Synthesis and anticancer activity of novel quinazolinone-based rhodanines

BACKGROUND: Rhodanines and quinazolinones have been reported to possess various pharmacological activities. RESULTS: A novel series of twenty quinazolinone-based rhodanines were synthesized via Knoevenagel condensation between 4-[3-(substitutedphenyl)-3,4-dihydro-4-oxoquinazolin-2-yl)methoxy]substituted-benzaldehydes and rhodanine. Elemental and spectral analysis were used to confirm structures of the newly synthesized compounds. The newly synthesized compounds were biologically evaluated for in vitro cytotoxic activity against the human fibrosarcoma cell line HT-1080 as a preliminary screen using the MTT assay. CONCLUSIONS: All the target compounds were active, displaying IC(50) values roughly in the range of 10–60 µM. Structure–activity relationship study revealed that bulky, hydrophobic, and electron withdrawing substituents at the para-position of the quinazolinone 3-phenyl ring as well as methoxy substitution on the central benzene ring, enhance cytotoxic activity. The four most cytotoxic compounds namely, 45, 43, 47, and 37 were further tested against two human leukemia cell lines namely, HL-60 and K-562 and showed cytotoxic activity in the low micromolar range with compound 45 being the most active, having IC(50) values of 1.2 and 1.5 μM, respectively. Interestingly, all four compounds were devoid of cytotoxicity against normal human fibroblasts strain AG01523, indicating that the synthesized rhodanines may be selectively toxic against cancer cells. Mechanistic studies revealed that the most cytotoxic target compounds exhibit pro-apoptotic activity and trigger oxidative stress in cancer cells. [Image: see text]