Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials

J. Med. Chem. 2007, 50, 4585-4605

4585

Second Generation Tetrahydroquinoline-Based Protein Farnesyltransferase Inhibitors as

Antimalarials

Pravin Bendale,^†Srinivas Olepu,^†Praveen Kumar Suryadevara,^†Vivek Bulbule,^†Kasey Rivas,^‡,§Laxman Nallan,^†Brian Smart,^†

Kohei Yokoyama,^†Sudha Ankala,^†Prakash Rao Pendyala,^|David Floyd, Louis J. Lombardo,^#David K. Williams,^#

Frederick S. Buckner,^‡,§Debopam Chakrabarti,^|Christophe L. M. J. Verlinde,⁾Wesley C. Van Voorhis,^‡,§and

Michael H. Gelb*^,†,)

Departments of Chemistry, Medicine, Pathobiology, and Biochemistry, UniVersity of Washington, Seattle, Washington 98195, Department of

Molecular Biology and Microbiology, UniVersity of Central Florida, Orlando, Florida 32826, Pharmacopeia Drug DiscoVery, Princeton, New

Jersey, and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000

ReceiVed March 22, 2007

Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein

farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death

and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs).

We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme

in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the low-

nanomolar range. This body of structure-activity data can be rationalized in most cases by consideration

of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural

model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs

for further evaluation in preclinical drug discovery assays.

Introduction

New antimalarial drugs are needed because of widespread

resistance to well-established agents such as chloroquine (ww-

w.mmv.org). We have been working on inhibitors of malaria

protein farnesyltransferase (PFT^a) because earlier studies showed

that such agents are cytotoxic to Plasmodium falciparum,^1-3

the causative agent of falciparum malaria. PFT catalyzes the

transfer of the 15-carbon farnesyl group from farnesyl-pyro-

phosphate to the SH group of the tetrapeptide motif CaaX (C

is cysteine, a is usually but not necessarily an aliphatic amino

acid, and X is a variety of amino acids) present at the C-terminus

of proteins that become farnesylated. Inhibitors of mammalian

PFT have been extensively developed as anticancer agents by

the pharmaceutical industry,⁴and thus, we have the opportunity

to extend the medicinal chemistry and preclinical pharmacology

of PFT inhibitors toward the development of antimalarial drugs

(piggy-back drug development). To this end, we tested many

of the known classes of PFT inhibitors and found that tetrahy-

droquinoline (THQ)-based PFT inhibitors developed at Bristol

Myers Squibb⁵are the most potent against P. falciparum PFT

(Pf-PFT) and against parasite growth in human red blood cells.³

Our previous medicinal chemistry efforts led to the identification

of THQ 1 (Figure 1) and a few related compounds that inhibit

Pf-PFT in vitro, with IC₅₀(concentration of inhibitor that 50%

inhibits Pf-PFT) values of ∼0.6 nM, and inhibit parasite growth

in red cells with ED₅₀(concentration of inhibitor that 50%

Figure 1. Tetrahydroquinoline-based protein farnesyltransferase inhibi-

tors. See main text for discussion.

inhibits the growth of P. falciparum in red blood cells in vitro)

values of ∼5 nM.³Studies with mammalian PFT have shown

that the 6-cyano group on the THQ ring is important in

conferring tight enzyme binding,⁶and structural studies show

that the imidazole appended to N-1 of the THQ ring directly

coordinates the Zn²⁺ion at the active site of mammalian PFT.^7,8

Continuous dosing of THQ 1 using surgically implanted,

osmotic minipumps in mice infected with rodent malaria (P.

berghei) led to a dramatic reduction in parasite number.³Studies

of malaria resistance to these Pf-PFT inhibitors provided very

strong evidence that blocking Pf-PFT action is the basis for

parasite killing.^7,8The reasons that PFT inhibitors are very toxic

to malarial cells but not to mammalian cells are not known.

One hypothesis is that the malaria parasite appears to lack

protein geranylgeranyltransferase type I, the enzyme responsible

for the monogeranylgeranylation of proteins in mammalian cells.

Thus, some critical housekeeping proteins may be farnesylated

in malaria but geranylgeranylated in mammalian cells.

The purpose of the present study is to report our continued

efforts to develop THQ-based antimalarials. A number of THQs

were prepared with various groups attached to the sulfonyl group

of 1 (R₁of THQ 2 in Figure 1) or to the sulfonamide nitrogen

(R₂in THQ 2 in Figure 1). Less extensive structure-activity

studies were carried out by variation of other groups attached

to the THQ core. We were able to identify several new THQ-

based Pf-PFT inhibitors with sub- to low-nanomolar potency

* To whom correspondence should be addressed. Phone: 206-543-7142.

Fax: 206-685-8665. E-mail: gelb@chem.washington.edu.

^†Department of Chemistry, University of Washington.

^‡Department of Medicine, University of Washington.

^§Department of Pathobiology, University of Washington.

^|Department of Molecular Biology and Microbiology, University of

Central Florida.

Pharmacopeia Drug Discovery.

^#Bristol-Myers Squibb Pharmaceutical Research Institute.

⁾Department of Biochemistry, University of Washington.

^aAbbreviations: ED₅₀, effective dose of inhibitor that reduces parasite

growth in vitro by 50%; IC₅₀, inhibitor concentration that reduces the rate

of PFT in vitro by 50%; PFT, protein farnesyltransferase, PFTI, PFT

inhibitor, THQ, tetrahydroquinoline.

Published on Web 08/28/2007

4586 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Bendale et al.

Scheme 1^a

Scheme 4^a

^aReagents and conditions: (i) R₁SO₂Cl, DIPEA, CH₃CN; (ii) 1-methyl-

1H-imidazole-5-carboxaldehyde, triethylsilane, 1,2-dichloroethane:trifluo-

roacetic acid (1:1); (iii) R₂-Br, Cs₂CO₃, DMF.

^aReagents and conditions: (i) 3H-imidazole-4-carboxaldehyde, trieth-

ylsilane, 1,2-dichloroethane/trifluoroacetic acid (1:1); (ii) trityl chloride,

DIPEA, DMF; (iii) R₂-Br, Cs₂CO₃, DMF; (iv) CH₂Cl₂, trifluoroacetic acid.

Scheme 2^a

Scheme 5^a

^aReagents and conditions: (i) 10% trifluoroacetic acid, CH₂Cl₂; (ii)

RCOCl or ROCOCl or RNCO or RSO₂Cl, CH₂Cl₂, DIPEA.

^aReagents and conditions: (i) R₂-Br, Cs₂CO₃, DMF; (ii) 3-methyl-3H-

imidazole-4-sulfonyl chloride, DMAP, CH₃CN.

Scheme 3^a

Scheme 6^a

^aReagents and conditions: (i) Cbz-Cl, Et₃N, CH₃CN; (ii) 1-methyl-1H-

imidazole-5-carboxaldehyde, triethylsilane, 1,2-dichloroethane:trifluoroacetic

acid (1:1); (iii) 10% Pd/C, CH₃OH; (iv) R₂-Br, Cs₂CO₃, DMF; (v) R₁COOH,

EDC, HOBt, Et₃N, DMF, or R₁COCl, Et₃N, CH₂Cl₂or R₁SO₂Cl, Et₃N,

CH₂Cl₂.

^aReagents and conditions: (i) BOC-anhydride, K₂CO₃, dioxane-water

(4:1); (ii) phenylboronic acid, Ba(OH)₂, tetrakis triphenylphosphine pal-

ladium, DME-water (5:1); (iii) 20% trifluoroacetic acid, CH₂Cl₂; (iv)

R₁SO₂Cl, DIPEA, CH₂Cl₂; (v) 1-methyl-1H-imidazole-5-carboxaldehyde,

triethylsilane, 1,2-dichloroethane/trifluoroacetic acid (1:1); (vi) R₂-Br,

Cs₂CO₃, DMF.

on Pf-PFT and with low nanomolar potency on P. falciparum

growth in vitro.

group on the zinc-binding imidazole. In this case, tritylation of

the imidazole was required prior to alkylation of the sulfonamide

nitrogen. Scheme 5 shows the synthesis of a THQ analog in

which the methylene bridge between the N-1 of the THQ core

and the Zn²⁺-binding imidazole group is replaced with a sulfonyl

group or with a CH(CH₃) group. THQs containing a 6-phenyl

group in place of the 6-cyano group were prepared according

to Scheme 6. The key step is the introduction of the phenyl

group via Suzuki coupling (conversion of 21 to 22). Scheme 7

shows the synthesis of THQ analogs in which the 6-CN is

replaced with carbonyl-bearing functional groups. Scheme 8 was

used to prepare the THQ analog 34. The key reaction is

Chemistry

Many of the THQs 2 prepared in this study were prepared

by the route shown in Scheme 1 starting from racemic 6-cyano-

3-amino-THQ (compound 3, Scheme 1), which was made as

described.⁵This route is useful for variation of the R₂group,

which is added in the last synthetic step. Scheme 2 was used to

prepare analogs of 2 in which the R group attached to the

piperidine nitrogen is varied. Scheme 3 was used to allow easier

variation of both the R₁and R₂groups because, unlike in

Scheme 1, the R₁group is introduced later in the synthesis.

Scheme 4 was used to prepare THQs, which lack the methyl

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4587

Scheme 7^a

nM. Compound 106 shows exceptional potency with an ED₅₀

) 1.8 nM. This is the most potent compound in terms of ED₅₀

that we found in the current study and among the most potent

antimalarials ever reported. In general, the compounds with R₁

) N₁-methyl-4-imidazolyl are more potent than the analogous

compounds with R₁) 2-pyridyl.

We also carried out side-by-side pharmacokinetic studies of

potent THQ-based Pf-PFT inhibitors to discover a compound

that could be tested in malaria-infected rodents.⁹We measured

the rate of flux of THQ-based PFT inhibitors across a tight-

junction monolayer of Caco-2 cells and showed that this in vitro

assay is a good predictor of oral bioavailability of these

compounds in rodents.⁹In general, we found that R₁) 2-pyridyl

promotes better Caco-2 permeability and oral bioavailability than

compounds with R₁) N₁-methyl-4-imidazolyl.⁹Because it

appears that THQ-based PFT inhibitors are cleared in rodents

by hepatic metabolism, we measured the half-time for metabo-

lism of THQs by rat and mouse liver microsomes in vitro.⁹

Based on an overall balance of desirable properties, 6 emerged

as a promising antimalarial lead compound.⁹Thus, we inves-

tigated in detail the structure-activity relationships among 6

analogs. Table 3 shows the results with 6 analogs in which the

R group attached to the piperidine N of the R₂group is varied.

In general, we found a good correlation between IC₅₀values

for Pf-PFT inhibition and ED₅₀values for blocking the growth

of parasites in vitro.

^aReagents and conditions: (i) concd HCl, 80 °C; (ii) H₂SO₄, R₄-OH;

(iii) R₄-NH₂, EDC, DMAP, DMF; (iv) alkyl bromide, Cs₂CO₃, DMF.

Scheme 8^a

When those compounds in Table 3 with values of ED₅₀

<

∼100 nM were tested for Caco-2 permeability and microsomal

stability,⁹162 emerged as a compound with a good balance of

potency and desirable pharmacokinetic properties. In Table 4,

we summarize results with compounds in which R₂is held as

the R₂of 162 and R₁is varied. We also studied compounds

with R₂) 2-fluorophenylCH₂, 4-MeSO₂-phenylCH₂, and t-

BuNHCOCH₂because these groups led to potent compounds

in the early scans. Most compounds in this series were

significantly less potent on Pf-PFT and on parasites compared

to 162. The exceptions were those with a small heterocyclic R₁

group, that is, 191.

Molecular modeling studies described below suggested that

addition of a Me group to R₁) N₁-methyl-4-imidazolyl at the

5-position would better fill the R₁-binding pocket on Pf-PFT.

Table 5 shows a scan of R₂groups keeping R₁as 4-(N₁-methyl-

5-Me-imidazolyl). Compound 234 with the same R₂as in 162

emerged as the best compound.

^aReagents and conditions: (i) trityl chloride, Et₃N, DMF; (ii) MeMgBr,

THF, 0 °C; (iii) MsCl, CH₃CN, 60 °C; (iv) trifluoroacetic acid, CH₂Cl₂.

nucleophilic displacement between the mesylate derived from

the indicated secondary alcohol 32 and secondary amine 33.

Inhibition of Pf-PFT and P. falciparum Growth by THQ-

Based Pf-PFT Inhibitors. We first give a general description

of the potencies of THQ-based Pf-PFT inhibitors on the enzyme

and on P. falciparum growth in Vitro, and then we attempt to

provide a structural rational for some of the activity data. Our

initial structure-activity data on THQ-based inhibitors of Pf-

PFT led to the discovery of compounds with R₁) 2-pyridyl or

N₁-methyl-4-imidazolyl as being potent inhibitors of Pf-PFT.³

In Table 1, we report a study of THQs with R₁) 2-pyridyl

and with a variety of substituents as R₂groups. A number of

THQs were found that inhibited Pf-PFT in vitro by 50% (IC₅₀)

in the low nanomolar range and that also inhibited the growth

of P. falciparum in erythrocyte cultures in vitro by 50% (ED₅₀)

in the low nanomolar range (i.e., 48, 55, 56, 57, 61, and 62).

Table 6 gives the activity of compounds in which the sulfonyl

is replaced by carbonyl (sulfonamide to amide change). In

general, these compounds are much poorer inhibitors of Pf-

PFT and of P. falciparum growth than the corresponding

sulfonyl-containing THQ compounds. Thus, we prepared only

a limited set of these amide-containing THQ compounds.

The most potent compound in the series is 55 with an ED₅₀

)

Table 7 shows THQ-based compounds with alteration to the

N-Me-imidazoleCH₂group attached to the THQ ring N. This

substituted imidazole is a direct ligand to the Zn²⁺at the active

site of Pf-PFT (see below). Removal of the Me group from the

imidazole has only a minimal effect on binding to Pf-PFT (as

predicted by modeling) but greatly increases ED₅₀for killing

parasites, suggesting that methylation of the Zn²⁺-binding

imidazole promotes penetration of compound across erythrocyte

and parasite membranes. Replacement of the CH₂that links the

imidazole to the THQ ring N by SO₂obliterates binding to Pf-

PFT and antiparasite activity. Addition of a Me group to this

CH₂bridge (mixture of four stereoisomers) also greatly reduces

activity as does replacement of the imidazole by a 3-pyridylCH₂

group.

17 nM for the 3D7 strain and 10 nM for the K1 strain. Well-

established antimalarial drugs such as chloroquine display ED₅₀

values in the low nanomolar range. Thus, the potency achieved

for some of our THQ-based PFT inhibitors is probably sufficient

for an antimalarial drug discovery effort. In general, we did

not find any compound that inhibited P. falciparum growth in

the low nanomolar range that was a relatively poor inhibitor of

Pf-PFT.

Table 2 summarizes results for THQ-based PFT inhibitors

with R₁) N₁-methyl-4-imidazolyl and with variation of the

R₂group. Many compounds were found with IC₅₀s and ED₅₀s

in the low nanomolar range. The most potent in the series are

106, 107, 102, 104, 115, and 131 with values of ED₅₀< 10

4588 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Table 1. 6-CN-THQs with R₁) 2-Pyridyl^a

Bendale et al.

