A novel class of small-molecule caspase-3 inhibitors prepared by multicomponent reactions.
A series of tetra- and pentasubstituted polyfunctional dihydropyrroles 5 and 6 were synthesized via practical multicomponent reactions (MCRs) for research on their structure-activity relationship as caspase-3 inhibitors. Among 39 compounds evaluated, 14 of them exhibited inhibition against caspase-3 with IC(50) ranging from 5 to 20 μM. The inhibitory activities of 5 and 6 depend on the nature of substituents on different positions. 5 and 6 possess a different scaffold from those previously reported and are the first caspase-3 inhibitors prepared via MCRs. The most active compounds 5k (IC(50) = 5.27 μM) could therefore be used as a lead for the development of highly potent caspase-3 inhibitors as drug candidates for therapeutic agents by taking advantage of MCRs.
School of Pharmaceutical Sciences, Southern Medical University, 1838 Northern Guangzhou Road, Guangzhou, Guangdong 510515, China.
Qiuhua
Q
Zhu
Lixin
L
Gao
Zhipeng
Z
Chen
Sichao
S
Zheng
Huafei
H
Shu
Jia
J
Li
Huanfeng
H
Jiang
Shuwen
S
Liu
D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D020128:Inhibitory Concentration 50; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D011758:Pyrroles; C013231:pyrroline; D053148:Caspase 3