RECENT PROGRESS AND PROSPECTS ON PLANT-DERIVED ANTI-HIV AGENTS AND ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 358

Ta rget
Identification

Drug Discovery
Stage

Drug Development
Stage

Clinical Trial
Stage

ADMET

Production
Formulation

Lead
Optimization

Synthesis

Screening

Rational Drug Design-
Based Analog Synthesis

Analysis*

Design

Structure-based:
De novo Design
Virtual Screening

Lead
Discovery

Natural Products
Bioactivity-Directed Isolation

High-Throughput
Screening (HTS)

Combinatorial
Libraries

* including QSAR and molecular modeling

Figure 9-1. General drug research process.

find new anti-HIV compounds with unique structure characters or mechanisms of
action. 11-14 Bioactivity-directed fractionation and isolation (BDFI) is a major
approach for new lead generation. Rational drug design, synthesis, bioevaluation,
and structure activity relationship (SAR) and quantitive SAR (QSAR) studies
form a design circle, which optimizes the lead until it reaches a preclinical trial.
Currently, driven by exciting technologic advances, enhanced efficiency in gather-
ing absorption, distribution, metabolism, excretion, and toxicity (ADMET) data has
been realized, which permits ADMET scientists to contribute more effectively to
the drug discovery process as well.
In our long-term screening of plant extracts, particularly anti-infective or immu-
nomodulative Chinese herbal medicines, we focus on lead identification followed
by the structural modification of discovered leads. The author's laboratory has over 10
years of experience on plant-derived anti-HIV natural products, including polycyclic
diones, saponins, alkaloids, terpenes, polyphenols, flavonoids, and coumarins. 11 This
chapter will focus on the detailed investigation of structural modifications based on
rational analog design, in vitro anti-HIV activity, SAR analysis, mechanisms of
action, current status, and future prospects of the following natural product leads
(categories): suksdorfin (khellactone coumarin analogs), dibenzocycloocadiene lig-
nans (biphenyl derivatives), betulinic acid (triterpene derivatives), and their deriva-
tives and analogs.

9.2 KHELLACTONE COUMARIN ANALOGS
AS ANTI-HIV AGENTS

9.2.1 Suksdorfin as a New Anti-HIV Agent

Anti-HIV coumarins have been found to inhibit viral adsorption, reverse transcrip-
tion (RT), protease (PR) inhibition, and integrase (IN) in the HIV replication