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4589

Table 1. Continued^a

^aAll prepared according to Scheme 1.

THQ compounds with a 6-phenyl instead of 6-CN were

available to us from a different drug discovery program. Some

of these compounds maintain modest potency as inhibitors of

Pf-PFT and as antimalarials (266, 267), but in general, we could

not find a 6-phenyl THQ with a potency approaching our best

compounds in the 6-CN-THQ series. It may be noted that the

length of the phenyl is about the same as the length of the CN

group, and thus, compounds like 267 may be binding to Pf-

PFT in the same way as the 6-CN-THQ compounds, but we

have no experimental evidence for this.

Moreover, each enantiomer can exist in two conformations, with

the 3-substituent either axial or equatorial. Hence, it is crucial

to know which of the two enantiomers block the enzyme. To

gain insight, we first determined the IC₅₀of the individual

enantiomers of 162. This was carried out by coupling 6-cyano-

1,2,3,4-tetrahydro-quinolin-3-ylamine hydrochloride to S-man-

delic acid and separating the diastereomers as described.^5,10The

two enantiomeric amines were then converted to the two

enantiomers of 162, 163, and 164, as shown in Scheme 1. The

R-enantiomer of 162, 163, displayed an IC₅₀against Pf-PFT

that is 10 times below that of the S-enantiomer, 164 (Table 3).

This difference is recapitulated in the observed ED₅₀s for

blocking P. falciparum growth. The 10-fold difference in

enzyme binding is modest, corresponding to a difference in

binding energy of 1.3 kcal/mol. Superposition of the two

enantiomers shows that the first substituent atoms of the two

possible equatorial enantiomers at C3 of the THQ ring are only

0.8 Å apart, thereby, allowing for the C3 substituents to adopt

similar positions in the binding site regardless of the stereo-

chemistry (Figure 2).

Figure 3 (top panels) shows the experimental, ternary structure

of rat-PFT with bound 162 inhibitor and farnesyl-pyrophosphate

substrate.⁸The THQ ring of 162 stacks face-on-face and at an

angle of about 25° with Tyr 361â (Tyr 837â in the Pf-PFT

homology model), projecting the N-methyl-imidazole so that it

coordinates the catalytic Zn²⁺of the enzyme (Figure 3). The

6-CN sits in a narrow groove made by Leu-96â (Leu 446 â in

Pf-PFT)), Trp-106â (Trp-456â in Pf-PFT), Asp-359â (Asp-835

â in Pf-PFT), and Tyr-361â (Tyr-837â in Pf-PFT). In this way,

the 6-CN-benzo group of 162 adopts a similar but not identical

position as the group of 3-benzyl-1-(3H-imidazol-4-ylmethyl)-

4-(thiophene-2-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-

diazepine-7-carbonitrile (BMS-214662), a tetrahydrobenzodi-

azepine-based PFT inhibitor for which an X-ray structure of its

complex with rat PFT has been published;¹¹the difference in

6-CN-benzo group atoms ranges from 0.5 to 0.9 Å (Figure 3,

bottom left panel). The X-ray structure of bound 162 (obtained

The data in Table 9 shows that replacement of the 6-CN group

on the THQ core with various amides or a carboxylate is very

detrimental to Pf-PFT binding and parasite killing.

Structural Rational of the Structure-Activity Results for

THQ-Based PFT Inhibitors. To date, we have not been able

to obtain Pf-PFT in amounts sufficient for crystallization trials.

However, the X-ray structure of rat and human PFTs are

available alone and with a number of bound inhibitors, including

the structure of the rat-PFT/162 complex.⁸As described in

General Methods, we made a homology model of Pf-PFT based

on this experimental structure. Most of the residues in the 162

binding site are conserved between rat- and Pf-PFT. The only

differences are that Pro-150â of rat-PFT, which resides in the

vicinity of the terminal methyl of the R₂carbamate of 162, is

replaced with Thr-512â in Pf-PFT. Tyr-93â, adjacent to the

6-CN of 162, is Leu-443â in Pf-PFT. Two more conservative

changes, somewhat further away from 162, play a role in the

binding of other THQ-based inhibitors discussed in this paper:

Tyr-166R (Phe-151R in Pf-PFT) and Phe-360â (Tyr-836â in

Pf-PFT). Thus, the crystal structure of the complex of 162 with

the rat enzyme is of great value despite only 23% sequence

identity for rat- versus Pf-PFT R-subunits and 37% identity

between the â-subunits.

The elucidation of the structure-activity relationships of 162

and other THQ-based PFT inhibitors is complicated by the use

of racemates. Each compound is a mixture of two enantiomers

due to the chiral center at carbon-3 of the THQ ring (Figure 1).

4590 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Table 2. 6-CN-THQs with R₁) 4-(1-Me-1H-Imidazolyl)^a

Bendale et al.

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4591

Table 2. Continued^a

^aAll prepared according to Scheme 1 except compound 104 (Scheme 2).

by soaking the rat PFT crystals with racemic 162) shows that

only one enantiomer binds; the data is consistent with our

observation that the enantiomer 163 is the better inhibitor (see

above). The C3 substituent is equatorial, reflecting the 2.7 kcal/

mol calculated preference for this conformation over the axial

one in solution. The 2-pyridyl R₁substituent makes a hydrogen

bond with Tyr-361â (Tyr-837â in Pf-PFT) and stacks against

the second isoprene unit of farnesyl-pyrophosphate. The 2-py-

ridyl also stacks against the Zn²⁺-binding N-Me-imidazole of

162. The R₂substituent resides in a large, mainly hydrophobic

pocket, which is normally occupied by the side chain of the X

residue of the CaaX motif of proteins that are farnesylated

(Figure 3, bottom right panel). The R₂group only partially fills

this pocket. The carbonyl oxygen of the carbamate portion of

the R₂substituent of 162 accepts hydrogen bonds with the side

chains of Ser-99â and Trp-102â of rat-PFT (Ser-449â and Trp-

452â in Pf-PFT). The terminal Me of the carbamate portion of

the R₂group makes hydrophobic contacts with the side chains

of His-149â (His-509â in P. fal.) and Ala-151â (Ala-511â in

Pf-PFT). The R₂piperidine contacts Trp-102â (Trp-452â in Pf-

PFT). Remarkably, the two oxygens of the sulfonamide do not

make direct hydrogen bonds to the protein.

The R₂groups of all other THQs contain one or more rings.

The best R₂groups have a short ethylene linker (thus minimizing

entropic cost of enzyme binding) followed by a five-membered,

aromatic heterocycle (55, 56, 57). They are predicted to bind

in the same way as 162 (Figure 4, top right), engaging in

extensive hydrophobic interactions with Leu-446â, Trp-456â,

Trp-452â, and C4 of their own THQ scaffold; the latter probably

stabilizes the enzyme-bound R₂conformation for the inhibitor

free in solution. Two of the R₂ring atoms remain solvent

exposed, which explains why those two positions can be

replaced by nitrogen atoms (56, 57). However, a slightly larger

benzene ring cannot be accommodated in the same position (74,

75, 76), but further para-substitution with MeSO₂leads to two

hydrogen bonds of this group with Arg-564â and Gln-152R,

plus hydrophobic contacts with His-509â (69), explaining the

decent potency of this compound. Expansion of the pyrrole ring

to an indole (64) leads to reduced inhibition because the R₂

conformation cannot be maintained due to steric clash with Leu-

446â. Expansion of the pyrrole ring to phthalimide (85) also

leads to a different conformation because of steric reasons,

though the benzo part is now predicted to interact with His-

509â.

Most R₂groups with a single methylene linker to an aromatic

ring are unable to make an efficient contact with the hydrophobic

residues in the pocket of Pf-PFT as the ethylene-linked ones,

even when they in turn carry a hydrophobic substituent (58,

59, 60, 61, 62, 63, 65, 66, 68, 70, 71, 69, 73, 77, 78, 79, 80, 81,

83, 6, 84). Longer linkers to a ring also do not allow for efficient

contact of hydrophobic residues in the pocket (82, 86, 88).

Replacement of the sulfonamide group of THQs with amides

universally leads to a loss of binding to Pf-PFT (Table 6). In

the crystal structure of rat PFT with 162, and by homology with

Pf-PFT, the sulfonamide moiety adopts a known low-energy

conformation. Sulfonamides, which have a pyramidalized

nitrogen atom, adopt two low-energy conformations because

the N-S bond has partial double character. One is eclipsed,

thereby allowing for maximal overlap of the nitrogen lone pair

electrons and the SdO bonds (Figure 5). The other one is

obtained by nitrogen inversion, thereby reducing the steric

interactions.¹²Ab initio calculations at the MP2/6-31+G* level

for the model compound N,N-dimethylmethanesulfonamide, the

closest analog to the sulfonamide substructure in our molecules,

shows that this compound prefers the inverted conformation with

a CsNsSdO torsion angle of 30°.¹³This conformation is

similar to what is observed in the X-ray structure of 162 bound

We used the 162/PFT structural information as a starting point

for constructing models of many of the other THQ-based PFT

inhibitors prepared in this paper. Rather than discuss each

compound, we describe the trends that are supported by the

structural information. Figure 4 (top panel) shows the predicted

binding mode of 162 in the active site of Pf-PFT. As already

noted, THQ-based compounds in Table 1 have a 6-CN group,

R₁) 2-pyridyl, and variation of the R₂group. Most of the

compounds in Table 1 are predicted to be able to bind with R₂

in the a₂X region of the Ca₁a₂X pocket, while maintaining the

pose of the THQ scaffold and R₁and R₃groups as seen

experimentally. R₂groups that end in a polar group are poor

Pf-PFT binders because they cannot interact favorably with the

largely hydrophobic environment (38, 39, 52, 53, 54, 90).

Moreover, THQs with small R₂groups (38, 52, 53, 90) barely

fill the pocket and therefore display poor enzyme inhibition.

On the other hand, the R₂group of 87 is too large to fill the

pocket. Long, linear R₂groups, some with a small branch, that

provide several apolar atoms work better as Pf-PFT inhibitors

as they can reach Trp-456â, Trp-452â, Ala-511â, and His-509â,

but this comes at a cost of the loss in conformational entropy

when the flexible side chain rigidifies in the active site of Pf-

PFT (35, 36, 40, 41, 42, 43, 44, 45, 48, 46, 47, 49, 50, 38).

4592 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Bendale et al.

Table 3. Analogs of 6 with a Variation of the R Group Attached to the Piperidine N

to rat PFT (Figure 5). Simple stereochemical considerations

indicate why the amide analogs of our sulfonamide THQ PFTIs

are poor inhibitors. The amide function has two trigonal centers,

and thus, a planar arrangement of all substituents. This leads to

an orientation of the R₁group in the amides that is 90° off from

the orientation of the R₁of 162 (Figure 5), and this altered

orientation is sterically disallowed by the active site of the PFT.

Modeling showed that there is space in the active site of Pf-

PFT to accommodate groups other than N-methyl on the Zn²⁺

-

binding imidazole. A benzyl (254, Table 7) was not very

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4593

a

Table 4. 6-CN-THQs with a Variation of R₁

^aAll prepared according to Scheme 1.

4594 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Table 5. 6-CN-THQs with Dimethyl Imidazole^a

Bendale et al.

Table 6. 6-CN-THQs with Amides^a

^aAll were prepared according to Scheme 1.

effective probably because of the extra entropy loss due to two

extra rotatable bonds. Replacement of the methylene linker in

the Zn²⁺-binding arm (attached to N1 of the THQ ring) by an

SO₂(255, Table 7) leads to an inactive compound. This is most

likely because of the increased electron-withdrawing character

of the SO₂linker, thereby decreasing the basicity of the

imidazole N and, thus, the coordination affinity to the active

site Zn²⁺. Using the SPARC v3.1 program,^14,15we calculated

that the pK_aof the protonated imidazole drops from 6.8 to 5.1

when the CH₂linker is replaced with SO₂. If the drop in proton

affinity is the same for Zn²⁺, this drop in pK_aof 1.7 would

give a drop in IC₅₀by 50-fold.

^aAll were prepared according to Scheme 3.

Table 7. 6-CN-THQs with a Variation of R₃

Replacement of the 6-CN group with phenyl is tolerated

(Table 8). Replacement with more polar substituents (Table 9)

is not tolerated, which is consistent with the lack of apporpriate

hydrogen bond donors and acceptors in the pocket on Pf-PFT

that binds the 6-CN group.

Inhibition of Mammalian PFT. A subset of THQ-based

PFTIs were tested for inhibition of rat PFT, and results are

summarized in Table 10 and compared to those obtained with

Pf-PFT. Most compounds displayed comparable potency on both

enzymes. The exceptions are 84 and 129, which are about 10-

fold more potent on Pf-PFT than on rat PFT, and 126, which

shows the reverse preference. As noted in our earlier publica-

tions, clinical trials have shown that PFTIs are well tolerated

in man after several weeks of continuous dosing. Thus,

specificity toward Pf-PFT versus mammalian PFT is probably

not required for a drug that would be used to treat malaria over

the course of a few days.

Conclusions

In this study we show that THQ-based PFTIs are potent

inhibitors of Pf-PFT activity and of erythrocytic stage P.

falciparum growth. Several compounds were found with growth

inhibition potency down in the low nanomolar range, with

several compounds blocking parasite growth at concentrations

<5 nM. A good deal of the structure-activity data for the

inhibition of Pf-PFT can be accounted for based on the structural

consideration of one of the compounds, 162, bound to mam-

malian PFT. In a companion study, we have carried out detailed

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4595

Table 9. 6-Acyl-THQs^a

Table 8. 6-Phenyl-THQs^a

^aAll were prepared according to Scheme 7.

Figure 2. Near coincidence of the sulfonamide nitrogen positions of

the C3 enantiomers of THQ inhibitors like 162. The figure shows the

superposition of the two possible envelope conformations of the THQ

ring, resulting in the positions of the exocyclic sulfonamide nitrogens

being only 0.8 Å apart (only the equatorial conformations are shown;

they are 2.7 kcal/mol more stable than the axial conformations). The

R/S designation is specifically for the sulfonamide substitution. All

figures of 3-dimensional molecular scenes were made with PyMOL

(http://www.pymol.org).

Experimental Section

Synthesis of Compounds. General Methods. Unless otherwise

indicated, all anhydrous solvents were commercially obtained and

stored under nitrogen. Reactions were performed under an atmo-

sphere of dry nitrogen in oven-dried glassware and were monitored

for completeness by thin layer chromatography (TLC) using silica

1

gel 60 F-254 (0.25 mm) plates with detection with UV light. H

NMR spectra were recorded on dilute solutions in CDCl₃, CD₃-

OD, or DMSO-d₆at 300 or 500 MHz. Chemical shifts are reported

in parts per million (δ) downfield from tetramethylsilane (TMS).

Coupling constants (J) are reported in Hz. Electrospray ionization

mass spectra were acquired on an Bruker Esquire LC00066. Flash

chromatography was carried out with silica gel (40-63 µm).

