Discovering of new anticancer agents with potential activity against tubulin polymerisation is still a promising approach. Colchicine binding site inhibitors are the most relevant anti-tubulin polymerisation agents. Thus, new quinoline derivatives have been designed and synthesised to possess the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesised compounds were tested in vitro against a panel of three human cancer cell lines (HepG-2, HCT-116, and MCF-7) using colchicine as a positive control. Comparing to colchicine (IC 50 = 7.40, 9.32, and 10.41 µM against HepG-2, HCT-116, and MCF-7, respectively), compounds 20 , 21 , 22, 23, 24, 25, 26, and 28 exhibited superior cytotoxic activities with IC 50 values ranging from 1.78 to 9.19 µM. In order to sightsee the proposed mechanism of anti-proliferative activity, the most active members were further evaluated in vitro for their inhibitory activities against tubulin polymerisation. Compounds 21 and 32 exhibited the highest tubulin polymerisation inhibitory effect with IC 50 values of 9.11 and 10.5 nM, respectively. Such members showed activities higher than that of colchicine (IC 50 = 10.6 nM) and CA-4 (IC 50 = 13.2 nM). The impact of the most promising compound 25 on cell cycle distribution was assessed. The results revealed that compound 25 can arrest the cell cycle at G2/M phase. Annexin V and PI double staining assay was carried out to explore the apoptotic effect of the synthesised compounds. Compound 25 induced apoptotic effect on HepG-2 thirteen times more than the control cells. To examine the binding pattern of the target compounds against the tubulin heterodimers active site, molecular docking studies were carried out.

Various new substituted and fused coumarin analogues have been synthesized via different synthetic pathways. Among which are variable substituted coumarin derivatives bearing either biologically active side chains or rings at 5, 6, and 3 positions of the coumarin nucleus as indicated in compounds 10, 12, 13, 16–19, 21, 23–32, 38, and 42–45. In addition, different pyranocoumarin derivatives either substituted as in compounds 2, 3, and 6 or fused as compounds 33–36, pyranoxanthene analogues such as compounds 4 and 46, coumarinotriazolothiadiazine derivative 8, coumarinonaphthodiazocin analogue 39 and coumarinopyrazolone derivative 40 were synthesized. Thirty‐eight of the synthesized compounds were subjected to in vitro anticancer screening against mammalian liver carcinoma HepG2 and breast carcinoma MCF7 cell lines using Cisplatin as a standard reference. The anticancer activity screening results revealed that, among the tested compounds, compounds 16, 40, and 43 bearing 4‐chlorophenyl‐2‐aminopyridine‐3‐carbonitrile attached to C6 position, fused pyrazolone ring or attached to 4‐chlorophenyl‐2‐oxo‐dihydropyridine‐3‐carbonitrile at C3 position of the coumarin nucleus, respectively, exhibited moderate to strong activity against both cell lines.

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In this approach we applied a green synthetic protocol for the preparation of a novel series of imidazotriazole derivatives under solvent free conditions and shorter reaction times utilizing the reactive 2-thioxoimidazolidinone derivative 1 as a starting substrate. Different substituted imidazo[2,1-c][1,2,4] triazolone derivatives 2-4,6 and imidazo[1,2-b][1,2,4]triazolone derivatives 8-10, 12, 13, 15, 16 and 18 were synthesized. We carried out the synthesis of the open chain analogues phenylimidazolidin-2-ylidenepicolinohydrazide 5, dihydroimidazolylacetamide 11, imidazolylpicolinamide 14, pentahydroxyhexylideneaminoimidazol-5-one derivative 17, dihydroimidazolyl-N,N-dimethylformimidamide 19 and the dihydroimidazo[1,2-b] [1,2,4]triazepine-7-carbonitrile 20. The synthetic methods involved mainly fusion of compound 1 with the appropriate reagents. The in vitro anticancer evaluation at the National Cancer Institute (NCI), USA at a single dose (10 À 5 M) in full NCI 60 cell panel revealed that a significant inhibition for some cancer cells was observed with compounds 11 and 17-19 (38-67.5 % inhibition).These novel compounds displayed appreciable anticancer activities against different cancer cell lines including leukemia, colon cancer, melanoma, ovarian cancer, renal cancer and non-small cell lung cancer cell lines.

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In continuation of our program for synthesizing novel imidazotriazole scaffolds, we report herein the synthesis of new fifteen substituted and fused imidazotriazole derivatives via different addition and cyclocondensation pathways. Thirteen compounds have been tested for their antiproliferative activity against 60 NCI cell lines. Compounds 3, 15 and 17 were the most active among the synthesized series. Imidazo[2,1-c][1,2,4]triazolone derivative 3 showed high activity against leukemia K-562 (51.00%), RPMI-8226 (68.36%) and breast cancer MCF-7 (56.76%) cell lines. While compound 15 exhibited high potency against colon cancer HCT-15 (59.33%), CNS cancer SNB-75 (57.06%) and renal cancer UO-31 (50.5%) cell lines. Bis[1,2,4]triazolopurin-7-one derivative 17 showed strong activity against CNS cancer SNB-75 cell line (54.32%). Compounds 3, 15 and 17 were evaluated through molecular modeling and docking techniques to give us a closer look on their binding mode with CDK2. The in vitro inhibitory activity against CDK2 was also performed for compounds 3 and 17. Compound 3 was subjected to further investigations by studying its effect on cell cycle progression and cell apoptosis in MCF-7 cell line. It caused apoptosis, necrosis and induced cell cycle arrest at G2/M phase in MCF-7 cell.

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