Nano-ZrO2-Catalyzed Biginelli Reaction and the Synthesis of Bioactive Dihydropyrimidinones That Targets PPAR-γ in Human Breast Cancer Cells
Suresha N. Deveshegowda, Ji-Rui Yang, Xi Zhang, Omantheswara Nagaraja, Kashifa Fazl-Ur-Rahman, Bhanuprakash C. Narasimhachar, Gautam Sethi, Ganga Periyasamy, M. Mahendra, Shobith Rangappa, Vijay Pandey, Peter E. Lobie, Basappa Basappa
Abstract
Bioactive dihydropyrimidinones (DHPs) were designed and synthesized by a multicomponent Biginelli reaction. The reaction was catalyzed by the polarized surface of nano-zirconium dioxide with partial positive charge of 0.52e at the Zr center and a negative charge of −0.23e at the oxygen center. There was good corroboration between the computed and experimental ZrO2 cell parameters and bond distances as determined by in silico and in vitro experimental methods. Since DHPs were found to target the peroxisome proliferator-activated receptor (PPAR)-γ, we tested these ligands toward MCF-7 cell toxicity, which revealed that the compounds 4d [ethyl-4-(4′-fluoro-[1,1′-biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] and 4e [ethyl-4-(3′-methoxy-[1,1′-biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] inhibited proliferation with IC50 values of 11.8 and 15.8 μM, respectively. Further, our bioinformatic analysis found that the active molecule 4d, fit into the enzyme’s catalytic site, almost in the same position as rosiglitazone, which was buried deep inside the cavity. In conclusion, we herein report novel DHPs which could be better structures to help explore a new class of synthetic PPAR-γ ligands.