Design, Synthesis, and Biological Evaluation of Novel PARP-1 Inhibitors Based on a 1H-Thieno[3,4-d] Imidazole-4-Carboxamide Scaffold.
A series of poly(ADP-ribose)polymerase (PARP)-1 inhibitors containing a novel scaffold, the 1H-thieno[3,4-d]imidazole-4-carboxamide moiety, was designed and synthesized. These efforts provided some compounds with relatively good PARP-1 inhibitory activity, and among them, 16l was the most potent one. Cellular evaluations indicated that the anti-proliferative activities of 16g, 16i, 16j and 16l against BRCA-deficient cell lines were similar to that of olaparib, while the cytotoxicities of 16j and 16l toward human normal cells were lower. In addition, ADMET prediction results indicated that these compounds might possess more favorable toxicity and pharmacokinetic properties. This study provides a basis for our further investigation.
Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. momo9060@163.com.
Lingxiao
L
Wang
Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. pharmacare@126.com.
Feng
F
Liu
Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. jiangning@bmi.ac.cn.
Ning
N
Jiang
Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. zhouwx@nic.ac.cn.
Wenxia
W
Zhou
Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. hapwave@163.com.
Xinbo
X
Zhou
Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. zzbcaptain@aliyun.com.
Zhibing
Z
Zheng
D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D010793:Phthalazines; D010879:Piperazines; C032566:imidazole-4-carboxamide; D000620:Aminoimidazole Carboxamide; D000071137:Poly (ADP-Ribose) Polymerase-1; C531550:olaparib
BRCA1/2; PARP-1 inhibitor; anti-tumour; thieno[3,4-d]imidazole