Xiaoli Zhou, Xilei Xie, Gang Liu
Jan 26, 2013
Citations
0
Influential Citations
9
Citations
Quality indicators
Journal
Molecular Diversity
Abstract
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.