Preparative reverse phase HPLC was performed on an automated

^aAll were prepared according to Scheme 6.

preclinical pharmacokinetic studies of our most potent Pf-PFT

inhibitors.⁹Together, these two studies provide the basis for

further development of Pf-PFT inhibitors as novel antimalarial

drugs.

4596 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Bendale et al.

Figure 3. Experimental binding mode of 162 to rat PFT (top left); molecular surface of rat-PFT (left; C, gray; N, blue; O, red; S, orange), with

farnesyl-pyrophosphate (red, orange, and cyan) and Zn²⁺(green) in CPK representation and 162 in stick model representation; equivalent all-stick

model (top right); comparison of the binding modes of 162 (yellow carbons) and 3-benzyl-1-(3H-imidazol-4-ylmethyl)-4-(thiophene-2-sulfonyl)-

2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carbonitrile (cyan carbons, see ref 11 for the structure) to rat PFT (bottom left); superposition of

162 (green carbon atoms) and the C-terminal tetrapeptide fragment of the Rap2a peptide farnesyl acceptor substrate (cyan carbon atoms) as bound

in PFT (bottom right; catalytic Zn²⁺shown).

Figure 4. Predicted binding mode of 162 in the active site of Pf-PFT (top left); molecular surface of PFT (left; C, gray; N, blue; O, red; S, orange),

with farnesyl-pyrophosphate (red, orange, and cyan) and Zn²⁺(green); predicted binding mode of 55 in the active site of Pf-PFT (top right). Note

how the R₂pyrrole group is wedged between C4 of the THQ ring and Trp-452â and Trp-456â.

(those tested on Pf-PFT and on parasites cultures) were purified

by HPLC as above to single eluting peaks.

General Procedure for Synthesis of Compounds According

to Scheme 1. Sulfonation. A solution of 6-cyano-1,2,3,4-tetrahy-

Figure 5. Comparison of the experimentally observed conformation

of THQ PFTIs with a sulfonamide linker (left) and the conformation

accessible to the analogous amides (right). The latter projects the R₁

group into a sterically poorly accessible area of PFT (not shown).

dro-quinolin-3-ylamine hydrochloride 3 (5 mmol), sulfonyl chloride

(10 mmol; for example, ref 16, and N,N-diisopropylethyl amine

(15 mmol) in 25 mL of anhydrous CH₃CN was stirred at room

temperature overnight. A light-colored precipitate of 4 was isolated

by vacuum filtration. More often, product 4 was obtained by flash

chromatography on a silica gel column, eluting with 50% ethyl

acetate/hexane: yields 85-95%.

Varian Prep star system using a gradient of 20% MeOH to 100%

MeOH (with 0.1% trifluoroacetic acid) over 30 min using a YMC

S5 ODS column (20 × 100 mm, Waters, Inc.). All final compounds

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4597

Table 10. Potency on Mammalian versus Pf-PFT

Hz, 1H), 2.88 (dd, J ) 4.2, 15.9 Hz, 1H), 2.70 (dd, J ) 8.7, 15.9

Hz, 1H). MS m/z 409.3 (M + H⁺).

IC₅₀on mammalian

Approximate

PFT

IC₅₀on Pf-PFT^a

(nM)

N-[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-4-fluoro-benzenesulfonamide (5). ¹H NMR

(500 MHz, methanol-d₄) δ 8.35 (s, 1H), 7.95-7.93 (m, 2H), 7.46

(s, 1H), 7.39 (d, J ) 8.5 Hz, 1H), 7.35 (t, J ) 8.0 Hz, 2H), 7.24

(s, 1H), 6.82 (d, J ) 8.5 Hz, 1H), 4.82 (d, J ) 17.0 Hz, 1H), 4.65

(d, J ) 17.0 Hz, 1H), 3.95-3.85 (m, 4H), 3.69-3.65 (m, 1H),

3.55-3.45 (m, 1H), 2.97-2.96 (m, 1H), 2.71-2.61 (m, 1H). MS

m/z 426.12 (M + H⁺).

N-Alkylation. To a suspension of 5 (5 mmol) and Cs₂CO₃(9.8

mmol) in dry DMF (5 mL) was added the appropriate alkyl halide

(5.4 mmol), and the mixture was stirred at room temperature

overnight under argon. After addition of water (20 mL), the solution

was extracted with ethyl acetate (3 × 20 mL). The organic layer

was extracted with brine (3 × 10 mL). The combined organic layers

were dried over MgSO₄and evaporated under reduce pressure. The

residue was purified by HPLC.

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(4-methanesulfo-

nyl-benzyl)-amide (69). ¹H NMR (300 MHz, methanol-d₄) δ 8.86

(s, 1H), 8.71 (d, J ) 7.2 Hz, 1H), 8.10 (td, J ) 1.5, 8.1 Hz, 1H),

7.99 (dt, J ) 1.2, 8,1 Hz, 1H), 7.90 (d, J ) 8.1 Hz, 2H), 7.69 (ddd,

J ) 1.2, 4.8, 7.5 Hz, 1H), 7.61 (d, J ) 8.1 Hz, 2H), 7.33 (dd, J )

2.1, 9.0 Hz, 1H), 7.28 (s, 1H), 7.25 (d, J ) 2.1 Hz, 1H), 6.65 (d,

J ) 8.7 Hz, 1H), 4.79 (d, J ) 17.1 Hz, 1H), 4.62 (d, J ) 17.1 Hz,

1H), 4.39-4.59 (m, 3H), 3.8 (s, 3H), 3.55-3.62 (m, 1H), 3.42-

3.47 (m, 1H), 3.15 (s, 3H), 3.07-3.14 (m, 1H), 2.97 (dd, J ) 4.5,

15.9 Hz, 1H). MS m/z 577.4 (M + H⁺).

6-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(pyridine-2-sulfonyl)-amino]-methyl}-py-

ridine-2-carboxylic Acid Methyl Ester (67). ¹H NMR (300 MHz,

CDCl₃) δ 8.78 (s, 1H), 8.63 (d, J ) 7.0 Hz, 1H), 7.78-8.04 (m,

5H), 7.51-7.76 (m, 1H), 7.30-7.34 (m, 2H), 7.18 (s, 1H), 6.56

(d, J ) 8.7 Hz, 1H), 4.76 (d, J ) 17.1 Hz, 1H), 4.65 (d, J ) 17.1

Hz, 1H), 4.47-4.61 (m, 3H), 3.96 (s, 3H), 3.85 (s, 3H), 3.54-

3.62 (m, 1H), 3.42-3.51 (m, 1H), 3.13 (dd, J ) 11.1, 15 Hz, 1H),

2.91 (dd, J ) 3.6, 15 Hz, 1H). MS m/z 558.3 (M + H⁺).

cmpd

(nM)

81

10

50

2

50

0.2

0.5

2

20

2

4

0.4

4

3

0.5

40

2

40

1

65

84

55

62

3.8

440

1.7

3

6

7

226

151

152

162

158

167

165

134

129

91

5

7.8

6.5

3.2

16

25

5.5

2.6

1000

7.5

105

4.8

3.4

101

126

123

^aIC₅₀values were estimated based on the % inhibition of Pf-PFT at

0.5, 5, and 50 nM inhibitor using the data in Tables 1-9.

1-Methyl-1H-imidazole-4-sulfonic Acid (6-Cyano-1,2,3,4-tet-

1

rahydro-quinolin-3-yl)-amide (4). H NMR (500 MHz, DMSO-

d₆) δ 7.80 (s, 1H), 7.78 (s,1H), 7.70 (br s, 1H), 7.25 (d, J ) 8.7

Hz, 1H), 7.20 (s, 1H), 6.81 (s, 1H), 6.51 (d, J ) 8.6 Hz, 1H), 3.78

(s, 3H), 3.52-3.43 (m, 1H), 3.25-3.20 (m, 1H), 3.15-2.9 (m, 1H),

2.81-2.73 (m, 1H), 2.65-2.53 (m, 1H). MS m/z 318.5 (M + H⁺).

Pyridine-2-sulfonic Acid (6-Cyano-1,2,3,4-tetrahydro-quino-

1

lin-3-yl)-amide (4). H NMR (300 MHz, methanol-d₄) δ 8.51 (d,

J ) 7.2 Hz, 1H), 8.02 (td, J ) 2.1, 7.8 Hz, 1H), 7.92 (dt, J ) 1.8,

7.5 Hz, 1H), 7.47 (ddd, J ) 1.2, 4.8, 7.5 Hz, 1H), 7.12 (dd, J )

2.1, 8.4 Hz, 1H), 7.0 (d, J ) 1.8 Hz, 1H), 6.3 (d, J ) 8.4 Hz, 1H),

5.87 (d, J ) 7.8 Hz, 1H), 3.94-4.01 (m, 1H), 3.36 (dd, J ) 2.7,

12 Hz, 1H), 3.25 (ddd, J ) 2.1, 4.5, 12.3 Hz, 1H), 2.87 (dd J )

4.2, 16.5 Hz, 1H), 2.71 (ddd, J ) 2.1, 4.8, 16.5 Hz, 1H). MS m/z

315 (M + H⁺).

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(pyridine-2-sulfonyl)-amino]-methyl}-pi-

1

peridine-1-carboxylic Acid tert-Butyl Ester (6). H NMR (300

Reductive Amination. A mixture of sulfonamide 4 (5 mmol),

1-methyl-1H-imidazole-5-carboxaldehyde (10 mmol),¹⁶and 20 mL

of 50% trifluoroacetic acid in dichloroethane was warmed at 50

°C under argon. After 2 h, triethylsilane (20 mmol) was added.

After 48 h, the solvent was removed under reduced pressure, and

the crude product was partitioned between methylene chloride and

1 N NaOH (45 mL). The organic layer was separated, and the

aqueous layer was extracted with CH₂Cl₂(3 × 25 mL). The

combined organic layers were dried over MgSO₄, filtered, and

concentrated. The crude residue was either recrystallized with

dichloromethane or purified on a flash silica gel chromatography

to afforded 5 in 45-50% yield.

MHz, methanol-d₄) δ 8.93 (s, 1H), 8.71 (d, J ) 7.2 Hz, 1H), 8.05

(td, J ) 1.8, 7.5 Hz, 1H), 8.01-8.02 (m, 1H), 7.66 (ddd, J ) 1.2,

4.8, 7.5 Hz, 1H), 7.43 (s, 1H), 7.39 (dd, J ) 1.5, 8.4 Hz, 1H), 7.33

(s, 1H), 6.80 (d, J ) 9.7 Hz, 1H), 4.81 (d, J ) 16.8 Hz, 1H), 4.68

(d, J ) 16.8 Hz, 1H), 4.32-4.44 (m, 1H), 4.05-4.09 (m, 2H),

3.91 (s, 3H), 3.58-3.66 (m, 2H), 3.53-3.55 (m, 1H), 3.11-3.21

(m, 3H), 2.87-2.88 (m, 1H), 2.63-2.69 (m, 1H), 1.64-1.77 (m,

3H), 1.3 (s, 9H), 1.01-1.11 (m, 2H). MS m/z 606.6 (M + H⁺).

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(2-pyrazol-1-yl-

1

ethyl)-amide (56). H NMR (300 MHz, methanol-d₄) δ 8.92 (s,

1H), 8.73 (d, J ) 6.9 Hz, 1H), 8.01-8.12 (m, 2H), 7.64-7.71 (m,

1H), 7.61 (d, J ) 2.1 Hz, 1H), 7.50 (d, J ) 1.5 Hz, 1H), 7.32-

7.38 (m, 2H), 7.21 (s, 1H), 6.79 (d, J ) 8.7 Hz, 1H), 6.30 (t, J )

2.1 Hz, 1H), 4.68 (d, J ) 18.3 Hz, 1H), 4.60 (d, J ) 18.3 Hz, 1H),

4.70 (t, J ) 6.3 Hz, 2H), 4.25-4.35 (m, 1H), 3.83 (s, 3H), 3.74 (t,

J ) 6.3 Hz, 2H), 3.10-3.21 (m, 2H), 2.86 (dd, J ) 12, 15.3 Hz,

1H), 2.58 (dd, J ) 3.9, 15.3 Hz, 1H). MS m/z 503.4 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-

amide Trifluoro Acetate Salt (5). Recrystallized from CH₂Cl₂

1

afforded the product as a white solid (70%). H NMR (300 MHz,

methanol-d₄) δ 8.89 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.41 (s,

1H), 7.36 (d, J ) 8.2 Hz, 1H,), 7.22 (s, 1H), 6.80 (d, J ) 8.6 Hz,

1H), 4.80 (d, J ) 16.80 Hz, 1H), 4.65 (d, J ) 16.80 Hz, 1H), 3.87

(s, 3H), 3.85-3.79 (m, 1H), 3.78 (s, 3H), 3.55 (dd, J ) 11.9 Hz,

1H), 3.42 (dd, J ) 12.4 Hz, 1H), 3.05 (dd, J ) 15.78 Hz, 1H),

2.71 (dd, J ) 15.78 Hz, 1H). MS m/z 412.5 (M + H⁺).

{3-[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(pyridine-2-sulfonyl)-amino]-propyl}-

1

methyl-carbamic Acid Methyl Ester (48). H NMR (300 MHz,

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-amide (5). ¹H NMR

(300 MHz, DMSO-d₆) δ 8.70 (d, J ) 4.8 Hz, 1H), 8.14 (d, J ) 6.6

Hz, 1H), 8.06 (dt, J ) 1.8, 7.5 Hz, 1H), 7.99 (s, 1H), 7.67 (ddd, J

) 1.2, 4.8, 7.8 Hz, 1H), 7.37 (dd, J ) 2.1, 8.7 Hz, 1H), 7.27 (d, J

) 1.8 Hz, 1H), 6.88 (s, 1H), 6.8 (d, J ) 8.7 Hz, 1H), 4.62 (d, J )

16.5 Hz, 1H), 4.59 (d, J ) 16.5 Hz, 1H), 3.73-3.85 (m, 1H), 3.60

(s, 3H), 3.38 (dd, J ) 2.4, 11.7 Hz, 1H), 3.17 (dd, J ) 8.7, 12.9

methanol-d₄) δ 8.94 (d, J ) 0.9 Hz, 1H), 8.70 (d, J ) 7.5 Hz, 1H),

8.08 (td, J ) 1.8, 7.8 Hz, 1H), 8.0 (dt, J ) 1.2, 7.8 Hz, 1H), 7.66

(ddd, J ) 1.5, 4.8, 7.5 Hz, 1H), 7.43 (d, J ) 1.2 Hz, 1H), 7.38 (dd,

J ) 2.1, 8.7 Hz, 1H), 7.33 (s, 1H), 6.81 (d, J ) 8.7 Hz, 1H), 4.82

(d, J ) 17.5 Hz, 1H), 4.62 (d, J ) 17.5 Hz, 1H), 4.40-4.52 (m,

1H), 3.92 (s, 3H), 3.65 (s, 3H), 3.55-3.47 (m, 4H), 3.28-3.05

(m, 4H), 2.93 (s, 3H), 1.78-1.88 (m, 2H). MS m/z 538.4 (M +

H⁺).

4598 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Bendale et al.

