Design and synthesis of indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-1-carbothioic acid amide derivatives as novel HCV inhibitors.
An efficient synthetic methodology to provide indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-1-carbothioic acid amide derivatives is described. These conformationally restricted heterobicyclic scaffolds were evaluated as a novel class of HCV inhibitors. Introduction of an acyl group at the NH(2) of the thiourea moiety has been found to enhance inhibitory activity. The chain length and the position of the alkyl group on the indoline aromatic ring markedly influenced anti-HCV activity. The indoline scaffold was more potent than the corresponding indole and tetrahydroquinoline scaffolds and analogue 31 displayed excellent activity (EC(50)=510nM) against HCV without significant cytotoxicity (CC(50) >50microM).
Kang
Iou-Jiun
IJ
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Wang
Li-Wen
LW
Hsu
Sheng-Ju
SJ
Lee
Chung-Chi
CC
Lee
Yen-Chun
YC
Wu
Yen-Shian
YS
Hsu
Tsu-An
TA
Yueh
Andrew
A
Chao
Yu-Sheng
YS
Chern
Jyh-Haur
JH
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000737:chemistry
D000998:Antiviral Agents; D007211:Indoles; D011804:Quinolines; D017361:Viral Nonstructural Proteins