Bioorganic & Medicinal Chemistry Letters 19 (2009) 6582–6584
Bioorganic & Medicinal Chemistry Letters
Isoquinoline-based analogs of the cancer drug clinical candidate tipifarnib
as anti-Trypanosoma cruzi agents
Naveen Kumar Chennamaneni a, Jenifer Arif b, Frederick S. Buckner b, Michael H. Gelb a,c,
*
a Department of Chemistry, Campus Box 351700, University of Washington, Seattle, WA 98195, USA
b Department of Medicine, University of Washington, Seattle, WA 98195, USA
c Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed a synthetic route to prepare isoquinoline analogs of the cancer drug clinical candidate tipi-
farnib. We show that these compounds kill Trypanosoma cruzi amastigotes grown in mammalian host
cells at concentrations in the low nanomolar range. These isoquinolines represent new leads for the
development of drugs to treat Chagas disease.
Received 28 August 2009
Revised 6 October 2009
Accepted 7 October 2009
Available online 13 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Enzyme inhibitors
Anti-parasite therapeutics
Chagas disease
Lanosterol 14a-demethylase
Sterol biosynthesis
Chagas disease is caused by infection with the protozoan para-
site Trypanosoma cruzi (T. cruzi). Approximately 8–11 million peo-
ple in Latin America are infected with this parasite, and 30% of
those can be expected to develop complications ranging from mild
to terminal.1 There is no effective treatment for Chagas disease at
this time.
OMe group in place of this amino group. We are hopeful that these
tipifarnib analogs can be taken into clinical development for Cha-
gas disease because they are highly potent at killing the parasite,
and they are expected to have the desirable oral bioavailability
and pharmacokinetics that tipifarnib has.
Our modeling studies of tipifarnib docked into the active site of
We have previously shown that the protein farnesyltransferase
inhibitor tipifarnib (compound 1, Fig. 1) kills T. cruzi parasites by
T. cruzi lanosterol 14a-demethylase shows that the carbonyl and
N-Methyl portions of the amide of the quinoline ring are in contact
with enzyme surface residues only (Fig. 2). Since such interactions
are usually not strong because of the inherent flexibility of protein
surface residues, we considered making a new series of analogs in
which the quinolone ring is replaced with a quinoline ring. How-
ever, quinolines are well known to be susceptible to oxidative
metabolism in which carbon-2 is hydroxylated leading to the quin-
olone ring after tautomerization of the 2-hydroxyquinoline (Fig. 3).
Thus, we decided to make isoquinoline analogs of the general core
structure 3 (Fig. 3).
binding to lanosterol 14a
-demethylase.2 This enzyme is required
for production of ergosterol, a required component of the parasite’s
membranes, which cannot be replaced by mammalian host cell de-
rived cholesterol.3 Using the X-ray structure of tipifarnib bound to
mammalian protein farnesyltransferase and a homology model of
T. cruzi lanosterol 14a-demethylase with tipifarnib docked into
the active site2, we designed compound 2 (Fig. 1) which no longer
inhibits protein farnesyltransferase (IC50 >5000 nM vs ꢀ1 nM for
tipifarnib) and is about 10-fold more potent at killing T. cruzi
amastigotes (clinically relevant parasite life cycle stage that grows
in mammalian host cells) (EC50 = 0.6 nM) than is our lead com-
pound tipifarnib (EC50 = 4 nM).4 The extra methyl group present
in 2 clashes with the surface of protein farnesyltransferase. In addi-
tion, the amino group of tipifarnib is part of a hydrogen bond net-
work in the active site of protein farnesyltransferase, which does
not exist in the sterol demethylase.4 Compound 2 contains a
Cl
Cl
N
N
N
N
Me
Me
Me
MeO
H2N
Cl
O
Cl
N
O
N
Me
2
tipifarnib, 1
Me
* Corresponding author. Tel.: +1 206 543 7142; fax: +1 206 685 8665.
Figure 1. Structure of tipifarnib 1 and analog 2.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
Chennamaneni, Naveen Kumar
