الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
This work aimed to synthesize novel biologically active compounds as anticancer or antiviral agents through the following three parts
Part 1: Synthesis, Molecular Modeling and Anti-Proliferative Activity of Novel Fused Tricyclic Pyrazole and Pyridine Derivatives Derived from 2-Arylsubstituted 1,3-Indandione.
1,3-Indandione 1 was reacted with aromatic aldehydes 2a–e to give the corresponding 2-aryl substituted derivatives 3a–e. One-pot reaction of 1,3-indandione with ethyl cyanoacetate and aromatic aldehydes 2a-b via intermediates A and B affording 2-pyridinone derivatives 4a-b (Scheme 1).
Scheme 1
Reaction of arylidineindanedione 3a-b with hydrazine hydrate in absolute ethanol gave indenopyrazole derivatives 5a-b. Also, arylidineindanedione 3b react with hydrazine hydrate in acetic acid and gave indenopyrazole derivative 6 (scheme 2). On the other hand, compounds 3a-b were reacted with 2,4-dinitrophenylhydrazine or phenyl hydrazine to give the corresponding arylindenopyrazole derivatives 7a-b. Reaction of compounds 3a-c with semicarbazide or thiosemicarbazide gave amide or thioamide derivatives 8a–d. The precursors 3a–c reacted with hydroxylamine hydrochloride to give the respective oxazole derivatives 9a–c (Scheme 2).
Scheme 2
2-Substituted arylindene-1,3-diones 3a-b were reacted with ethyl cyanoacetate to give indenocyanopyridone derivatives 10a-b. Reaction of the same precursors 3a-b with malononitrile in different reaction media gave the corresponding pyridino and pyrano derivatives 11a–d, 12a-b and 13a-b (Scheme 3).
Scheme 3
The newly synthesized indanone derivatives were tested for their in-vitro antiproliferative activities against breast, leukemia, lung, melanoma, prostate cancer cell lines and kinase inhibition activity. Molecular modeling was carried out for their molecular structures. The results obtained revealed that compounds 11a and 11c displayed the highest potency.
Part 2: Synthesis, Anti-Viral Activity and Mechanism of Action of Novel Fused Tricyclic, Tetracyclic and Pentacyclic Pyrimidinethione, Thiazolopyrimidine and Triazolopyrimidine Derivatives Derived from 2-Arylsubstituted 1,3-Indandione.
Arylmethylenes 3a-c were submitted to react with thiourea to afford pyrimidinethione derivatives 14a-c (scheme 4). Pyrimidinethiones 14a-c were also prepared in a one pot reaction by refluxing of 1,3-indandione, proper aromatic aldehyde (2,5-dimethoxy benzaldehyde 2a, 3-methoxy benzaldehyde 2b and 4-chloro-3-nitro benzaldehyde 2c) and thiourea in glacial acetic acid (scheme 4).
Scheme 4
Pyrimidinethione 14a was reacted with chloroacetic acid and anhydrous sodium acetate to give the thiazole compound 16 not 15. On the other hand, compound 14a-b were refluxed in one pot reaction with equimolecular amount of appropriate aldehydes, chloroacetic acid and anhydrous sodium acetate to give the corresponding thiazole derivatives 17a-h (scheme 5). Also, pyrimidinethione 14a was refluxed with 2-bromo propanoic acid, or 3-bromo propanoic acid and anhydrous sodium acetate and afforded the methylthiazolo derivative 18 or the thiazino derivative 19, respectively (scheme 5).
Scheme 5
A mixture of pyrimidinethione 14a, 3-chloroacetyl acetone, and potassium hydroxide
was refluxed to form compound 20 (scheme 6). Compound 20 was refluxed with 3,4,5-trimethoxy benzaldehyde to give the corresponding compound 21 (scheme 6). Also, A mixture of compound 20, ethyl cyanoacetate, 3,4,5-trimethoxy benzaldehyde and anhydrous ammonium acetate was refluxed to give compound 22 (scheme 6). On the other hand, Compound 20 was refluxed with 3,4,5-trimethoxy benzaldehyde, malononitrile, and anhydrous ammonium acetate to give compound 23 (scheme 6).
Scheme 6
Prymidinethione 14a was refluxed with the appropriate hydrazonyl chloride to afford triazolo pyrimidine derivatives 24a-c via two intermediates C and D (scheme 7).
