摘要
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 logGI} 50 =-6.1), 65 (average logGI}50 = -6.13), 69 (average logGI50 = -6.44), 72 (average logGI50 = -6.39), and 86 (average logGI50 = -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 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 D2 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 D1 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.