Identification of novel 5-hydroxy-1H-indole-3-carboxylates
with anti-HBV activities based on 3D QSAR studies

Abstract Infection with hepatitis B virus (HBV) is a major
cause of liver diseases such as cirrhosis and hepatocellular
carcinoma. In our previous studies, we identified indole
derivatives that have anti-HBV activities. In this study, we
optimize a series of 5-hydroxy-1H-indole-3-carboxylates,
which exhibited potent anti-HBV activities, using threedimensional
quantitative structure-activity relationship (3D
QSAR) studies with comparative molecular field analysis
(CoMFA) and comparative molecular similarity indices
analysis (CoMSIA). The lowest energy conformation of
compound 3, which exhibited the most potent anti-HBV
activity, obtained from systematic search was used as the
template for alignment. The best predictions were obtained
with the CoMFA standard model (q2=0.689, r2 = 0.965,
SEE=0.082, F=148.751) and with CoMSIA combined
steric, electrostatic, hydrophobic and H-bond acceptor
fields (q2=0.578, r2=0.973, SEE=0.078, F=100.342).
Both models were validated by an external test set of six
compounds giving satisfactory prediction. Based on the
clues derived from CoMFA and CoMSIA models and their
contour maps, another three compounds were designed and
synthesized. Pharmacological assay demonstrated that the
newly synthesized compounds possessed more potent anti-
HBV activities than before (IC50: compound 35a is
3.1 μmol/l, compound 3 is 4.1 μmol/l). Combining the
clues derived from the 3D QSAR studies and from further
validation of the 3D QSAR models, the activities of the
newly synthesized indole derivatives were well accounted
for. Furthermore, this showed that the CoMFA and
CoMSIA models proved to have good predictive ability.
Keywords Anti-HBV. Anti- hepatitis B virus activity .
CoMFA . CoMSIA . Indole derivatives . QSAR .
Synthesis . 3D QSAR