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 $H$ -benzob]1,4]thiazin-3(4 $H$ )-one.