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(4-fluoro-benzyl)-

amide (71). ¹H NMR (300 MHz, methanol-d₄) δ 8.89 (s, 1H), 8.74

(d, J ) 6.5 Hz, 1H), 8.09 (td, J ) 1.8, 7.8 Hz, 1H), 8.0 (dt, J )

1.2, 7.8 Hz, 1H), 7.67 (ddd, J ) 1.5, 4.8, 7.5 Hz, 1H), 7.39-7.43

(m, 2H), 7.35 (dd, J ) 2.1, 8.7 Hz, 1H), 7.33 (s, 1H), 7.25 (s, 1H),

7.01-7.07 (m, 2H), 6.75 (d, J ) 8.7 Hz, 1H), 4.43-4.69 (m, 5H),

3.82 (s, 3H), 3.55-3.47 (m, 1H), 3.17-3.25 (m, 1H), 3.07 (dd, J

) 12, 15 Hz, 1H), 2.91 (dd, J ) 3.9, 15 Hz, 1H). MS m/z 517.4

(M + H⁺).

Hz, 1H), 4.48-4.52 (m, 2H), 4.51 (d, J ) 17.7 Hz, 1H), 4.45 (d,

J ) 17.7 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.55-3.60 (m, 2H),

3.40-3.55 (m, 2H), 2.95-3.05 (m, 1H), 2.68-2.75 (m, 1H). MS

m/z 608.4 (M + H⁺).

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(1,5-dimethyl-1H-imidazole-4-sulfonyl)-

amino]-methyl}-piperidine-1-carboxylic Acid Methyl Ester (234).

¹H NMR (300 MHz, methanol-d₄) δ 8.93 (s, 1H), 7.73 (s, 1H),

7.40 (s, 1H), 7.37 (dd, J ) 3.0, 9.0 Hz, 1H), 7.32 (d, J ) 1.8 Hz,

1H), 6.79 (d, J) 9 Hz, 1H), 4.81 (d, J ) 18.0 Hz, 1H), 4.68 (d, J

) 18.0 Hz, 1H), 4.32-4.42 (m, 1H), 4.08-4.18 (m, 2H), 3.92 (s,

3H), 3.67 (s, 3H), 3.68 (s, 3H), 3.51-3.58 (m, 2H), 2.98-3.17

(m, 3H), 2.73-2.87 (m, 3H), 2.48 (s, 3H), 1.69-1.85, (m, 3H),

1.01-1.27 (m, 2H). MS m/z 581.6 (M + H⁺).

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-[2-(2-trifluorom-

1

ethyl-phenyl)-ethyl]-amide (76). H NMR (300 MHz, methanol-

d₄) δ 8.87 (s, 1H), 8.74 (d, J ) 4.5 Hz, 1H), 8.12 (td, J ) 1.8, 7.8

Hz, 1H), 8.0 (dt, J ) 1.2, 7.8 Hz, 1H), 7.63-7.71 (m, 2H), 7.58-

7.63 (m, 1H), 7.37-7.49 (m, 5H), 6.81 (d, J ) 8.7 Hz, 1H), 4.92

(d, J ) 17.7 Hz, 1H), 4.82 (d, J ) 17.7 Hz, 1H), 4.50-4.56 (m,

1H), 3.98 (s, 3H), 3.55-3.47 (m, 4H), 3.18-3.31 (m, 3H), 3.02-

3.08 (m, 1H). MS m/z 581.4 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-[2-(2-

fluoro-phenyl)-ethyl]-amide (113). ¹H NMR (300 MHz, methanol-

d₄) δ 8.93 (s, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.38

(dd, J ) 2.1, 8.7 Hz, 1H), 7.23-7.32 (m, 3H), 7.10-7.17 (m, 2H),

6.84 (d, J ) 8.6 Hz, 1H), 4.92 (d, J ) 17.7 Hz, 1H), 4.82 (d, J )

17.7 Hz, 1H), 4.48-4.50 (m, 1H), 4.07 (s, 3H), 3.82 (s, 3H), 3.35-

3.57 (m, 4H), 3.16-3.29 (m, 3H), 2.92-3.00 (m, 1H). MS m/z

534.4 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-[2-(4-

fluoro-phenyl)-ethyl]-amide (112). ¹H NMR (300 MHz, acetone-

d₆) δ 8.93 (s, 1H), 7.75 (s, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.38

(dd, J ) 2.1, 8.7 Hz, 1H), 7.32 (s, 1H) 7.22-7.25 (m, 2H), 7.01-

7.07 (m, 2H), 6.93 (d, J ) 8.6 Hz, 1H), 4.93 (d, J ) 16.8 Hz, 1H),

4.80 (d, J ) 16.8 Hz, 1H), 4.38-4.46 (m, 1H), 4.07 (s, 3H), 3.82

(s, 3H), 3.34-3.54 (m, 4H), 3.07 (dd, J ) 12, 15 Hz, 1H), 2.98 (t,

J ) 8.1 Hz, 2H) 2.90 (dd, J ) 3.7, 15.2 Hz, 1H). MS m/z 534.4

(M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(4-

fluoro-benzyl)-amide (109). ¹H NMR (300 MHz, methanol-d₄) δ

8.90 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.36-7.42 (m, 3H), 7.33

(s, 1H), 7.27 (s, 1H), 7.10-7.17 (m, 2H), 6.84 (d, J ) 8.6 Hz,

1H), 4.28-4.65 (m, 5H), 3.87 (s, 3H), 3.80 (s, 3H), 3.34-3.39

(m, 1H), 3.18-3.26 (m, 1H), 3.07 (dd, J ) 11.4, 15.3 Hz, 1H),

2.87 (dd, J ) 3.7, 15.2 Hz, 1H). MS m/z 520.4 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(4-

ethanesulfonyl-benzyl)-amide (132). ¹H NMR (300 MHz, methanol-

d₄) δ 8.87 (s, 1H), 7.87 (d, J ) 8.1 Hz, 2H), 7.85 (s, 1H), 7.77 (s,

1H), 7.62 (d, J) 8.1 Hz, 2H), 7.34 (dd, J ) 1.8, 8.7 Hz, 1H), 7.25

(d, J ) 1.8 Hz, 1H), 6.68 (d, J ) 8.7 Hz), 4.75 (d, 2H), 4.53-4.55

(m, 1H), 4.51 (d, J ) 17.7 Hz, 1H), 4.45 (d, J ) 17.7 Hz, 1H),

3.81 (s, 3H), 3.80 (s, 3H), 3.10-3.25 (m, 6H), 2.95-3.05 (m, 1H),

1.21-1.25 (t, 3H). MS m/z 594.5 (M + H⁺).

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3yl]-(1,5-dimethyl-1H-imidazole-4-sulfonyl)-

amino]-methyl}-piperidine-1-carboxylic Acid tert-Butyl Ester

1

(235). H NMR (300 MHz, methanol-d₄) δ 8.93 (s, 1H), 7.73 (s,

1H), 7.43 (d, J ) 1.8 Hz, 1H), 7.37 (dd, J ) 3, 9 Hz, 1H), 7.32 (s,

1H), 6.79 (s, 1H), 4.81 (d, J ) 18.0 Hz, 1H), 4.68 (d, J ) 18.0 Hz,

1H), 4.33-4.40 (m, 1H), 4.06-4.11 (m, 2H), 3.92 (s, 3H), 3.67

(s, 3 H), 3.53-3.58 (m, 2H), 3.09-3.17 (m, 3 H), 2.64-2.81 (m,

3H), 2.48 (s, 3H), 1.63-1.81 (m, 3H), 1.4 (s, 9 H), 0.90-1.13 (m,

2H). MS m/z 623.6 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-[2-(2-

oxo-pyrrolidin-1-yl)-ethyl]-amide (117). ¹H NMR (300 MHz,

methanol-d₄) δ 8.91 (s, 1H), 7.30-7.45 (m, 2H), 7.17-7.24 (m,

1H), 7.12 (s, 1H), 6.82 (d, J ) 9.0 Hz, 1H), 6.52 (d, J ) 9.0 Hz,

1H), 4.28-4.40 (m, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.66-3.73

(m, 1H), 3.51-3.63 (m, 2H), 3.40-3.48 (m, 2H), 3.03-3.21 (m,

2H), 2.78-2.93 (m, 2H), 2.62-2.76 (m, 2H), 2.38 (t, J ) 6.0 Hz,

2H), 2.07 (t, J ) 6.0 Hz, 2H). MS m/z 523.3 (M + H⁺).

1,5-Dimethyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-

methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-

yl]-(4-methanesulfonyl-benzyl)-amide (236). ¹H NMR (300 MHz,

methanol-d₄) δ 8.85 (s 1H), 7.91 (d, J ) 9.0 Hz, 2H), 7.77 (s, 1H),

7.60 (d, J ) 9.0 Hz, 2H), 7.35 (d, J ) 9.0 Hz 2H), 7.29 (s, 1H),

6.68 (d, J ) 9.0 Hz, 1H), 4.40-4.71 (m, 5H), 3.83 (s, 3H), 3.68

(s, 3H), 3.45-3.55 (m, 2H), 3.17 (s, 3H), 2.88-3.02 (m, 2H), 2.42

(s, 3H). MS m/z 594.5 (M + H⁺).

1,5-Dimethyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-

methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-

1

yl]-(4-ethanesulfonyl-benzyl)-amide (237). H NMR (300 MHz,

methanol-d₄) δ 8.88 (s 1H), 7.85 (d, J ) 9.0 Hz, 2H), 7.78 (s, 1H),

7.60 (d, J ) 9.0 Hz, 2H), 7.35 (d, J ) 9.0 Hz 2H), 7.29 (s, 1H),

6.68 (d, J ) 9.0 Hz, 1H), 4.40-4.76 (m, 5H), 3.97 (s, 3H), 3.82

(s, 3H), 3.45-3.55 (m, 2H), 3.15-3.30 (m, 2H), 2.88-3.05 (m,

2H), 2.48 (s, 3H), 1.22 (t, J ) 9.6 Hz, 3H). MS m/z 608.4 (M +

H⁺).

1,5-Dimethyl-1H-imidazole-4-sulfonic Acid (5-Bromo-2-fluoro-

benzyl)-[6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-

tetrahydro-quinolin-3-yl]-amide (238). ¹H NMR (300 MHz,

methanol-d₄) δ 8.92 (s, 1H), 7.76 (s, 1H), 7.53 (m, 1H), 7.31-

7.45 (m, 3H), 7.28 (s, 1H), 6.99 (d, J ) 9.0 Hz, 1H), 6.72 (d, J )

9.0 Hz, 1H), 4.42-4.75 (m, 5H), 3.89 (s, 3H), 3.67 (s, 3H), 3.50-

3.62 (m, 2H), 2.95-3.10 (m, 2H), 2.40 (s, 3H). MS m/z 612.8 (M

+ H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(4-

methanesulfonyl-benzyl)-amide (131). ¹H NMR (300 MHz,

methanol-d₄) δ 9.0 (s 1H), 7.95-7.85 (m, 3H), 7.60 (d, J ) 8.7

Hz, 2H), 7.35 (t, J ) 7.8 Hz, 3H), 7.29 (s, 1H), 6.70 (d, J ) 8.7

Hz, 1H), 4.60-4.40 (m, 4H), 4.40-4.30 (m, 1H), 3.85 (s, 3H),

3.80 (s, 3H), 3.40-3.30 (m, 2H), 3.0-2.90 (m, 1H), 2.83-2.75

(m, 1H), 2.50 (s, 3H). MS m/z 580.5 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid (4-Benzenesulfonyl-

benzyl)-[6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-

tetrahydro-quinolin-3-yl]-amide (145). ¹H NMR (300 MHz,

methanol-d₄) δ 8.89 (s, 1H), 7.89-8.10 (m, 4H), 7.87 (d, J ) 8.1

Hz, 2H), 7.77 (s, 1H), 7.50-7.72 (m, 5H), 7.34 (dd, J ) 1.8, 8.7

Hz, 1H), 7.25 (d, J ) 1.8 Hz, 1H), 6.68 (d, J ) 8.7 Hz, 1H), 4.75

(m, 2H), 4.53-4.55 (m, 1H), 4.51 (d, J ) 17.7 Hz, 1H), 4.45 (d,

J ) 17.7 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.40-3.45 (m, 2H),

2.95-3.05 (m, 1H). MS m/z 642.6 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(4,4-

dioxo-3,4-dihydro-2H-4λ6-benzo[1,4]oxathiin-7-ylmethyl)-

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-yl-methyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(3-

1

amide (146). H NMR (300 MHz, methanol-d₄) δ 8.90 (s, 1H),

1

7.85 (s, 1H), 7.68 (d, J ) 8.1 Hz, 1H), 7.45 (s, 1H), 7.30 (s, 1H),

7.28 (dd, J ) 1.8, 8.7 Hz, 1H), 7.25 (d, J ) 1.8 Hz, 1H), 7.15 (dd,

J ) 8.7, 1.8 Hz, 1H), 7.08 (d, J ) 2.1 Hz, 1H), 6.68 (d, J ) 8.7

methoxy-propyl)-amide (91). H NMR (300 MHz, methanol-d₄)

δ 8.92 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 7.39 (d, J

) 8.7 Hz, 1H), 7.32 (s, 1H), 6.81 (d, J ) 8.7 Hz, 1H), 4.78 (d, J

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4599

) 16.7 Hz, 1H), 4.69 (d, J ) 16.7 Hz, 1H), 4.45-4.38 (m, 1H),

3.92 (s, 3H), 3.81 (s, 3H), 3.59-3.51 (m, 2H), 3.43-3.38 (m, 2H),

3.32 (s, 3H), 3.28-3.20 (m, 2H), 3.12-3.07 (m, 1H), 2.85 (dd, J

) 3.3, 15.3 Hz, 1H), 1.96-1.85 (m, 4H). MS m/z 484.5 (M +

H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(5-tri-

fluoromethyl-furan-2-ylmethyl)-amide (108). ¹H NMR (300 MHz,

methanol-d₄) δ 8.90 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.42-7.36

(m, 2H), 7.40 (s, 1H), 6.90 (s, 1H), 6.70 (d, J ) 8.5 Hz, 1H), 6.50

(s, 1H), 4.75-4.45 (m, 5H), 3.90 (s, 3H), 3.75 (s, 3H), 3.50-3.40

(m, 2H), 3.20-3.12 (m, 1H), 2.89 (dd, J ) 3.2, 15.1 Hz, 1H). MS

m/z 560.4 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-[4-

(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-butyl]-amide (143). ¹H

NMR (300 MHz, methanol-d₄) δ 8.90 (s 1H), 7.78-7.65 (m, 6H),

7.60 (s, 1H), 7.40-7.30 (m, 2H), 6.80 (d, J ) 8.7 Hz, 1H), 4.85

(d, J ) 16.7 Hz, 1H), 4.75 (d, J ) 16.7 Hz, 1H), 4.50-4.40 (m,

1H), 4.20 (t, 2H), 4.0 (s, 3H), 3.80 (s, 3H), 3.70-3.55 (m, 2H),

3.40-3.20 (m, 3H), 2.89 (dd, J ) 3.2, 15.1 Hz, 1H), 1.96-1.70

(m, 4H). MS (EI) m/z 629.6 (M + H⁺).

