A series of novel bicyclic, substituted pyrimidinone compounds were designed, synthesized and characterized. In vitro antiproliferative activity of the synthesized compounds was evaluated against six different human cancer cell lines using MTT assay. Among all twenty four compounds tested, compound 22 (N-([1,1'-biphenyl]-4-yl)-2-((3-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2-a]pyrimidin-2-yl)oxy)acetamide) exhibited significant cell growth inhibition of human liver cancer cells HepG2 with GIC 50 (50% growth inhibitory concentration) value of 120 + 10 nM and was found to be selective over healthy human embryonic kidney (HEK) cell line (33.1% inhibition at 20 μM). Further studies demonstrated that compound 22 induced cell apoptosis in HepG2 cells and resulted in similar effect to Staurosporine, a well known proapoptopic compound widely used to induce apoptosis in various cancer cell lines. Compound 22 also rendered acceptable aqueous solubility (3.5 + 0.37 μM, at pH 7.4) and attractive metabolic stability against human liver microsomes with a half-life of 34.63 + 0.33 minutes. Based on the similarity observed between the known tankyrase-1 inhibitors available in literature and compound 22, in silico docking study was performed and the results suggested that the compound interacted with the key amino acid residues present in the tankyrase-1 enzyme active site.

Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = −13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = −9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC 50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CL int = 15.6 μl/min/mg; T 1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.

Synthesis of deuterium labeled organic compounds is of increased interests especially after the approval of deutetrabenazine by the Food and Drug Administration in 2014. Selective incorporation of deuterium in the...

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