الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Chalcones are aromatic ketones that represent the main moiety of many important biologically active compounds. The most important part in chalcones molecules is the α, β-unsaturated carbonyl system links the two aromatic rings together, that results in making chalcones the precursor for the synthesis of many important heterocyclic compounds. The importance of the chalcone is also, due to their significant therapeutic potential against various diseases.
This work aimed to synthesize some novel heterocyclic compounds (2a -14a) and (2b-8b), that are expected to have antitumor applications and biological activities, starting with the α, β-unsaturated carbonyl chalcones; 3-(1H-indol-3-yl)-1-(naphthalen-2-yl)prop-2-en-1-one (1a), and 3-(benzo[d][1,3]dioxol-5-yl)-1-(naphthalen-2-yl)prop-2-en-1-one (1b), as the main precursors.
The structural formulas of the synthesized compounds are confirmed by their elemental analysis, FTIR, 1H NMR, 13C NMR and MS.
Synthesis of Compounds (2a-7a, and 2b-7b) from Compounds (1a and 1b)
Chalcone (1a, or 1b) reacted with (hydrazine hydrate, 6-amino-2-thiouracil, 2-aminophenol, 2,3-diaminomaleonitrile, 3-amino-1,2,4-triazole), or thiourea in the appropriate solvent to give the corresponding derivatives; 3-(3-(naphthalen-2-yl)-1H-pyrazol-5-yl)-1H-indole (2a), 5-(benzo[d][1,3]dioxol-5-yl)-3-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazole (2b), 5-(1H-indol-3-yl)-7-(naphthalen-2-yl)-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3a), 5-(benzo[d][1,3]dioxol-5-yl)-7-(naphthalen-2-yl)-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3b), 2-(1H-indol-3-yl)-4-(naphthalen-2-yl)benzo[b][1,4]oxazepine (4a), 2-(benzo[d][1,3]dioxol-5-yl)-4-(naphthalen-2-yl)benzo[b][1,4]oxazepine (4b), 7-(1H-indol-3-yl)-5-(naphthalen-2-yl)-4,5-dihydro-1H-1,4-diazepine-2,3-dicarbonitrile (5a), 7-(benzo[d][1,3]dioxol-5-yl)-5-(naphthalen-2-yl)-4,5-dihydro-1H-1,4-diazepine-2,3-dicarbonitrile (5b), 7-(1H-indol-3-yl)-5-(naphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (6a), 7-(benzo[d][1,3]dioxol-5-yl)-5-(naphthalen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine (6b), 4-(1H-indol-3-yl)-6-(naphthalen-2-yl)pyrimidine-2-thiol (7a), or 4-(benzo[d][1,3]dioxol-5-yl)-6-(naphthalen-2-yl)pyrimidine-2-thiol (7b), respectively.
Synthesis of Compounds (8a and 8b) from Compound (7a), (7b)
An equimolar mixture of compound (7a) or (7b) and hydrazine hydrate reacted to afford 3-(2-hydrazinyl-6-(naphthalen-2-yl)pyrimidin-4-yl)-1H-indole (8a), and 4-(benzo[d][1,3]dioxol-5-yl)-2-hydrazinyl-6-(naphthalen-2-yl)pyrimidine (8b), respectively. The element test showed no sulfur in products either compound (8a) or (8b).
Synthesis of Compounds (9a and 10a) from Compound (3a)
Reaction of an equimolar mixture of compound (3a) with chloroacetic acid afforded 2-((5-(1H-indol-3-yl)-7-(naphthalen-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)thio)acetic acid (9a), whereas its reaction with hydrazine hydrate in absolute ethanol it gave 2-hydrazinyl-5-(1H-indol-3-yl)-7-(naphthalen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (10a).
Synthesis of Compounds (11a-14a) from Compound (10a)
Compound 2-hydrazinyl-5-(1H-indol-3-yl)-7-(naphthalen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (10a) was allowed to react with benzaldehyde in glacial acetic acid to give 2-(2-benzylidenehydrazinyl)-5-(1H-indol-3-yl)-7-(naphthalen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (11a), with maleic anhydride to give 1-((5-(1H-indol-3-yl)-7-(naphthalen-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-1H-pyrrole-
2,5-dione (12a), whereas when reacted with phenylisothiocyanate it gave 2-(5-(1H-indol-3-yl)-7-(naphthalen-2-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-N-phenylhydrazinecarbothioamide (13a). It was also, reacted with acetyl chloride to give 6-(1H-indol-3-yl)-3-methyl-8-(naphthalen-2-yl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one (14a).
