Aim: Design and synthesis of thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors. Material and methods: A series of novel 6,7,8,9-tetrahydro-5 H -cyclohepta[4,5]thieno[2,3- d ]pyrimidine derivatives with different substituents on C-4 position was synthesized and evaluated for their anticancer activity against MCF-7 cell line. EGFR, VEGFR-2 inhibitory assay, the cell cycle analysis and apoptosis induction ability of the most potent compound 5f were evaluated. Results: Most of the compounds showed moderate to significant anticancer activity. Compound 5f exhibited the most potent anticancer activity being 1.73- and 4.64-folds more potent than erlotinib and doxorubicin, respectively. Compound 5f showed potent EGFR inhibitory activity being 1.18-folds more potent than reference standard erlotinib and it also showed good VEGFR-2 inhibitory activity at the micromolar level with IC 50 value 1.23 µM. Compound 5f caused induction of cell cycle arrest at G2/M phase and accumulation of cells in pre-G1 phase. Compound 5f induced cellular apoptosis.

Three series of benzothiophene derivatives were designed and synthesized as cytotoxic agents. The compounds were subjected to in vitro antitumor screening at the National Cancer Institute (NCI), Bethesda, MD. The results of the single dose screening indicated that only the benzothieno[3,2-b]pyran series 3a-f exhibited potent and broad spectrum cytotoxic activity and was subjected to five dose cytotoxic screening. The most active compound in this study was 2-amino-6-bromo-4-(4-nitrophenyl)-4H-[1]benzothieno[3,2-b]pyran-3-carbonitrile (3e) with MG-MID GI 50 , TGI, and LC 50 values of 0.11, 7.94 and 42.66 mM, respectively. Compound 3e exhibited broad spectrum anticancer activity against a panel of 59 cell lines. To elucidate the underlying mechanism of compound 3e cytotoxic activity, we examined its effect on cell cycle progression and its ability to induce apoptosis using human colon adenocarcinoma cell line (HCT-116). The effect of compound 3e on the cell cycle progression indicated that exposure of HCT-116 cells to compound 3e for 24 and 48 h, induced a significant disruption in the cell cycle profile including time dependent decrease in cell population at G1 phase with concomitant increase in pre-G and G2/M cell population. Moreover, compound 3e induced time dependent increase in the percentage of early and late apoptotic and necrotic cell population. In conclusion, we were able to successfully design a new series of benzothieno [3,2-b]pyran derivatives with potent cytotoxic activity and their mechanism of cytotoxicity was examined.

2-Amino-3-cyanothiophenes were successfully condensed with a number of cycloalkanones to afford tacrine analogues in a one-step reaction mediated with Lewis acid. The newly synthesized compounds have been tested for their ability to inhibit acetylcholine esterase (AChE) activity using tacrine as standard drug. Some of the tested compounds showed moderate inhibitory activity in comparison with tacrine, especially compounds 6a which displayed the highest inhibitory activity. Furthermore, molecular-modeling studies were performed in order to rationalize the obtained biological results.

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Certain pyridazine containing compounds 2a-f, 3a, b, 4a, b, 5a, b, 6a and b were synthesized and characterized by spectroscopic means and elemental analysis. All the synthesized compounds were screened for their cytotoxic activity in vitro on colon cancer cell line (HCT-116) and breast cancer cell line (MCF-7). In addition, the antitumor activity of the synthesized compounds was tested in vivo against Ehrlich's ascites carcinoma (EAC) solid tumor grown in mice. The in vitro vascular endothelial growth factor receptor (VEGFR) enzyme inhibition assay was carried out for the most active compounds at a single dose of 10 µM. The obtained results revealed that compound 5b, which showed potent cytotoxic activity against HCT-116 also, exhibited the highest inhibition in the VEGFR kinase assay (92.2%).

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In this study, a novel series of 6-oxopyridazinyl benzazoles and 3, 6-dioxopyridazinyl benzazoles were prepared from the starting compounds, 2-hydrazinobenzimidazole, 2-hydrazinobenzothiazole and 2-hydrazinobenzoxazole by reaction with butyric acid derivatives and cyclic anhydrides respectively. The structures of the new compounds were confirmed by elemental analysis as well as 1H NMR, IR and MS data. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity using carrageenan induced paw edema at dose 100 mg kg−1 using indomethacin as a reference standard and were found to be bioactive.

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