Scheme 7
Pyrimidinethione 14a was refluxed in a mixture of glacial acetic acid and acetic anhydride to give the corresponding –N acetylated compound 25 (scheme 8). Also, a mixture of pyrimidinethione 14a and benzoyl chloride was refluxed to form compound 26 (scheme 8). On the other hand, a mixture of thiopyrimidine 14a, formaldehyde and morpholine was refluxed to give the corresponding derivative 27 (scheme 8).
Scheme 8
Pyridopyrimidinethione derivatives 28a-b were prepared either via one pot reaction by refluxing indandione, aromatic aldehydes and 6-aminothiouracil or by refluxing a mixture of arylmethylenes 3a-b and 6-aminothiouracil (scheme 9).
Scheme 9
Pyridoprymidinethione 28a was refluxed with chloroacetic acid and anhydrous sodium acetate to give compound 29 (Scheme 10). On the other hand, compounds 28a-b were refluxed in one pot reaction with equimolecular amount of p-chlorobenzaldehyde, chloroacetic acid, anhydrous sodium acetate to give compounds 30a-b respectively. Compound 30a was also prepared by refluxing of compound 29 with p-chlorobenzaldehyde (scheme 10).
Scheme 10
A mixture of pyridopyrimidinethione 28a-b and the appropriate hydrazonyl chloride was refluxed to give the corresponding pyridotriazolopyrimidine derivatives 31a-f through the two intermediates E and F (scheme 11).
Scheme 11
Pyridohydrazinopyrimidine derivatives 32a-b were prepared by refluxing thiopyrimidine 28a-b with hydrazine hydrate (scheme 12). Triazolopyrimidine 33a-b were prepared from the reaction of thiopyrimidine derivatives 28a-b with hydrazine hydrate in dimethyl formamide (DMF) or by refluxing pyridohydrazinopyrimidine 32a-b in dimethylformamide (DMF) (Scheme 12). A mixture of compound 32a and aromatic aldehydes namely p-nitro benzaldehyde or p-chlorobenzaldehyde was refluxed to give the corresponding schiff-base derivatives 34a-b (scheme 12).
Scheme 12
A mixture of pyridopyrimidinethiones derivatives 28a-b, chloroacetone, and anhydrous sodium acetate were refluxed to give the corresponding compounds 35a-b (scheme 13). Also, a mixture of pyrimidinethione derivative 28a, 3-chloroacetylacetone, and anhydrous sodium acetate was refluxed, to give the corresponding compound 36 (scheme 13).
Scheme 13
Some new synthesized derivatives tested for anti-HSV-1 activity including their cytotoxicity. Compounds (14c, 16, 17b, 28b) were found to have higher activity than Acyclovir at low concentrations. Possible mechanism of action of HSV-1 inhibition by these compounds were studied at three different levels (Viral replication, Viral adsorption, Virucidal).
Part 3: Synthesis, characterization, and Anti-Cancer Screening of Novel Macrocyclic Indenedione-Based Tröger’s Base and its N,N`- Disubstituted Phenhomazine Derivatives.
The 1,3-indaenedione-based Tröger’s base 37 was synthesized by treating 2-(4-aminobenzylidene)-1H-indene-1,3(2H)-dione 3e with paraformaldehyde (scheme 14).
Scheme 14
Compound 37 was reacted with dimethylsulphate to give the N,N’-dimethyl phenhomazine derivative 38 (scheme 15). The Tröger base analogue 37 was boiled with acetic anhydride to give good crystals of the corresponding N,N’-diacetyl phenhomazine 39 (scheme 15). The Tröger’s base analogue 37 was reacted with benzoyl chloride to give the corresponding N,N’-dibenzoyl phenhomazine 40 (scheme 15).
Scheme 15
The Tröger base analogue 37 was refluxed in trifluoroacetic anhydride to give the corresponding trifluoroacetamide trifluoroacetate salt 41. When, a mixture of the trifluoroacetate salt 41 and potassium carbonate in methanol was stirred, we obtained the corresponding tetrahydrophenhomazine derivative 42 (scheme 16).
Scheme 16
Compound 37 was refluxed with ferric nitrate trihydrate or nickel (II) chloride to obtain the corresponding complex derivatives 43 and 44 respectively (scheme 17).
Scheme 17
The eight compounds belonged to our study 37-44 were assessed on 3 cancer cell lines namely hepatocellular carcinoma (Hep G2), breast adenocarcinoma (MCF-7) and Colon Carcinoma (HCT-116). N,N’-diacetylphenhomazine 39 has shown a promising activity against the three human cancer cell lines.