الفهرس 
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Abstract
A Series Of 1,2,4-Triazolo[1,5-A]Pyrimidine Derivatives Have Been Designed And Synthesized As Combretastatin CA-4 Analogs. They Were Screened For Anticancer And Tubulin Polymerization Inhibition Activities. The Trimethoxyphenyl 1,2,4- Triazolo[1,5-A]Pyrimidine Derivative Ivc Showed Significant Antiproliferative Activity. It Exhibited An IC50 Value Of 0.53 Μm Against HCT-116 Cancer Cell Line. It Was Further Tested As A Tubulin Polymerization Inhibitor Showing An IC50 = 3.84 Μm If Compared To Combretastatin (IC50 = 1.10 Μm). Further Mechanistic Studies Revealed That Compound Ivc Could Obviously Inhibit The Proliferation Of HCT-116 Cancer Cells By Inducing Apoptosis And Arresting The Cell Cycle At G2/M Phase. Docking Studies Showed That Compound Ivc Illustrated Good Fitting To The Colchicine Binding Site Of Tubulin. Thus, It Could Considered As An Anticancer Lead Compound, Worthy Of Further Development As A Tubulin Polymerization Inhibitor.
This Thesis Consists Of The Following Parts:
I. Introduction:
In This Section, A Literature Review About Pharmacological Activities Of 1,2,4- Triazolo[1,5-A]Pyrimidines Nucleus. In Addition, A Survey On The Colchicines Binding Site Inhibitors Was Also Reported.
II. Aim Of The Work
The Goal Of This Research Was To Find New Tubulin Inhibitors By Designing And Synthesising New Compounds. These Compounds Were Obtained Based On Earlier SAR Research Studies Of 1,2,4-Triazolo[1,5-A]Pyrimidines.
III. Discussion Of The Synthesis Part
3.1. Chemistry
It Discussed The Experimental Procedures Used To Synthesise The Designed Compounds And The Confirmation Of Their Structures Using Various Elemental And Spectral Measurements. The Steps For The Synthesis Of The Target Compounds Was Depicted In Schemes 1-3.
3.2. Biological Evaluation
This Section Reviewed The Findings Of Screening Of The Target Compounds Against Various Biological Activities, As Shown Below:
3.2.1. In Vitro Antitumor Evaluation Results.
The New Compounds Iva-F, Ivj-L, Ivn-O And Va-C Were Evaluated For Their Antiproliferative Activity Against HCT-116 Colon Cancer Cells Using MTT Assay. Compounds Ivg-I, Ivm And Vd-F Were Evaluated By The US National Cancer Institute For Their In Vitro Antiproliferative Activity Against NCI 60 Cancer Cell Line Plate.
3.2.2 Tubulin Polymerization Inhibition Assay.
Compound Ivc Showed The Most Effective Anticancer Activity Against HCT- 116, (IC50 Value Of 0.53±0.06 Μm), Was Evaluated For Tubulin Polymerization Inhibitory Activity, where It Shows IC50 Value Of 3.84±0.12 Μm.
3.2.3 Colchicine Binding Site Competitive Binding Assay.
Compounds Ivc, Ivn, Va, And Vb Were Evaluated For Their Affinity Towards The Colchicine Binding Site Of Tubulin And Compared To Combretastine-4 (CA-4).
3.2.4 Cell Cycle Analysis.
HCT-116 Cells Were Exposed To Compound Ivc For 24 And 48 H At Its IC50 Concentration (0.53 µm) To Induce A Significant Disruption In The Cell Cycle Profile And Cell Cycle Arrest At The G2/M Phase .
3.2.5 Effect Of Compound Ivc On HCT-116 Cells Apoptosis.
Compound Ivc Resulted In A 39.51 Percent Increase In The Percentage Of Apoptotic HCT-116 Cells (1.86 Percent). Compound Ivc Triggered Apoptosis In Both Early (12.61%) And Late (18.68%) Cell Stage .
3.3. Molecular Modeling Study.
The Design Of This Work Was Based On A Molecular Modelling Investigation Of The Target Chemicals’ Critical Binding characteristics To Tubulin At The Colchicine Binding Region. MOE 2021 Software Was Used To Conduct A Molecular Docking Investigation On Tubulin In Combination With Colchicine.
