Design, synthesis, anti-cancer screening and structure activity relationship studies of biphenyl linked fused imidazoles

Biphenyl is a privileged scaffold observed in several marketed drugs and is known to predominantly bind to a wide range of proteins with high specificity. Fused imidazole is another privileged structure which is found in several bioactive compounds. The present investigation describes the design and synthesis of a biprivileged compound library comprising biphenyl linked fused imidazoles and their activity against NCI-60 cell line to identify potential 'hits' for further anti-cancer drug discovery. In the preliminary investigation, imidazo[1,2-a]pyridine based heterocycles having tert-alkyl amine and a biphenyl substituent demonstrated promising results against some of the leukaemia, colon cancer, ovarian cancer as well as breast cancer cell lines. The active compounds were also found to be non-toxic to several other cancer cell lines, warranting further structure activity relationship (SAR) investigation. A systematic structural modifications and bioactivity evaluation against NC-I60 cell line resulted in the identification of 2-aryl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrazin-3-amine scaffold with biphenyl, benzo[d][1,3]dioxole and 4-(trifluoromethyl)benzene as substituents at C-2 position showing anticancer activity.