Elucidation of Molecular Structure of Synthesized Compounds
The molecular structural formulas of the synthesized compounds obtained (2a -14a) and (2b -8b) have been assigned and confirmed by their melting points, admixed melting points, spectral analysis (13C NMR, 1H NMR, FTIR and MS).
Biological Activities of the Synthesized Compounds
Biological and medicinal assessments for some of the newly synthesized compounds were evaluated as antibacterial and antifungal agents and also as antitumor potent agents against two cell lines; MCF-7 breast carcinoma and HCT116 colon carcinoma.
a-Antibacterial and Antifungal Activities
Well diffusion method was employed to assess in vitro the antibacterial activity of the synthesized compounds (2a-14a) and their synonyms (2b-8b) against two Gram-positive bacteria, Staphylococcus aureus (S. a.) and Bacillus subtilis (B. S.), and two Gram-negative bacteria, Escherichia coli (E. c.) and Proteus vulgaris (P. v.), and also, their antifungal activity against fungus strains namely, Aspergillus fumigatus have been evaluated.
In this method, screening tests the compounds were dissolved in (DMSO) as a solvent in different concentrations (10, 5, and 2.5 mg/ml) and the inhibition zone of bacterial and fungal growth around the disc was measured after 24h at 37oC.
The bacterial and fungi growth around the disc showed that the compounds containing indole moiety (2a-14a) are more biologically active more than their synonyms containing benzodioxole moiety (2b-8b).
The results of the antibacterial and antifungal activities showed that compounds that are containing indole moiety are generally, more biologically active than those containing benzodioxole moiety.
Among the compounds that are containing indole moiety, compounds (4a, 6a, 13a) are the most potent towards all the
studied Gram-positive and Gram-negative bacteria, as well as fungi, whereas, the other compounds have moderate to high effects toward the studied bacteria and fungi.
On the other hand, the results represented that among the synonyms compounds that are containing benzodioxole moiety (2b-8b), only compound (2b) has high effect against Proteus Vulgaris (P.V.) bacteria and low, or no effect against the other species, whereas the other compounds containing benzodioxole moiety have low or no effect against the studied bacteria and fungi.
b- Antitumor Activity
The antitumor activity (IC50 ) of some of the newly synthesized compounds that are containing indole moiety (3a-5a, 7a, and 13a) and their synonyms that are containing benzodioxole moiety (3b-5b and 7b) has been evaluated against two tumor cell lines (MCF-7 breast carcinoma cell line and HCT-116 colon carcinoma cell line). The results obtained shows that compounds containing indole moiety are having higher antitumor activity than those which are having benzodioxole moiety.
Compound (5a) showed the highest antitumor activity against HCT-116 and MCF-7 cell lines, whereas compounds (7a), and
(13a) show high antitumor activity against HCT-116 and
moderate against MCF-7cell line. Compound (4a) shows moderate activity against both HCT-116 and MCF-7 cell lines, whereas (3a) showed the lowest activity against both the two cell lines. Compounds (3b-5b and 7b) showed that compound (4b) is the most active among them, against both HCT-116 and MCF-7 cell lines. However, all compounds (3a-5a, 7a, and 13a) and (3b-5b and 7b) are having antitumor activity against the HCT-116 cell more than against MCF-7 cell line.
Reactions Heating Techniques:
In this work, we aimed to use eco-friendly synthesis of chalcones (1a, 1b) which are considered as precursors for the synthesis of important novel heterocyclic derivatives as potential anticancer, antibacterial and antifungal agents. Such as, pyrimidine-2-thioxo-4-one derivatives (3a and 3b). Moreover, pyrimidine-2-thioxo-4-one derivatives (3a), reacted with hydrazine hydrate to give 2-hydrazinylpyrido[2,3-d]pyrimidine derivative (10a) which on its turn is used as a functionalizing agent for preparation of compounds (11a-14a), through its reaction with benzaldehyde, maleic anhydride phenylisothiocyanate and acetyl chloride, respectively.
Herein, a rapid synthetic protocol was developed to use different heating techniques; conventional heating (A), ultrasonic (B) and microwave irradiation (C) technology, and compare
between their efficiency in preparation of the new series of the derivatives. The strategy was emanated from the synthesis of compounds (1a, 1b, 3a, 3b, 10a), via the three techniques (A), (B), and (C), to define the highly efficient simple, novel, and eco-friendly manner to synthesize the new derivatives.
The most noticeable advancement in microwave-assisted technique in synthesis of these compounds is the spectacular decrease of reaction times, typically from days or hours into minutes or even seconds rather than ultrasonic technique.
Furthermore, upon comparison with the conventional method or ultrasonic irradiation technique, microwave-assisted reactions provides the highest yields and purity, minimizes the energy consumption, eliminates or minimizes the utilization of hazardous solvents (green chemistry).