Quinazoline-2,4( $$1H,3H$$ )-diones inhibit the growth of multiple human tumor cell lines

Quinazoline-2,4( $$1H,3H$$ )-diones exhibit a wealth of biological activities including antitumor proliferation. We established an improved method for the synthesis of quinazoline-2,4( $$1H,3H$$ )-dione derivatives with three points of molecular diversity. Data indicate that compounds 60 (average $$\text{ logGI}_{50} \!=\! -6.1$$ ), 65 (average $$\text{ logGI}_{50} \!=\! -6.13$$ ), 69 (average $$\text{ logGI}_{50} \!=\! -6.44$$ ), 72 (average $$\text{ logGI}_{50} \!=\! -6.39$$ ), and 86 (average $$\text{ logGI}_{50} = -6.45$$ ) significantly inhibited the in vitro growth of 60 human tumor cell lines tested. Structure–activity relationship analyses indicate that chlorophenethylureido is the necessary substituent at the $$\text{ D}_{3}$$ diversity point (7-position of quinazoline-2,4( $$1H,3H$$ )-dione), in particular, $$o$$ -chlorophenethylurea (69) achieved optimal activity. $$o$$ - or $$m$$ -Chlorophenethyl substitutions (69 and 72) at the $$\text{ D}_{2}$$ diversity point (3-position of quinazo line-2,4( $$1H,3H$$ )-dione) gave the most potent compounds. Methoxyl and 4-methylpiperazin-1-yl substitution at the $$\text{ D}_{1}$$ diversity point (6-position of quinazoline-2,4( $$1H,3H$$ )-dione skeleton) may yield better activity than other groups. The quinazoline-2,4( $$1H,3H$$ )-dione scaffold can be effectively replaced by 2 $$H$$ -benzo[b][1,4]thiazin-3(4 $$H$$ )-one.