Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutical Chemistry

Cancer represents a major health problem. Although there has been a progress in the treatment and prevention of cancer, this disease remains the second major cause of death after cardiovascular diseases in the world. Accordingly, continued research is needed to develop new antitumor agents. Imidazopyridine scaffold had considerable therapeutic activities in the treatment of different cancer types such as breast, colon, glioma, prostate, colorectal and lung through inhibition of cyclin-dependent kinase enzymes (CDKs). Therefore, novel imidazopyridine were designed and synthesized starting from 4- (1H-imidazo[4,5-b]pyridin-2-yl)aniline I either via preparation of the diethyl methylene malonate derivative II followed by cyclization to pyrazolidine III-V, pyrimidine VI-VII, triazepine derivative VIII or diazotization of the amino functionality of I followed by coupling with phenol, aniline or active methylene derivatives to afford IXa-f, X and XI, respectively. The cytotoxic activity of the synthesized compounds was investigated against two cell lines, namely: MCF-7 and HCT-116. Compounds showing promising activity were further evaluated for their CDK9 inhibitory activity where they exhibited remarkable activity. Furthermore, molecular docking of the tested compounds was established with the active site of CDK9 enzyme domain to investigate the possible binding mode between the synthesized compounds and the binding pocket in the active site of the enzyme. In conclusion, based on both in vitro cytotoxicity study and CDK9 enzyme assay, most of the synthesized compounds exhibited significant anti-proliferative and CDK9 inhibitory activity, which suggests that these compounds might possible act as CDK9 inhibitors

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