General Procedure for the Synthesis of Compounds Accord-

ing to Scheme 2. Compound 6 (400 mg) was dissolved in

dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added.

The reaction mixture was stirred for 45 min. Solvent was removed

in vacuo with care to be sure that all trifluoroacetic acid was

removed. The residue was used without further purification.

The residue (0.28 mmol) was dissolved in dichloromethane (2.5

mL) together with diisopropylethyl amine (0.33 mmol). To this

solution was added the appropriate chloroformate, isocyanate, or

sulfonyl chloride (0.30 mmol) dropwise at 0 °C, and the mixture

was stirred for 1 h. Aqueous NH₄OH (1 mL) was added to the

reaction mixture. After being stirred for an additional 15 min, the

mixture was diluted with ethyl acetate (50 mL) and washed with

brine. The organic layer was dried over MgSO₄and evaporated

under reduced pressure to yield the crude product, which was

purified by preparative HPLC. The appropriate fractions were

combined and concentrated in vacuo to give the corresponding

derivatives as the trifluoroacetate salt.

6.6 Hz, 2H), 3.51-3.62 (m, 2H), 3.21-3.26 (m, 2H), 3.11-3.18

(m, 1H), 2.79-2.87 (m, 3H), 1.91-1.99 (m, 1H), 1.68-1.88, (m,

3H), 1.05-1.17 (m, 2H), 0.95 (d, J ) 6.9 Hz, 6H). MS m/z 606.5

(M + H⁺).

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-[1-(2,2-dimethyl-

propionyl)-piperidin-4-ylmethyl]-amide (150). ¹H NMR (500

MHz, methanol-d₄) δ 8.94 (s, 1H), 8.71 (d, J ) 6 Hz, 1H), 8.09

(td, J ) 1, 8 Hz, 1H), 8.01 (dt, J ) 1, 8 Hz, 1H), 7.66 (ddd, J )

1.5, 5, 7.5 Hz, 1H), 7.43 (s, 1H), 7.38 (dd, J ) 2, 8 Hz, 1H), 7.33

(s, 1H), 6.82 (d, J ) 9 Hz, 1H), 4.82 (d, J ) 18.5 Hz, 1H), 4.69 (d,

J ) 18.5 Hz, 1H), 4.38-4.45 (m, 3 H), 3.92 (s, 3H), 3.61-3.66

(m, 1H), 3.52-3.55 (m, 1H), 3.15-3.30 (m, 3H), 2.76-2.88 (m,

3H), 1.93-1.97 (m, 1H), 1.77-1.85 (m, 2H), 1.27 (s, 9H), 1.07-

1.15 (m, 2H). MS m/z 590.6 (M + H⁺).

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-[1-(3,3,3-trifluoro-

propionyl)-piperidin-4-ylmethyl]-amide (155). ¹H NMR (300

MHz, methanol-d₄) δ 8.85 (s, 1H), 8.67 (d, J ) 6 Hz, 1H), 8.09

(td, J ) 1, 8 Hz, 1H), 8.01 (dt, J ) 1, 8 Hz, 1H), 7.60 (m, 1H),

7.43 (s, 1H), 7.38 (d, J ) 8 Hz, 1H), 7.23 (s, 1H), 6.82 (d, J ) 9

Hz, 1H), 4.82 (d, J ) 18.5 Hz, 1H), 4.69 (d, J ) 18.5 Hz, 1H),

4.38-4.45 (m, 3 H), 3.92 (s, 3H), 3.61-3.66 (m, 1H), 3.50-3.52

(m, 1H), 3.12-3.28 (m, 5H), 2.71-2.81 (m, 3H), 1.93-1.97 (m,

1H), 1.72-1.80 (m, 2H), 1.03-1.12 (m, 2H). MS m/z 616.4 (M +

H⁺).

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(1-methanesulfo-

nyl-piperidin-4-ylmethyl)-amide (177). ¹H NMR (300 MHz,

methanol-d₄) δ 8.93 (d, J ) 1.2 Hz, 1H), 8.71 (d, J ) 7.5 Hz, 1H),

8.08 (dt, J ) 1.8, 7.8 Hz, 1H), 8.02 (td, J ) 1.2, 8.1 Hz, 1H), 7.66

(ddd, J ) 1.5, 4.8, 7.5 Hz, 1H), 7.42 (d, J ) 1.5 Hz, 1H), 7.38 (dd,

J ) 2.1, 8.7 Hz, 1H), 7.33 (s, 1H), 6.80 (d, J ) 8.7 Hz, 1H), 4.8

(d, J ) 17.7 Hz, 1H), 4.68 (d, J ) 17.7 Hz, 1H), 4.37-4.48 (m,

1H), 3.91 (s, 3H), 3.69-3.72 (m, 2H), 3.58-3.65 (m, 1H), 3.49-

3.55 (m, 1H), 3.22-3.28 (m, 2H), 3.13-3.20 (m, 1H), 2.85-2.89

(m, 1H), 2.82 (s, 3H), 2.64-2.74 (m, 2H), 1.75-1.93 (m, 3H),

1.17-1.35 (m, 2H). MS m/z 584.4 (M + H⁺).

Pyridine-2-sulfonic Acid (1-Benzenesulfonyl-piperidin-4-yl-

methyl)-[6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-

tetrahydro-quinolin-3-yl]-amide (180). ¹H NMR (300 MHz,

methanol-d₄) δ 8.93 (d, J ) 1.2 Hz, 1H), 8.71 (d, J ) 7.5 Hz, 1H),

8.08 (dt, J ) 1.8, 7.8 Hz, 1H), 8.02 (td, J ) 1.2, 8.1 Hz, 1H),

7.56-7.78 (m, 6H), 7.32 (s, 1H), 7.29 (d, J ) 8.7 Hz, 1H), 7.21

(s, 1H), 6.80 (d, J ) 8.7 Hz, 1H), 4.75 (d, J ) 17.7 Hz, 1H), 4.60

(d, J ) 17.7 Hz, 1H), 4.37-4.48 (m, 1H), 3.91 (s, 3H), 3.69-3.72

(m, 2H), 3.58-3.65 (m, 1H), 3.49-3.55 (m, 1H), 3.22-3.28 (m,

2H), 3.13-3.20 (m, 1H), 2.85-2.89 (m, 1H), 2.64-2.74 (m, 2H),

1.75-1.93 (m, 3H), 1.17-1.35 (m, 2H). MS m/z 646.5 (M

+ H⁺).

Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imidazol-

4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-piperidin-4-ylmethyl-

amide (54). ¹H NMR (300 MHz, methanol-d₄) δ 8.93 (s, 1H), 8.71

(d, J ) 7.2 Hz, 1H), 8.07 (td, J ) 1.5, 7.5 Hz, 1H), 8.01 (dt, J )

0.9, 7.8 Hz, 1H), 7.66 (ddd, J ) 1.5, 4.8, 7.5 Hz, 1H), 7.40 (s,

1H), 7.37 (d, J ) 2.1 Hz, 1H), 7.33 (s, 1H), 6.79 (d, J ) 8.7 Hz,

1H), 4.80 (d, J ) 17.4 Hz, 1H), 4.65 (d, J ) 17.4 Hz, 1H), 4.33-

4.44 (m, 1H), 3.91 (s, 3H), 3.63 (t, J ) 10.8 Hz, 1H), 3.40-3.54

(m, 4H), 3.14-3.23 (m, 2H), 2.82-3.02 (m, 3H), 1.97-2.09 (m,

3 H), 1.30-1.52 (m, 2H). MS m/z 506.5 (M + H⁺).

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(pyridine-2-sulfonyl)-amino]-methyl}-pi-

peridine-1-carboxylic Acid Methyl Ester (162). H NMR (300

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(pyridine-2-sulfonyl)-amino]-methyl}-pi-

peridine-1-carboxylic Acid Ethylamide (170). ¹H NMR (300

MHz, methanol-d₄) δ 8.93 (s, 1H), 8.70 (d, J ) 7.2 Hz, 1H), 8.04-

8.10 (m, 1H), 8.99-8.02 (m, 1H), 7.66 (ddd, J ) 1.5, 4.8, 7.5 Hz,

1H), 7.42 (s, 1H), 7.39 (dd, J ) 2.1, 8.4 Hz, 1H), 7.33 (s, 1H),

6.82 (d, J) 8.7 Hz, 1H), 4.8 (d, J ) 17.7 Hz, 1H), 4.69 (d, J )

17.7 Hz, 1H), 4.38-4.47 (m, 1H), 3.98-4.02 (m, 2H), 3.91 (s,

3H), 3.62 (t, J ) 10.8 Hz, 1H), 3.54-3.56 (m, 1H), 3.12-3.29

(m, 5H), 2.81-2.90 (m, 1H), 2.66-2.74 (m, 2H), 1.65-1.87 (m,

3H), 1.17-1.18 (m, 2H), 1.10 (t, J ) 7.2 Hz, 3H). MS m/z 577.5

(M + H⁺).

[2-(4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-

tetrahydro-quinolin-3-yl]-(pyridine-2-sulfonyl)-amino]-methyl}-

piperidin-1-yl)-2-oxo-ethyl]-carbamic Acid tert-Butyl Ester (157).

A mixture of 54 (22 mg, 0.044 mmol), Boc-Gly-OH (9.2 mg, 0.051

mmol), dicyclohexylcarbodiimide (10 mg, 0.051 mmol), 4-dim-

ethylamino-pyridine (2 mg), and dichloromethane (5 mL) was

stirred at room temperature for 18 h. Upon completion of reaction,

the mixture was filtered to remove dicyclohexylurea, and the residue

was washed with dichloromethane (5 mL). The filtrate and washings

1

MHz, methanol-d₄) δ 8.94 (d, J ) 0.9 Hz, 1H), 8.70 (d, J ) 7.5

Hz, 1H), 8.08 (td, J ) 1.8, 7.8 Hz, 1H), 8.0 (dt, J ) 1.2, 7.8 Hz,

1H), 7.66 (ddd, J ) 1.5, 4.8, 7.5 Hz, 1H), 7.43 (d, J ) 1.2 Hz,

1H), 7.38 (dd, J ) 2.1, 8.7 Hz, 1H), 7.33 (s, 1H), 6.81 (d, J ) 8.7

Hz, 1H), 4.84 (d, J ) 17.7 Hz, 1H), 4.68 (d, J ) 17.7 Hz, 1H),

4.38-4.51 (m, 1H), 4.08-4.16 (m, 2H), 3.92 (s, 3H), 3.65 (s, 3H),

3.51-3.62 (m, 2H), 3.21-3.26 (m, 2H), 3.11-3.18 (m, 1H), 2.79-

2.87 (m, 3H), 1.68-1.88 (m, 3H), 1.05-1.17 (m, 2H). MS m/z

564.4 (M + H⁺).

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(pyridine-2-sulfonyl)-amino]-methyl}-pi-

1

peridine-1-carboxylic Acid Isobutyl Ester (167). H NMR (300

MHz, methanol-d₄) δ 8.94 (d, J ) 0.9 Hz, 1H), 8.70 (d, J ) 7.5

Hz, 1H), 8.08 (td, J ) 1.8, 7.8 Hz, 1H), 8.0 (dt, J ) 1.2, 7.8 Hz,

1H), 7.66 (ddd, J ) 1.5, 4.8, 7.5 Hz, 1H), 7.43 (d, J ) 1.2 Hz,

1H), 7.38 (dd, J ) 2.1, 8.7 Hz, 1H), 7.33 (s, 1H), 6.81 (d, J ) 8.7

Hz, 1H), 4.84 (d, J ) 17.7 Hz, 1H), 4.68 (d, J ) 17.7 Hz, 1H),

4.38-4.51 (m, 1H), 4.08-4.16 (m, 2H), 3.92 (s, 3H), 3.85 (d, J )

4600 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Bendale et al.

were combined and evaporated to dryness in Vacuo. The residue

was purified by HPLC to afford 15 mg (54%) of 157 as the

trifluoroacetate salt. H NMR (500 MHz, methanol-d₄) δ 8.94 (s,

(dd, J ) 4.5, 12.1 Hz, 1H), 2.03 (dd J ) 5.1, 15.9 Hz, 1H), 2.71

(dd, J ) 4.8, 16.2 Hz, 1H). MS m/z 402.2 (M + H⁺).

1

3-Amino-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahy-

dro-quinoline-6-carbonitrile (11). ¹H NMR (300 MHz, methanol-

d₄) δ 7.61 (s, 1H), 7.32 (dd, J ) 2.1, 8.4 Hz, 1H), 7.29 (s, 1H),

6.83 (d, J ) 8.4 Hz, 1H), 6.80 (s, 1H), 4.64 (d, J ) 16.5 Hz, 1H),

4.58 (d, J ) 16.5 Hz, 1H), 3.57 (s, 3H), 3.42 (dd, J ) 2.4, 11.7

Hz, 1H), 3.35 (m, 1H), 3.21 (m, 1H), 2.98 (dd, J ) 4.1, 16.5 Hz,

1H), 2.67 (dd, J ) 4.8, 16.4 Hz, 1H). MS m/z 268.3 (M + H⁺).

3-(2-Fluoro-benzylamino)-1-(3-methyl-3H-imidazol-4-ylmethyl)-

1,2,3,4-tetrahydro-quinoline-6-carbonitrile Trifluoroacetate Salt

(12). ¹H NMR (300 MHz, methanol-d₄) δ 8.83 (s, 1H), 7.20-7.48

(m, 5H), 7.12-7.17 (m, 2H), 6.82 (d, J ) 8.5 Hz, 1H), 4.74 (d, J

) 17.4 Hz, 1H), 4.60 (d, J ) 17.4 Hz, 1H), 4.35 (s, 2H), 3.88 (m,

1H), 3.75 (s, 3H), 3.74 (dd, J ) 2.1, 14.1 Hz, 1H), 3.49 (dd, J )

4.8, 14.5 Hz, 1H), 3.31 (dd, J ) 4.5, 16.5 Hz, 1H), 2.67 (dd, J )

6.6, 16.5 Hz, 1H). MS m/z 268.3 (M + H⁺).

1H), 8.71 (d, J) 7.5 Hz, 1H), 8.06-8.12 (m, 1H), 7.88-8.01 (m,

1H), 7.65-7.68 (m, 1H), 7.42 (s, 1H), 7.38 (dd, J ) 1.5, 8.5 Hz,

1H), 7.33 (s, 1H), 6.81 (d, J ) 8 Hz, 1H), 4.81 (d, J ) 18 Hz, 1H),

4.69 (d, J ) 18 Hz, 1H), 4.35-4.50 (m, 3H), 3.92 (s, 3H), 3.80-

3.92 (m, 2H), 3.59-3.63 (m, 1H), 3.52-3.54 (m, 1H), 3.13-3.33

(m, 3H), 3.00-3.12 (m, 1H), 2.82-2.88 (m, 1H), 2.57-2.65 (m,

1H), 1.72-1.95 (m, 3H), 1.46 (s, 9 H), 1.06-1.25 (m, 2H). MS

m/z 663.6 (M + H⁺).

