-4-(4-methoxyphenyl)-5,9-dioxo-8,9-dihydro-5H-oxazolo[3,2-a]pyrido[3,2-e]pyrimidine-3-carbonitrile 14.
Also, treatment of pyridopyrimidine derivative 1a with benzoyl chloride and p-toluene sulphonyl chloride afforded N-(6-cyano-5-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydro pyrido[2,3-d]pyrimidin-7-yl)benzamide 15 and 7-Amino-5-(4-methoxyphenyl)-2,4-dioxo-1-tosyl-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile 16, respectively.
Furthermore, Chlorination of derivative 1a with phosphorous oxychloride gave 7-Amino-4-chloro-5-(4-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine -6-carbonitrile 17. Treatment of chloropyrimidine derivative 17 with hydrazine hydrate (75%) gave 7-Amino-2-hydrazinyl-5-(4-methoxyphenyl)-4-oxo-1,4-dihydro pyrido [2,3-d]pyrimidine-6-carbonitrile 18 (Scheme 4).
Alkylation of 7-Amino-5-(4-methoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro pyrido[2,3-d]pyrimidine-6-carbonitrile 6 with different alkylating reagents such as ethyl iodide and/or bromo cyclohexane afforded the S-alkylated products7-Amino-2-(ethylthio)-5-(4-methoxyphenyl)-4-oxo-3,4-dihydropyrido [2,3-d]pyrimidine -6-carbonitrile 19 and 7-Amino-2-(cyclohexylthio)-5-(4-methoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile 20 .
Moreover, treatment of compound 6 with oxalyl chloride and chloro acetic acid afforded 2-Amino-4-(4-methoxyphenyl)-5,8,9-trioxo-8,9-dihydro-5H-pyrido[3,2-e] thiazolo[3,2-a]pyrimidine-3-carbonitrile 21 and 2-Amino-4-(4-methoxyphenyl)-5,8-dioxo-8,9-dihydro-5H-pyrido[3,2-e]thiazolo[3,2-a]pyrimidine-3-carbonitrile 22 (Scheme 5).
Pharmacological activity:
The second part aims to study the biological activities of the synthesized compounds as antioxidant, anticancer, molecular docking and DNA damage. Most of the synthesized compounds were tested for their in vitro and the resulted data were shown in the following.
1- Antioxidant activity:
The prepared compounds Have been evaluated for their antioxidant activities. The results show that Compound 9 showed the highest antioxidant activity while compounds 7 and 10 showed moderate activities while, the rest compounds showed the lowest activity compared to with ascorbic acid as the standard drug.
2- Cytotoxic activity of some compounds against human tumor cells:
Four human tumor cell lines namely; hepatocellular carcinoma (HePG-2), mammary gland (MCF-7), Colorectal carcinoma (HCT-116) and Human-prostate cancer (PC3) were used to establish the inhibitory effects of sixteen of the synthesized compounds on cell growth using 3-[4,5-dimethylthiazole -2-yl]-2,5-diphenyl tetrazolium bromide (MTT).
The results of the antiproliferative activity of pyridopyrimidine derivatives showed that Compound 9 exhibited very strong anti-proliferative activity against the-four carcinoma cell lines namely HePG-2, HCT-116, PC3 and MCF7 which are comparable with the reference anticancer drug DOX. Compounds 10 and 11a also showed a similar comparable trend with DOX with a very strong antitumor effect on PC3, MCF7 HCT-116, MCF7 cell lines . On the other hand, compound 7 showed strong anticancer activity against all four carcinoma cell lines tested in this. Moreover, compound 11a showed a similar trend against HePG-2 and PC3 cancer cell lines. Derivatives 4b and 15 showed strong anticancer activity against HePG-2, HCT-116 and MCF. While the other compounds showed moderate to weak activities against all the cell lines.
3- DNA damage
Bleomycin-dependent DNA damage
The results of the selected compounds showed that compounds 1b, 4b, 7, 9, 10, 11a,12 and 15 have the ability to protect DNA from the damage induced by bleomycin. On the other hand, the rest of the examined compounds exhibited weak activity.
4- Molecular docking:
A molecular docking study on the newly synthesized 2-amino-3-cyano pyridine derivatives with highest pharmaceutical activities had been carried out using it as new ligands into the binding site of CDK-5 enzyme.
