Anti-AIDS agents 82: synthesis of seco-(3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents.
Thirteen novel seco-DCK analogs (4-16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC(50) value of 0.058 microM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC(50): 0.126 microM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Jian
J
Tang
Keduo
K
Qian
Bei-Na
BN
Zhang
Ying
Y
Chen
Peng
P
Xia
Donglei
D
Yu
Yi
Y
Xia
Zheng-Yu
ZY
Yang
Chin-Ho
CH
Chen
Susan L
SL
Morris-Natschke
Kuo-Hsiung
KH
Lee
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation
D019380:Anti-HIV Agents; D003374:Coumarins; C520900:khellactone