General Procedure for the Synthesis of Compounds Accord-

ing to Scheme 3. To a solution of 6-cyano-1,2,3,4-tetrahydro-

quinolin-3-ylamine hydrochloride 3 (4.18 g, 20 mmol) and N,N-

diisopropylethyl amine (5.1 g, 40 mmol) in 25 mL of anhydrous

dichloromethane was added benzyl chloroformate (5.1 g, 30 mmol)

at 0 °C. After stirring at ambient temperature for 5 h, the reaction

mixture was quenched with water. The mixture was partitioned

between water and ethyl acetate. The organic layer was washed

with brine, dried over sodium sulfate, and evaporated under reduce

pressure. Purification by flash chromatography gave 9 (5.49 g 89%)

as a white foam.

To a solution of 9 (5 g, 16.2 mmol) and trifluoroacetic acid (14

mL) in 20 mL of dichloroethane (14 mL) at room temperature under

nitrogen was added 3-methyl-3H-imidazole-4-carboxaldehyde (5.37

g, 48.6 mmol). The mixture was stirred for 1 h at room temperature,

and then triethylsilane (7.75 mL, 48.6 mmol) was added dropwise.

The mixture was heated in an oil bath at 45 °C for 15 h. The volatile

materials were removed under vacuum. The reaction mixture was

diluted with ethyl acetate and washed with aqueous NaHCO₃, water,

and brine solution. The organic layer was dried over MgSO₄,

filtered, and concentrated. The crude residue was purified on a flash

silica column to afford 10 (3.1 g, 47%).

A solution of [6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-

1,2,3,4-tetrahydro-quinolin-3-yl]-carbamic acid benzyl ester 10 (1.3

g, 3 mmol), 15 mL methanol, and 10% Pd/C catalyst (0.5 g) was

stirred under atmospheric pressure of hydrogen for 4 h. The catalyst

was filtered off, and the filtrate was concentrated to give 11 as an

off-white foam (790 mg, 92%).

To a suspension of 11 (0.55 g, 0.2 mmol) and Cs₂CO₃(1.34 g,

0.4 mmol) in dry DMF (3 mL) was added the appropriate alkyl

halide (0.2 mmol), and the mixture was stirred at room temperature

overnight under argon. After addition of water (10 mL), the solution

was extracted with ethyl acetate (3 × 10 mL). The organic layer

was extracted with brine (3 × 10 mL). The combined organic layers

were dried over MgSO₄and evaporated under reduce pressure. The

residue was purified by HPLC. Appropriate fractions were collected,

and the pure product 12 was obtained as the TFA salt.

Compound 12 (0.1 mmol) dissolved in dichloromethane (1.5 mL)

together with N,N-diisopropylethyl amine (0.2 mmol) was cooled

to 0 °C. Acetyl chloride or sulfonyl chloride (0.1.2 mmol) dissolved

in dichloromethane (0.5 mL) was added dropwise, and the mixture

was stirred for 1 h. Aqueous NH₄OH (1 mL) was added to the

reaction mixture. After being stirred for an additional 15 min, the

reaction mixture was diluted with ethyl acetate (50 mL) and washed

with brine solution. The organic layer was dried over MgSO₄and

evaporated under reduced pressure, yielding the crude amide 13,

which was purified by HPLC. The appropriate fractions were

combined, concentrated in vacuo, and lyophilized to give the

corresponding compounds as the trifluoroacetate salt.

4-{[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-ylamino]-methyl}-piperidine-1-carboxylic Acid

1

Methyl Ester (12). H NMR (300 MHz, methanol-d₄) δ 8.87 (s,

1H), 7.43 (s, 1H), 7.38 (dd, J ) 2.1, 8.7 Hz, 1H), 7.33 (s, 1H),

6.81 (d, J ) 8.7 Hz, 1H), 4.84 (d, J ) 17.7 Hz, 1H), 4.68 (d, J )

17.7 Hz, 1H), 3.89-4.08 (m, 3H), 3.82 (s, 3H), 3.65 (s, 3H), 3.51-

3.62 (m, 2H), 3.21-3.26 (m, 2H), 3.11-3.18 (m, 1H), 2.79-2.87

(m, 3H), 1.68-1.88, (m, 3H), 1.05-1.17 (m, 2H). MS m/z 423.4

(M + H⁺).

N-[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-N-(2-fluoro-benzyl)-4-methoxy-benzene-

1

sulfonamide (215). H NMR (300 MHz, methanol-d₄) δ 8.91 (s,

1H), 7.83 (d, J ) 9.1 Hz, 2H), 7.49-7.52 (m, 1H), 7.28-7.33 (m,

3H), 7.16-7.19 (m, 2H), 7.1 (d, J ) 9.0 Hz, 2H), 6.96-7.03 (m,

1H), 6.71 (d, J ) 9.0 Hz, 1H), 4.30-4.61 (m, 5H), 3.91 (s, 3H),

3.81 (s, 3H), 3.30-3.39 (m, 2H), 2.94-3.04 (m, 1H), 2.75 (dd, J

) 4.8, 15.6 Hz, 1H). MS m/z 546.5 (M + H⁺).

1-Methyl-1H-pyrazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(2-

fluoro-benzyl)-amide (213). ¹H NMR (300 MHz, methanol-d₄) δ

8.91 (s, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 7.56-7.61 (m, 1H), 7.27-

7.36 (m, 4H), 7.14-7.22 (m, 1H), 7.01-7.09 (m, 1H), 6.72 (d, J

) 8.4 Hz, 1H), 4.32-4.59 (m, 5H), 3.96 (s, 3H), 3.82 (s, 3H),

3.30-3.39 (m, 2H), 3.03-3.12 (m, 1H), 2.86 (dd, J ) 4.8, 15.6

Hz, 1H). MS m/z 520.4 (M + H⁺).

3-Methyl-3H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(4-

methanesulfonyl-benzyl)-amide (221). ¹H NMR (300 MHz,

methanol-d₄) δ 8.89 (s, 1H), 7.93 (d, J ) 8.2 Hz, 2H), 7.83 (s,

1H), 7.76 (s, 1H), 7.62 (d, J ) 8.4 Hz, 2H), 7.31-7.35 (m, 2H),

7.26 (s, 1H), 6.68 (d, J ) 8.7 Hz, 1H), 4.39-4.68 (m, 5H), 3.81

(s, 6H), 3.40-3.46 (m, 2H), 3.15 (s, 3H), 3.03-3.11 (m, 1H), 2.86

(m, 1H). MS m/z 580.5 (M + H⁺).

N-[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-N-(4-methanesulfonyl-benzyl)-benzene-

1

sulfonamide (218). H NMR (300 MHz, methanol-d₄) δ 8.91 (s

1H), 7.92-7.96 (m, 4H), 7.67-7.72 (m, 5H), 7.31 (dd, J ) 2.1,

8.4 Hz, 1H), 7.27 (s, 1H), 7.16 (s, 1H), 6.63 (d, J ) 8.4 Hz, 1H),

4.35-4.70 (m, 5H), 3.82 (s, 3H), 3.41-3.46 (m, 2H), 3.17 (s, 3H),

2.95-3.05 (m, 1H), 2.79-2.82 (m, 1H). MS m/z 576.6 (M + H⁺).

4-({[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-ethanesulfonyl-amino}-methyl)-piperi-

dine-1-carboxylic Acid Methyl Ester (200). ¹H NMR (300 MHz,

methanol-d₄) δ 8.93 (s, 1H), 7.42 (s, 1H), 7.42 (s, 1H), 7.33 (dd,

J ) 1.8, 8.4 Hz, 1H), 6.82 (d, J ) 8.7 Hz, 1H), 4.79 (d, J ) 18

Hz, 1H), 4.70 (d, J ) 18 Hz, 1H), 4.05-4.18 (m, 3H), 3.92 (s,

3H), 3.65 (s, 3H), 3.51-3.56 (m, 2H), 3.12-3.24 (m, 6H), 2.71-

2.78 (m, 2H), 1.72-1.84 (m, 3H), 1.34 (t, J ) 7.5 Hz, 3H), 1.05-

1.14 (m, 2H). MS m/z 515.4 (M + H⁺).

(6-Cyano-1,2,3,4-tetrahydro-quinolin-3-yl)-carbamic Acid Ben-

zyl Ester (9). ¹H NMR (300 MHz, methanol-d₄) δ 7.02-7.15 (m,

7H), 6.58 (d, J ) 8 Hz, 1H), 5.09 (s, 2H), 3.94-3.98 (m, 1H),

3.45 (m, 1H), 3.20 (m, 1H), 2.99 (dd J ) 4.2, 16.5 Hz, 1H), 2.74

(ddd, J ) 2.1, 4.8, 16.5 Hz, 1H). MS m/z 308.2 (M + H⁺).

[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-carbamic Acid Benzyl Ester (10). ¹H

NMR (300 MHz, CD₃OD) δ 7.61 (s, 1H), 7.31-7.38 (m, 7H) 6.87

(d, J ) 8.7 Hz, 1H), 6.83 (s, 1H), 5.07 (s, 2H), 4.59 (s, 2H), 4.00-

4.02 (m, 1H), 3.64 (s, 3H), 3.36 (dd, J ) 2.7, 12 Hz, 1H), 3.23

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(3-methyl-3H-imidazole-4-sulfonyl)-amino]-

methyl}-piperidine-1-carboxylic Acid Methyl Ester (191). H

NMR (300 MHz, methanol-d₄) δ 8.93 (s 1H), 7.76 (s, 1H), 7.74

(s, 1H), 7.45 (s, 1H), 7.33 (dd, J ) 1.8, 8.4 Hz, 1H), 7.32 (s, 1H),

1

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4601

6.82 (d, J ) 8.7 Hz, 1H), 4.78 (d, J ) 17.4 Hz, 1H), 4.70 (d, J )

17.4 Hz, 1H), 4.32-4.41 (m, 1H), 3.99-4.1 (m, 2H), 3.92 (s, 3H),

3.80 (s, 3H), 3.65 (s, 3H), 3.51-3.56 (2H), 2.96-3.14 (m, 4H),

2.71-2.78 (m, 2H), 1.71-1.88 (m, 3 H), 1.00-1.13 (m, 2H). MS

m/z 567.5 (M + H⁺).

4-({(Benzo[1,2,5]thiadiazole-4-sulfonyl)-[6-cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-amino}-

methyl)-piperidine-1-carboxylic Acid Methyl Ester (188). ¹H

NMR (300 MHz, methanol-d₄) δ 8.94 (s 1H), 8.32-8.35 (m, 1H),

8.32 (s, 1H), 7.08-7.85 (m, 1H), 7.42 (s, 1H), 7.35 (dd, J ) 1.8,

8.7 Hz, 1H), 7.24 (s, 1H), 6.82 (d, J ) 8.7 Hz, 1H), 4.78 (d, J )

18 Hz, 1H), 4.62 (d, J ) 18 Hz, 1H), 4.04-4.08 (m, 3H), 3.91 (s,

3H), 3.66 (s, 3H), 3.49-3.51 (m, 3H), 3.03-3.10 (m, 2H), 2.61-

2.73 (m, 3H), 1.71-1.88 (m, 3 H), 1.02-1.14 (m, 2H). MS m/z

567.5 (M + H⁺).

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(3,4-dihydro-2H-benzo[b][1,4]dioxepine-

7-sulfonyl)-amino]-methyl}-piperidine-1-carboxylic Acid Methyl

Ester (204). ¹H NMR (300 MHz, methanol-d₄) δ 8.94 (s, 1H), 7.45

(s, 1H), 7.39 (dd, J ) 2.1, 8.7 Hz, 1H), 7.36 (dd, J ) 2.1, 8.7 Hz,

1H), 7.35 (d, J ) 2.1 Hz, 1H), 7.29 (s, 1H), 7.25 (d, J ) 8.7 Hz,

1H), 7.10 (d, J ) 8.7 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 1H), 4.64 (d,

J ) 16.7 Hz, 1H), 4.51 (d, J ) 16.7 Hz, 1H), 4.24-4.33 (m, 4H),

4.04-4.14 (m, 3H), 3.85 (s, 3H), 3.64 (s, 3H), 3.16-3.19 (m, 1H),

2.99-3.03 (m, 3H), 2.63-2.80 (m, 4H), 2.21-2.29 (m, 2H), 1.68-

1.78 (m, 3H), 1.00-1.06 (m, 2H). MS m/z 635.7 (M + H⁺).

4-({(Benzo[1,2,5]oxadiazole-4-sulfonyl)-[6-cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-amino}-

methyl)-piperidine-1-carboxylic Acid Methyl Ester (205). ¹H

NMR (300 MHz, methanol-d₄) δ 8.94 (s, 1H), 8.27-8.29 (m, 1H),

8.19-8.22 (m, 1H), 7.68 (s, 1H), 7.40-7.49 (m, 1H), 7.35 (dd, J

) 1.8, 8.7 Hz, 1H), 7.29 (s, 1H), 6.82 (d, J ) 8.7 Hz, 1H), 4.78 (d,

J ) 16.7 Hz, 1H), 4.62 (d, J ) 16.7 Hz, 1H), 4.04-4.08 (m, 3H),

3.91 (s, 3H), 3.66 (s, 3H), 3.49-3.51 (m, 3H), 3.03-3.10 (m, 2H),

2.61-2.73 (m, 3H), 1.71-1.88 (m, 3H), 1.02-1.14 (m, 2H). MS

m/z 605.4 (M + H⁺).

7.48 (d, J ) 2.0 Hz), 7.42 (s, 1H) 6.85 (d, J ) 8.7 Hz, 1H), 4.78

(d, J ) 16.7 Hz, 1H), 4.62 (d, J ) 16.7 Hz, 1H), 4.08-4.30 (m,

3H), 3.95 (s, 3H), 3.75 (s, 3H), 3.51-3.72 (m, 4H), 3.10-3.40

(m, 4H), 2.80-3.02 (m, 2H), 2.68-2.73 (m, 1H), 1.75-2.01 (m,

3H), 1.10-1.30 (brm, 6H). MS m/z 527.4 (M + H⁺).

3,4-Dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonic Acid [6-Cy-

ano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-

quinolin-3-yl]-(4-methanesulfonyl-benzyl)-amide (223). ¹H NMR

(300 MHz, methanol-d₄) δ 8.94 (s, 1H), 7.87 (d, J ) 8.1 Hz, 2H),

7.62 (d, J ) 8.1 Hz, 2H), 7.45 (s, 1H), 7.39 (dd, J ) 2.1, 8.7 Hz,

1H), 7.36 (dd, J ) 2.1, 8.7 Hz, 1H), 7.35 (d, J ) 2.1 Hz, 1H), 7.29

(s, 1H), 7.25 (d, J ) 8.7 Hz, 1H), 7.10 (d, J ) 8.7 Hz, 1H), 6.68

(d, J ) 8.7 Hz, 1H), 4.64 (d, J ) 16.7 Hz, 1H), 4.51 (d, J ) 16.7

Hz, 1H), 4.24-4.33 (m, 4H), 4.04-4.14 (m, 2H), 3.85 (s, 3H),

3.20 (s, 3H), 2.95-3.05 (m, 1H), 1.12-1.25 (m, 2H). MS m/z 648.5

(M + H⁺).