The docking results revealed that compound 9 showed the highest binding to CDK-5 enzyme with binding energy of -8.32 Kcal/mol, compound 16 also exhibited promising CDK-5 enzyme inhibitory activity (-8.24 Kcal/mol) and compound 15 also showed a very high ligand exposure makes CDK-5 enzyme inhibitory activity (-8.10 Kcal/mol).
CPd. NO. Docking score
(Kcal/mol) No. of hydrogen bonding No. of (arene-H) interaction
EFP -7.89 1 (Lys 33) -
4b -7.22 - 2 (arene-H) interaction (Gly 11)
7 -6.59 2 (Leu 83 and Asp 86) -
9 -8.32 1 (Leu 83) -
10 -7.03 3 (Leu 83,Gln 85 and Lys 89) -
12a -7.51 1 (Leu 83) -
12b -7.65 - -
15 -8.10 - -
16 -8.24 2 (Leu 83and Lys 89) -
19 -6.84 1 (Asp 86) -
20 -7.53 1 (Glu 81) 1 (arene-H) interaction (Leu 83)
part (II)
In continuation of our research on biologically important heterocycles, we hereby report the synthesis, characterization and antimicrobial studies of some new substituted imidazoles carrying pyrazole moiety.
synthesis of (Z)-5-((1H-indol-3-yl)methylene)-3-phenyl-2-thioxoimidazolidin-4-one 2 was achieved via the reaction of 3-phenyl-2-thioxoimidazolidin-4-one 1 and indole-3-aldehyde.
Moreover, reactions of 3-phenyl-2-thioxoimidazolidin-4-one 1, p-chlorobenzaldehyde and thiourea gave 7-(4-chlorophenyl)-2-phenyl-3,5-dithioxo hexahydro-1H-imidazo[1,5-c]imidazol-1-one 4 which can be obtained from the reaction of (Z)-5-(4-chlorobenzylidene)-3-phenyl-2-thioxo imidazolidin-4-one 3 and thiourea under the same condition.
Formylation of 3-phenyl-2-thioxoimidazolidin-4-one 1 via the VilsmeierHaack Reaction afforded 5-oxo-1-phenyl-2-thioxoimidazolidine-4-carbaldehyde 5 which further react with hydrazine hydrate to give 6-phenyl-3a,6-dihydroimidazo[4,5-c]pyrazole-5(4H)-thione 6 and/or ethylacetoacetate, ethyl cyanoacetate and thiourea to give 6-acetyl-2-phenyl-3-thioxo-2,3-dihydro-1H-pyrrolo[1,2-c]imidazole -1,5(7aH)-dione 7 and 1,5-dioxo-2-phenyl-3-thioxo-2,3,5,7a-tetrahydro-1H-pyrrolo [1,2-c]imidazole-6-carbonitrile 8, respectively. (Scheme 1).
On the other hand, arylidenes can be achieved from the reaction of 5-phenyl-2,4-dihydro-3H-pyrazol-3-one 9 with different aldehydes like p-chlorobenzaldehyde, indole-3-carbaldehyde, 4-hydroxy-2-oxo-2H-chromene-3-carbaldehyde and 5-oxo-1-phenyl-2-thioxoimidazolidine-4-carbaldehyde to afford (Z)-4-(4-chlorobenzylidene) -5-phenyl-2,4-dihydro-3H-pyrazol-3-one 10, (Z)-4-((1H-indol-3-yl)methylene)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one 11, (Z)-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methylene)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one 12 and (Z)-4-((5-oxo-1-phenyl-2-thioxoimidazolidin-4-yl)methylene)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one 13, respectively. (Scheme 2)
Potency of the imidazoles carrying pyrazole moiety in compound 13 were examined with different reagent to synthesize different derivatives. Reaction of (Z)-4-((5-oxo-1-phenyl-2-thioxoimidazolidin-4-yl) methylene)-5-phenyl-2,4-dihydro -3H-pyrazol-3-one 13 with 3-phenyl-2-thioxoimidazolidin-4-one 1 and/or hydrazine hydrate to give 4-(5-oxo-1-phenyl-2-thioxoimidazolidin-4-yl)-4-((5-oxo-1-phenyl-2-thioxoimidazolidin -4-yl)methyl)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one 14 and (Z)-5-hydrazineylidene-4-((Z)-((Z)-5-hydrazineylidene-3-phenyl-1,5-dihydro -4H-pyrazol-4-ylidene)methyl)-1-pheny limidazolidine-2-thione 15, respectively. (Scheme 3)