3.4. Computational Analysis:
The Most Active Compounds Ivc, Ivn, Va, And Vb Were Subjected To An In Silico Computational Study To Determine Physicochemical Properties Such As Drug Solubility (S), Partition Coefficient, Human Intestinal Absorption (HIA), Cell Permeability, Drug Likeness Score And Polar Surface Area (PSA) To Predict Their ADMET Properties.
IV. Experimental:
1. Chemistry
This Part Offered The Practical Procedures Used For The Synthesis Of The Reported Intermediates As Well As The Novel Final Compounds. Also, It Summarized Their Spectral And Elemental Data. The Following Compounds Were Synthesized.
Newly Synthesized Final Compounds: Include 21 New Compounds:
1. 5-(4-Methoxyphenyl)-7-(3,4,5-Trimethoxyphenyl)-1,2,4-Triazolo[1,5- A]Pyrimidin-2-Amine (Iva)
2. 5-Phenyl-7-(3,4,5-Trimethoxyphenyl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2-Amine(
Ivb)
3. 5-(4-Chlorophenyl)-7-(3,4,5-Trimethoxyphenyl)-1,2,4-Triazolo[1,5- A]Pyrimidin-2-Amine (Ivc)
4. 5,7-Bis(3,4,5-Trimethoxyphenyl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2-Amine (Ivd)
5. 5-(4-Bromophenyl)-7-(3,4,5-Trimethoxyphenyl)-1,2,4-Triazolo[1,5- A]Pyrimidin-2-Amine( Ive)
6. 5-(Pyridin-2-Yl)-7-(3,4,5-Trimethoxyphenyl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2- Amine( Ivf)
7. 5,7-Bis(4-Methoxyphenyl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2-Amine (Ivg)
8. 7-(4-Methoxyphenyl)-5-Phenyl-1,2,4-Triazolo[1,5-A]Pyrimidin-2-Amine (Ivh)
9. 5-(4-Chlorophenyl)-7-(4-Methoxyphenyl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2- Amine (Ivi)
10. 5-(4-Bromophenyl)-7-(4-Methoxyphenyl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2- Amine (Ivj)
11. 7-(4-Methoxyphenyl)-5-(Pyridin-2-Yl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2- Amine( Ivk)
12. 7-Phenyl-5-(Pyridin-2-Yl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2-Amine (Ivl)
13. 5-(4-Methoxyphenyl)-7-Phenyl-1,2,4-Triazolo[1,5-A]Pyrimidin-2-Amine (Ivm)
14. 5-(4-Chlorophenyl)-7-(4-(Dimethylamino)Phenyl)-1,2,4-Triazolo[1,5- A]Pyrimidin-2-Amine (Ivn)
15. 7-(4-(Dimethylamino)Phenyl)-5-(4-Methoxyphenyl)-1,2,4-Triazolo[1,5- A]Pyrimidin-2-Amine( Ivo)
16. N-(5-(4-Methoxyphenyl)-7-(3,4,5-Trimethoxyphenyl)- 1,2,4-Triazolo[1,5- A]Pyrimidin-2-Yl)Acetamide (Va)
17. N-(5-Phenyl-7-(3,4,5-Trimethoxyphenyl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2- Yl) Acetamide (Vb)
18. N-(5-(4-Bromophenyl)-7-(3,4,5-Trimethoxyphenyl)-1,2,4-Triazolo[1,5- A]Pyrimidin-2-Yl)Acetamide (Vc)
19. N-(5,7-Bis(4-Methoxyphenyl)-1,2,4-Triazolo[1,5-A]Pyrimidin-2-Yl)Acetamid
(Vd)
20. N-(7-(4-Methoxyphenyl)-5-Phenyl-1,2,4-Triazolo[1,5-A]Pyrimidin-2- Yl)Acetamide (Ve)
21. N-(5-(4-Chlorophenyl)-7-(4-Methoxyphenyl)- 1,2,4-Triazolo[1,5- A]Pyrimidin-2-Yl)Acetamide ( Vf).