3-Methyl-thiophene-2-sulfonic Acid [6-Cyano-1-(3-methyl-

3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-(4-

methanesulfonyl-benzyl)-amide (224). ¹H NMR (300 MHz,

methanol-d₄) δ 8.87 (s, 1H), 7.98 (d, J ) 8.1 Hz, 2H), 7.72 (d, J

) 5.1 Hz, 1H), 7.61 (dd, J ) 1.8, 8.7 Hz, 1H), 7.35 (d, J ) 8.7

Hz, 1H), 7.25 (m, 2H), 7.07 (d, J ) 5.1 Hz, 1H), 6.70 (d, J ) 8.7

Hz, 1H) 4.75 (d, 2H), 4.53-4.55 (m, 1H), 4.51 (d, J ) 17.7 Hz,

1H), 4.48 (d, J ) 17.7 Hz, 1H), 3.79 (s, 3H), 3.10-3.25 (m, 7H),

2.95-3.05 (m, 1H), 2.49 (s, 3H). MS m/z 596.6 (M + H⁺).

N-[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-2-dimethylamino-N-(2-fluoro-benzyl)-ac-

1

etamide (248). H NMR (300 MHz, methanol-d₄) δ 8.78 (s, 1H),

7.01-7.34 (m,7 H), 6.68 (d, J ) 8.7 Hz, 1H), 4.42-4.61 (m, 3H),

4.25 (d, J ) 15.9 Hz, 1H), 4.18 (d, J ) 15.9 Hz, 1H), 3.74 (s, 3H),

3.41-3.59 (m, 2H), 3.19 (s, 2H), 2.94-3.04 (m, 1H), 2.86 (m, 7

H). MS m/z 461.3 (M + H⁺).

N-[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-N-(2-fluoro-benzyl)-3-methylsulfanyl-

propionamide (247). ¹H NMR (300 MHz, methanol-d₄) δ 8.84 (s,

1H), 7.01-7.34 (m, 7H), 6.78 (d, J ) 7.6 Hz, 1H), 4.42-4.77 (m,

5H), 3.84 (s, 3H), 3.41-3.59 (m, 2H), 2.94-3.12 (m, 6H), 2.06

(s, 3H). MS m/z 478.4 (M + H⁺).

4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(2-oxo-2H-chromene-6-sulfonyl)-amino]-

1

methyl}-piperidine-1-carboxylic Acid Methyl Ester (206). H

General Procedure for the Synthesis of Compounds Accord-

ing to Scheme 4. 1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cy-

ano-1-(1-trityl-1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quin-

olin-3-yl]-amide (15). A solution of 14 (0.397 g, 1 mmol), N,N-

diisopropylethyl amine (2.37 mL, 2 mmol), and 3 mL of dry DMF

was stirred at room temperature for 30 min. To this solution was

added dropwise a solution of triphenylmethyl chloride (0.278 g, 1

mmol) dissolved in dry DMF (3 mL). The reaction mixture was

stirred at room temperature for 20 h. After addition of water (10

mL), the solution was extracted with dichloromethane (3 × 15 mL).

The combined organic layer was washed with brine (20 mL) and

the organic layer was dried over MgSO₄and evaporated under

reduce pressure, yielding the crude product, which was purified

on a silica gel column eluting with 10% methanol in ethyl acetate

to afford 15 (0.562 g, 88%). ¹H NMR (300 MHz, CDCl₃) δ 8.0 (s,

1H), 7.9 (s, 1H), 7.4 (s, 1H), 7.25-7.37 (m, 18 H), 6.48 (d, J )

8.7 Hz, 1H), 4.5 (d, J ) 16.2 Hz, 1H), 4.23 (d, J ) 16.2 Hz, 1H),

4.00-4.09 (m, 1H), 3.70 (s, 3H), 3.51-3.61 (m, 1H), 3.31-3.34

(m, 1H), 3.09-3.12 (m, 1H), 2.86-3.07 (m, 1H). MS m/z 640.3

(M + H⁺).

NMR (300 MHz, methanol-d₄) δ 8.93 (s, 1H), 8.22 (d, J ) 2.1

Hz, 1H), 8.07 (dd, J ) 2.1, 8.7 Hz, 1H), 8.04 (d, J ) 9.9 Hz, 1H),

7.53 (d, J ) 8.7 Hz, 1H), 7.41 (d, J ) 2.1 Hz, 1H), 7.37 (dd, J )

2.1, 8.7 Hz, 1H), 7.26 (s, 1H), 6.78 (d, J ) 8.7 Hz, 1H), 6.58 (d,

J ) 9.9 Hz, 1H), 4.75 (d, J ) 16.7 Hz, 1H), 4.68 (d, J ) 16.7 Hz,

1H), 4.04-4.08 (m, 3H), 3.90 (s, 3H), 3.66 (s, 3H), 3.49-3.51

(m, 1H), 3.03-3.15 (m, 3H), 2.61-2.80 (m, 3H), 1.60-1.71 (m,

3H), 1.02-1.16 (m, 2H). MS m/z 631.4 (M + H⁺).

4-({(4-Carboxy-furan-3-sulfonyl)-[6-cyano-1-(3-methyl-3H-

imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-amino}-

methyl)-piperidine-1-carboxylic Acid Methyl Ester (197). ¹H

NMR (300 MHz, methanol-d₄) δ 8.93 (s, 1H), 7.43(dd, J ) 2.1

Hz, 1H), 7.30 (d, J ) 8.7 Hz, 1H), 7.38 (d, J ) 6.0 Hz, 1H), 7.36

(s, 1H), 7.25 (d, J ) 6.0 Hz, 1H), 6.83 (d, J ) 8.7 Hz, 1H), 6.88

(d, J ) 8.7 Hz, 1H), 4.78 (d, J ) 16.7 Hz, 1H), 4.62 (d, J ) 16.7

Hz, 1H), 4.08-4.04 (m, 3H), 3.91 (s, 3H), 3.66 (s, 3H), 3.49-

3.51 (m, 3H), 3.03-3.10 (m, 2H), 2.61-2.73 (m, 3H), 1.71-1.88

(m, 3H), 1.02-1.14 (m, 2H). MS m/z 597.4 (M + H⁺).

4-({[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-methanesulfonylmethanesulfonyl-amino}-

methyl)-piperidine-1-carboxylic Acid Methyl Ester (207). ¹H

NMR (300 MHz, methanol-d₄) δ 8.96 (s, 1H), 7.49 (dd, J ) 2.1,

8.7 Hz, 1H), 7.47 (d, J ) 2.1 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 1H),

5.15 (s, 2H), 4.68 (d, J ) 16.7 Hz, 1H), 4.62 (d, J ) 16.7 Hz, 1H),

4.40-4.25 (m, 1H), 4.04-4.14 (m, 2H), 3.92 (s, 3H), 3.73 (s, 3H),

3.55-3.61 (m, 3H), 3.25 (s, 3H), 3.16-3.19 (m, 1H), 2.99-3.03

(m, 2H), 2.63-2.80 (m, 2H), 2.21-2.29 (m, 1H), 1.68-1.78 (m,

2H), 1.05-1.16 (m, 2H). MS m/z 579.2 (M + H⁺).

A solution of 16 (0.21 mmol), dichloromethane (3 mL), and

trifluoroacetic acid (0.5 mL) was stirred for 30 min. The reaction

mixture was filtered to remove trityl alcohol, and the residue was

washed with dichloromethane. The filtrate and washings were

combined and then evaporated to dryness via rotary evaporation.

The residue was purified by HPLC.

1-Methyl-1H-imidazole-4-sulfonic Acid Benzyl-[6-cyano-1-

(3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-

1

amide (253). H NMR (300 MHz, methanol-d₄) δ 8.86 (s, 1H),

4-({[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-3-yl]-cyclopropanesulfonyl-amino}-methyl)-

piperidine-1-carboxylic Acid Methyl Ester (202). ¹H NMR (300

MHz, methanol-d₄) δ 8.94 (s, 1H), 7.52 (dd, J ) 1.8, 8.7 Hz, 1H),

7.83 (s, 1H), 7.71 (s, 1H), 7.18-7.39 (m, 8 H), 6.71 (d, J ) 9.7

Hz, 1H), 4.29-4.73 (m, 5H), 3.80 (s, 3H), 3.36-3.42 (m, 1H),

3.18-3.26 (m, 1H), 3.12 (dd, J ) 8.7, 15.6 Hz, 1H), 2.89 (dd, J )

3.3, 15.3 Hz, 1H). MS m/z 488.1 (M + H⁺).

4602 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Bendale et al.

1-Methyl-1H-imidazole-4-sulfonic Acid (2-Bromo-allyl)-[6-

cyano-1-(3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinolin-

3-yl]-amide (252). H NMR (300 MHz, methanol-d₄) δ 8.86 (s,

1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.28 (s, 1H), 7.33 (dd, J ) 2.1, 9.0

Hz, 1H), 7.28 (s, 1H), 6.65 (d, J ) 8.7 Hz, 1H), 6.04 (s, 1H), 5.65

(s, 1H), 4.79 (d, J ) 17.1 Hz, 1H), 4.62 (d, J ) 17.1 Hz, 1H),

4.39-4.59 (m, 1H), 4.19 (d, J ) 17.1 Hz, 1H) 4.0 (d, J ) 17.1

Hz, 1H), 3.81 (s, 3H), 3.55-3.62 (m, 1H), 3.42-3.47 (m, 1H),

3.07-3.14 (m, 1H), 2.97(dd, J ) 4.5, 15.9 Hz, 1H). MS m/z 518.2

(M + H⁺).

3.37-3.33 (m, 1H), 3.19-3.16 (m, 1H), 3.09-3.02 (m, 1H), 2.77-

2.72 (m, 1H), 1.43 (s, 9H).

1

To a stirred solution of the phenyl derivative 22 (120 mg, 0.37

mmol) in CH₂Cl₂(1.6 mL) at room temperature, trifluoroacetic acid

(0.4 mL) was added, and the reaction mixture was stirred for 2 h.

The solution was concentrated under reduced pressure, and the crude

amine (trifluoroacetate salt) 23 was taken to the next step without

further purification.

To a mixture of the amine 23 in CH₂Cl₂(2 mL), diisopropyl-

ethylamine (0.5 mL) was added and the reaction mixture was stirred

at room temperature for 0.5 h. The appropriate sulfonyl chloride

(0.37 mmol) was added, and the reaction mixture was stirred for

an additional 2 h. The reaction mixture was partitioned between

water and ethyl acetate. The organic layer was washed with brine,

Synthesis of 255 According to Scheme 5. 4-{[(6-cyano-1,2,3,4-

tetrahydro-quinolin-3-yl)-(pyridine-2-sulfonyl)-amino]-methyl}-

1

piperidine-1-carboxylic Acid Methyl Ester (18). H NMR (300

MHz, methanol-d₄) δ 8.70 (d, J ) 7.5 Hz, 1H), 8.08 (td, J ) 1.8,

7.8 Hz, 1H), 8.0 (dt, J ) 1.2, 7.8 Hz, 1H), 7.66 (ddd, J ) 1.5, 4.8,

7.5 Hz, 1H), 7.43 (d, J ) 1.2 Hz, 1H), 7.38 (dd, J ) 2.1, 8.7 Hz,

1H), 6.81 (d, J ) 8.7 Hz, 1H), 4.38-4.51 (m, 1H), 4.08-4.16 (m,

2H), 3.65 (s, 3H), 3.51-3.62 (m, 2H), 3.21-3.26 (m, 2H), 3.11-

3.18 (m, 1H), 2.79-2.87 (m, 3H), 1.68-1.88, (m, 3H), 1.05-1.17

(m, 2H). MS m/z 470.2 (M + H⁺).

dried (Na₂SO₄), and evaporated under reduced pressure. Purification

by flash chromatography gave 24 (89%) as a pale yellow solid. ¹H

NMR (methanol-d₄) δ 7.93 (s, 1H), 7.76 (s, 1H), 7.69 (d, J ) 1.2

Hz, 1H), 7.49 (dd, J ) 1.2, 8.4 Hz, 2H), 7.35 (t, J ) 7.5 Hz, 2H),

7.22 (d, J ) 7.5 Hz, 1H), 7.11 (s, 1H), 6.60 (d, J ) 8.4 Hz, 1H),

3.77 (s, 3H), 3.74-3.69 (m, 1H), 3.39-3.36 (m, 1H), 3.09 (dd, J

) 8.1, 11.4 Hz, 1H), 2.93 (dd, J ) 4.5, 15.6 Hz, 1H), 2.76 (dd, J

) 8.1, 15.6 Hz, 1H).

4-{[[6-Cyano-1-(3-methyl-3H-imidazole-4-sulfonyl)-1,2,3,4-

tetrahydro-quinolin-3-yl]-(pyridine-2-sulfonyl)-amino]-methyl}-

piperidine-1-carboxylic Acid Methyl Ester (255). A solution of

18 (47 mg, 0.1 mmol), 3-methyl-3H-imidazole-4-sulfonyl chloride

hydrochloride salt (26 mg, 0.12 mmol, Apollo Scientific Intermedi-

ates), N,N-dimethyl pyridine (15 mg, 0.12 mmol), and 3 mL of

dry acetonitrile was refluxed overnight under nitrogen. Then the

reaction mixture was quenched with water and extracted with

dichloromethane (3 × 10 mL). The combine organic layer was

washed with brine (10 mL), and the organic layer was dried over

MgSO₄and evaporated under reduced pressure, yielding the crude

product, which was purified by HPLC. ¹H NMR (300 MHz,

methanol-d₄) δ 8.76 (d, J ) 4.8 Hz, 1H), 8.08 (td, J ) 1.8, 8.1 Hz,

1H), 8.0 (dt, J ) 1.2, 7.8 Hz, 1H), 7.89 (d, J ) 8.4 Hz, 1H), 7.81

(s, 1H), 7.66 (m, 2H), 7.48 (dd, J ) 2.1, 8.7 Hz, 1H), 7.43 (s, 1H),

4.32-4.38 (m, 1H), 4.14-4.25 (m, 1H), 4.09-4.13 (m, 2H), 3.72

(s, 3H), 3.68 (s, 3H), 3.51-3.62 (m, 1H), 3.21-3.26 (m, 2H), 3.11-

3.18 (m, 1H), 2.79-2.87 (m, 3H), 1.92-1.99 (m, 1H), 1.68-1.88

(m, 2H), 1.05-1.17 (m, 2H). MS m/z 614.4 (M + H⁺).

[[1-(3-Benzyl-3H-imidazol-4-ylmethyl)-6-cyano-1,2,3,4-tet-

rahydro-quinolin-3-yl]-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-

acetic Acid tert-Butyl Ester (254). ¹H NMR (300 MHz, methanol-

d₄) δ 8.86 (s, 1H), 7.11-7.50 (m, 10 H), 6.55 (d, J) 8.5 Hz, 1H),

5.12 (s, 2H), 4.62-4.78 (m, 2H), 4.39-4.59 (m, 1H), 4.19 (d, J)

17.1 Hz, 1H) 4.0 (d, J) 17.1 Hz, 1H), 3.81 (s, 3H), 3.55-3.62 (m,

1H), 3.42-3.47 (m, 1H), 3.07-3.14 (m, 1H), 2.97 (m, 1H), 1.42

(s, 9H). MS m/z 602.2 (M + H⁺).

