Novel Pyrimidinone Derivatives Show Anticancer Activity and Induce Apoptosis: Synthesis, SAR and Putative Binding Mode

Abstract

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.

Structure‐based discovery of (S)‐2‐amino‐6‐(4‐fluorobenzyl)‐5,6,11,11a‐tetrahydro‐1H‐imidazo[1′,5′:1,6]pyrido[3,4‐b]indole‐1,3(2H)‐dione as low nanomolar, orally bioavailable autotaxin inhibitor

“…The hydrophobic nature of this compound was reflected in its low aqueous solubility data (4.82 μM at pH 7.4). Moreover, to check whether the compound is cytotoxic or not, it was tested in healthy cells, for example, human embryonic kidney cell line using MTT assay (Roy et al, 2020). Gratifyingly, compound 1 exhibited only 19.02% cell growth inhibition at 20 μM in this cell line, suggesting the compound is safe indeed with a large therapeutic index (CC 50 :IC 50 (functional) = >800).…”

Cyclization of o-Alkynylisocyanobenzenes with 1,3-Dicarbonyl Compounds

“…Finally, a synthetic application of the prepared adduct 4aa was briefly demonstrated (Scheme 4 ). 16 Treatment of 4aa with 2-aminopyridine in diphenyl ether at 140 °C overnight (24 h) gave 3-(3-phenylquinolin-2-yl)-2 H -pyrido[1,2- a ]pyrimidine-2,4(3 H )-dione ( 9aa ) in 43% yield.…”

Identification of 5‐(3‐(methylsulfonyl)phenyl)‐3‐(4‐(methylsulfonyl)phenyl)‐3H‐imidazo[4,5‐b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

“…To check whether the compound is cytotoxic or not, it was tested in Caco-2 cell line using MTT assay (Roy et al, 2020). Gratifyingly, compound 1 exhibited negligible cell growth inhibition at 25 μM in this cell line suggesting compound is safe indeed with a large therapeutic index (CC 50 :IC 50 = >444).…”