A novel class of substituted spiro [quinazoline-2,1'-cyclohexane] derivatives as effective PPAR-1 inhibitors: molecular modeling, synthesis, cytotoxic and enzyme assay evaluation.
Molecular docking simulation study was carried out to design a novel series of spiro [(2H, 3H)quinazoline-2,1'-cyclohexan]-4(1H)-one derivatives as a new class of effective PARP-1 inhibitors. Spiro [2H-3,1-benzoxazine-2,1'-cyclohexan]-4(1H)-one (5) was the starting compound to synthesize the target proposed analogues. The derivatives that showed the top scores and had the best fitting in the binding sites of the target protein were selected to evaluate their in vitro anti-proliferative activity against the cultured human breast carcinoma cell line (MCF-7) using doxorubicin as a standard drug. Additionally, the compounds that exhibited the highest cytotoxic efficiency were further subjected to PARP-1 enzyme assay taking 3-aminobenzamide as the reference drug. The structures of the novel derivatives were confirmed on the bases of microanalytical and spectral data.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt.
Kamelia M
KM
Amin
Manal M
MM
Anwar
Yasmin M
YM
Syam
Mohammed A
MA
Khedr
Mohammed
M
Khedr
Mohsen M
MM
Kamel
Emad M M
EM
Kassem
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation; D017076:Computer-Aided Design; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D004317:Doxorubicin; C025160:3-aminobenzamide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases