Discovery of novel class of histone deacetylase inhibitors as potential anticancer agents

The New Compounds downregulate the proapoptotic oncogenes C-MYC, BCL2, BCL3 and NFkB. [Display omitted] •Novel imidazo[1,2-a]pyridine derivatives were synthesized using multicomponent reaction.•The HDACs inhibition activities of the novel ligands was determined using enzymatic, transcriptomic and cellular-based assays.•The imidazo[1,2-a]pyridinee derivatives 14, 15, 22 and 28 showed selective HDACs inhibition activities.•The HDAC1/2 dual inhibitor, compound 28, was found to be effective against breast (MCF7) and lung cancer cell lines (A549).•Compound 28 is a unique HDAC inhibitor containing a trifluoromethyloxadiazolyl moiety (TFMO) as a non-chelating metal-binding group.•The New Compounds downregulate the cyclin-dependent kinases CDK 1, 2, 4 and 6. Selective inhibition of histone deacetylases (HDACs) is an important strategy in the field of anticancer drug discovery. However, lack of inhibitors that possess high selectivity toward certain HDACs isozymes is associated with adverse side effects that limits their clinical applications. We have initiated a collaborative initiatives between multi-institutions aimed at the discovery of novel and selective HDACs inhibitors. To this end, a phenotypic screening of an in-house pilot library of about 70 small molecules against various HDAC isozymes led to the discovery of five compounds that displayed varying degrees of HDAC isozyme selectivity. The anticancer activities of these molecules were validated using various biological assays including transcriptomic studies. Compounds 15, 14, and 19 possessed selective inhibitory activity against HDAC5, while 28 displayed selective inhibition of HDAC1 and HDAC2. Compound 22 was found to be a selective inhibitor for HDAC3 and HDAC9. Importantly, we discovered a none-hydroxamate based HDAC inhibitor, compound 28, representing a distinct chemical probe of HDAC inhibitors. It contains a trifluoromethyloxadiazolyl moiety (TFMO) as a non-chelating metal-binding group. The new compounds showed potent anti-proliferative activity when tested against MCF7 breast cancer cell line, as well as increased acetylation of histones and induce cells apoptosis. The new compounds apoptotic effects were validated through the upregulation of proapoptotic proteins caspases3 and 7 and downregulation of the antiapoptotic biomarkers C-MYC, BCL2, BCL3 and NFĸB genes. Furthermore, the new compounds arrested cell cycle at different phases, which was confirmed through downregulation of the CDK1, 2, 4,