To a stirred solution of the sulfonamide 24 (0.33 mmol) in

dichloroethane (1 mL) and trifluoroacetic acid (1 mL) was added

3-methyl-3H-imidazole-4-carbaldehyde (91 mg, 0.83 mmol) at room

temperature, and the reaction mixture was heated to 50 °C for 1 h.

Triethylsilane (0.13 mL, 0.83 mmol) was added and stirring was

continued for an additional 48 h. Volatile materials were removed

under vacuum, and the reaction mixture was diluted with ethyl

acetate, washed with aqueous NaHCO₃solution, water, and brine,

dried (Na₂SO₄), filtered, and concentrated in vacuum. Purification

by flash chromatography afforded 25 (50 mg, 33%) as a pale yellow

foam. ¹H NMR (methanol-d₄) δ 8.89 (s, 1H), 8.06 (s, 1H), 7.67 (s,

1H), 7.49 (t, J ) 7.8 Hz, 3H), 7.37-7.33 (m, 3H), 7.24-7.20 (m,

2H), 6.85 (d, J ) 7.8 Hz, 1H), 4.74 (d, J ) 17.1 Hz, 1H), 4.57 (d,

J ) 17.1 Hz, 1H), 3.93-3.71 (m, 8H), 3.35-3.31 (m, 1H), 3.04

(dd, J ) 4.5, 15.6 Hz, 1H), 2.76 (dd, J ) 6.3, 15.9 Hz, 1H).

A mixture of 25 (1 equiv), Cs₂CO₃(2 equiv), and the appropriate

bromide (1 equiv) in anhydrous DMF was stirred overnight at room

temperature. The reaction mixture was partitioned between water

and ethyl acetate. The organic layer was washed with brine, dried

(Na₂SO₄), and evaporated under reduced pressure. The crude residue

was purified by HPLC.

1-Methyl-1H-imidazole-4-sulfonic Acid [1-(3-Methyl-3H-imi-

dazol-4-ylmethyl)-6-phenyl-1,2,3,4-tetrahydro-quinolin-3-yl]-(2-

pyrrol-1-yl-ethyl)-amide (272). ¹H NMR (methanol-d₄) δ 7.74 (d,

J) 1.0 Hz, 1H), 7.70 (d, J ) 1.5 Hz, 1H), 7.53 (br s, 1H), 7.52-

7.50 (m, 2H), 7.39-7.33 (m, 3H), 7.26-7.22 (m, 1H), 7.17-7.16

(m, 1H), 6.90 (d, J ) 8.5 Hz, 1H), 6.80 (br s, 1H), 6.63 (t, J ) 2.0

Hz, 2H), 6.04 (t, J ) 2.0 Hz, 2H), 4.44 (d, J ) 15.5 Hz, 1H), 4.27

(d, J) 15.5 Hz, 1H), 4.22-4.17 (m, 4H), 3.75 (s, 3H), 3.63 (s,

3H), 3.48-3.44 (m, 2H), 2.91 (dd, J ) 4.5, 11.5 Hz, 1H), 2.76-

2.66 (m, 2H). MS m/z 556.3 (M + H⁺).

N-tert-Butyl-2-{(1-methyl-1H-imidazole-4-sulfonyl)-[1-(3-meth-

yl-3H-imidazol-4-ylmethyl)-6-phenyl-1,2,3,4-tetrahydro-quino-

lin-3-yl]-amino}-acetamide (267). ¹H NMR (methanol-d₄) δ 8.87

(s, 1H), 7.78 (d, J ) 1.2 Hz, 2H), 7.45 (d, J ) 7.2 Hz, 2H), 7.41

(s, 1H), 7.32 (t, J ) 7.5 Hz, 3H), 7.19 (t, J ) 7.2 Hz, 2H), 6.82 (d,

J ) 7.8 Hz, 1H), 4.65 (d, J ) 15.6 Hz, 1H), 4.52 (d, J ) 15.6 Hz,

1H), 4.36-4.18 (m, 1H), 3.94-3.75 (m, 9H), 3.31-3.40 (m, 1H),

3.02-2.85 (m, 2H), 1.31 (m, 9H). MS m/z 576.4 (M + H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid (4-Methanesulfonyl-

benzyl)-[1-(3-methyl-3H-imidazol-4-ylmethyl)-6-phenyl-1,2,3,4-

tetrahydroquinolin-3-yl]-amide (278). ¹H NMR (300 MHz,

methanol-d₄) δ 8.87 (s, 1H), 7.92 (d, J ) 8.4 Hz, 2H), 7.85 (s,

1H), 7.80 (s, 1H), 7.62 (d, J ) 8.4 Hz, 2H), 7.52 (d, J ) 8.4 Hz,

2H), 7.40-7.30 (m, 4H), 7.28-7.22 (m, 2H), 6.72 (d, J ) 8.4 Hz,

1H), 4.75 (d, J ) 16.5 Hz, 2H), 4.55-4.50 (m, 1H), 4.48 (d, J )

17.4 Hz, 1H), 4.35 (d, J ) 16.5 Hz, 1H), 3.85 (s, 3H), 3.80 (s,

3H), 3.42-3.36 (m, 2H), 3.12 (s, 3H), 3.08-2.95 (m, 2H). MS

m/z 631.6 (M + H⁺).

4-{[(6-Cyano-1-pyridin-3-ylmethyl-1,2,3,4-tetrahydro-quino-

lin-3-yl)-(pyridine-2-sulfonyl)-amino]-methyl}-piperidine-1-car-

boxylic Acid Methyl Ester (256). ¹H NMR (300 MHz, methanol-

d₄) δ 8.84-8.89 (m, 2H), 8.70-8.75 (m, 1H), 8.49-8.51 (m, 1H),

8.03-8.19 (m, 3H), 7.68 (ddd, J ) 1.5, 4.8, 7.5 Hz, 1H), 7.43 (d,

J ) 1.2 Hz, 1H), 7.38 (dd, J ) 2.1, 8.7 Hz, 1H), 6.81 (d, J ) 8.7

Hz, 1H), 4.68-4.83 (m, 2H), 4.38-4.51 (m, 1H), 4.08-4.16 (m,

2H), 3.65 (s, 3H), 3.51-3.62 (m, 2H), 3.21-3.26 (m, 2H), 3.11-

3.18 (m, 1H), 2.79-2.87 (m, 3H), 1.68-1.88, (m, 3H), 1.05-1.17

(m, 2H). MS m/z 561.4 (M + H⁺).

General Procedure for the Synthesis of Compounds Accord-

ing to Scheme 6. A suspension of the aryl bromide 21 (500 mg,

1.53 mmol), phenyl boronic acid (559 mg, 4.58 mmol), and tetrakis

triphenylphosphine palladium (177 mg, 10 mol %) in dimethoxy-

ethane (15 mL) was thoroughly degassed and stirred under argon.

Deionized water (3 mL) and barium hydroxide octahydrate (1.45

gm, 4.58 mmol) were added, and the reaction mixture was heated

at reflux for 2 h. The reaction mixture was diluted with ethyl acetate,

washed with water and brine, dried (Na₂SO₄), and concentrated

under reduced pressure. The residue was purified by flash chro-

matography over a silica gel column to give 22 (120 mg, 45%) as

1

a colorless solid. H NMR (CDCl₃) δ 7.49 (d, J ) 8.1 Hz, 1H),

7.36 (t, J ) 7.8 Hz, 2H), 7.23 (t, J ) 7.4 Hz, 4H), 6.51 (d, J ) 8.1

Hz, 1H), 5.04 (d, J ) 7.5 Hz, 1H), 4.11 (br s, 1H), 3.95 (s, 1H),

Protein Farnesyltransferase Inhibitors Antimalarials

Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4603

1-Methyl-1H-imidazole-4-sulfonic Acid (2-Bromo-allyl)-[1-(3-

methyl-3H-imidazol-4-ylmethyl)-6-phenyl-1,2,3,4-tetrahydro-

quinolin-3-yl]-amide (264). H NMR (300 MHz, methanol-d₄) δ

1H), 4.62 (d, J ) 16.8 Hz, 1H), 3.92 (s, 3H), 3.90-3.82 (m, 1H),

3.80 (s, 3H), 3.55-3.45 (m, 1H), 3.43-3.38 (m, 1H), 3.03 (dd, J

) 4.8, 16.5 Hz, 1H), 2.76 (dd, J ) 6.3, 16.2 Hz, 1H). MS m/z

486.4 (M + H⁺).

To a mixture of the acid 27 (430 mg, 1.0 m mol) above, benzyl

amine (107 mg, 1 mmol), and N,N-dimethylamino pyridine (18 mg,

0.15 mmol) in DMF was added EDC (287 mg, 1.5 mmol), and the

mixture was stirred at room temperature for 20 h. The mixture was

concentrated under reduced pressure, and aqueous NaHCO₃solution

(20 mL) was added. The mixture was extracted with 10% MeOH

in CHCl₃(3 × 30 mL), and the organic layer was dried (Na₂SO₄)

and evaporated under reduced pressure. The crude product was

purified by flash chromatography to afford 28 (220 mg, 38%).

3-(1-Methyl-1H-imidazole-4-sulfonylamino)-1-(3-methyl-3H-

imidazol-4-ylmethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic

Acid Benzylamide (28). ¹H NMR (300 MHz, methanol-d₄) δ 8.90

(s, 1H), 7.76 (s, 1H), 7.70 (s, 1H), 7.62 (dd, J ) 2.1, 8.7 Hz, 1H),

7.50 (d, J ) 2.1 Hz, 1H), 7.46 (s, 1H), 7.36-7.30 (m, 5H), 6.82

(d, J ) 8.7 Hz, 1H), 4.75 (d, J ) 16.8 Hz, 1H), 4.62 (d, J ) 16.8

Hz, 1H), 4.55 (s, 2H), 3.92 (s, 3H), 3.90-3.82 (m, 1H), 3.80 (s,

3H), 3.53-3.48 (m, 1H), 3.43-3.39 (m, 1H), 3.03 (dd, J ) 4.8,

16.5 Hz, 1H), 2.75 (dd, J ) 6.3, 16.2 Hz, 1H).

1

8.92 (s, 1H), 7.80 (d, J ) 3.9 Hz, 2H), 7.55 (dd, J ) 1.2, 8.4 Hz,

2H), 7.45 (s, 1H), 7.40 (t, J ) 8.7 Hz, 3H), 7.32-7.20 (m, 2H),

6.90 (d, J ) 8.7 Hz, 1H), 6.10 (d, J ) 2.1 Hz, 1H), 5.65 (d, J )

2.1 Hz, 1H), 4.75 (d, J ) 16.8 Hz, 1H), 4.60 (d, J ) 17.1 Hz, 1H),

4.50-4.40 (m, 1H), 4.20 (d, J ) 18.0 Hz, 1H), 4.10 (d, J ) 18.0

Hz, 1H), 3.95 (s, 3H), 3.80 (s, 3H), 3.49-3.40 (m, 2H), 3.15-

3.05 (m, 1H), 2.87 (dd, ) 5.1, 15.6 Hz, 1H). MS m/z 583.0 (M +

H⁺).

1-Methyl-1H-imidazole-4-sulfonic Acid Ethyl-[1-(3-methyl-

3H-imidazol-4-ylmethyl)-6-phenyl-1,2,3,4-tetrahydro-quinolin-

1

3-yl]amide (259). H NMR (300 MHz, methanol-d₄) δ 8.90 (s,

1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.52 (dd, J ) 1.2, 8.7 Hz, 2H),

7.45 (s, 1H), 7.35 (t, J ) 7.2 Hz, 3H), 7.30-7.20 (m, 2H), 6.87 (d,

J ) 8.7 Hz, 1H), 4.75 (d, J ) 16.8 Hz, 1H), 4.57 (d, J ) 16.8 Hz,

1H), 4.47-4.37 (m, 1H), 3.95 (s, 3H), 3.80 (s, 3H), 3.45-3.25

(m, 4H), 3.20-3.10 (m, 1H), 2.90 (m, 1H), 1.25 (t, J ) 6.9 Hz,

3H). MS m/z 491.5 (M + H⁺).

{(1-Methyl-1H-imidazole-4-sulfonyl)-[1-(3-methyl-3H-imida-

zol-4-ylmethyl)-6-phenyl-1,2,3,4-tetrahydro-quinolin-3-yl]-amino}-

1

acetic Acid Methyl Ester (266). H NMR (300 MHz, methanol-

3-[(tert-Butylcarbamoyl-methyl)-(1-methyl-1H-imidazol-4-sul-

fonyl)-amino]-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-6-carboxylic Acid Benzylamide (291). Com-

pound 291 was prepared as described from the general procedure

for N-alkylation. ¹H NMR (300 MHz, methanol-d₄) δ 8.92 (s, 1H),

7.80 (s, 1H), 7.78 (s, 1H), 7.63 (dd, J ) 2.1, 8.7 Hz, 1H), 7.53 (d,

J ) 2.1 Hz, 1H), 7.42 (s, 1H), 7.36-7.30 (m, 5H), 6.82 (d, J )

8.7 Hz, 1H), 4.77 (d, J ) 16.8 Hz, 1H), 4.65 (d, J ) 17.4 Hz, 1H),

4.55 (s, 2H), 4.33-4.22 (m, 1H), 3.91 (s, 3H), 3.85 (s, 2H), 3.80

(s, 3H), 3.56-3.50 (m, 1H), 3.46-3.39 (m, 1H), 3.03 (dd, J )

5.1, 15.3 Hz, 1H), 2.86 (dd, J ) 5.1, 15.3 Hz, 1H), 1.4 (s, 9H).

MS m/z 633.8 (M + H⁺).

3-[(tert-Butylcarbamoyl-methyl)-(1-methyl-1H-imidazol-4-sul-

fonyl)-amino]-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-6-carboxylic Acid (289). Compound 289 was

prepared as described from general procedure for N-alkylation. ¹H

NMR (300 MHz, methanol-d₄) δ 8.92 (s, 1H), 7.82 (s, 1H), 7.79

(s, 1H), 7.62 (dd, J ) 2.1, 8.7 Hz, 1H), 7.52 (d, J ) 2.1 Hz, 1H),

7.42 (s, 1H), 6.80 (d, J ) 8.7 Hz, 1H), 4.75 (d, J ) 16.8 Hz, 1H),

4.65 (d, J ) 16.8 Hz, 1H), 4.35-4.25 (m, 1H), 3.92 (s, 3H), 3.85

(s, 2H), 3.80 (s, 3H), 3.60-3.51 (m, 1H), 3.50-3.40 (m, 1H), 3.03

(dd, J ) 4.8, 16.5 Hz, 1H), 2.80 (dd, J ) 6.3, 16.2 Hz, 1H), 1.40

(s, 9H). MS m/z 543.5 (M + H⁺).

Synthesis of 34 According to Scheme 8. Preparation of 1-[4-

(N-triphenylmethyl)imidazolyl]ethanol. To an ice-bath cooled

solution of 3.35 mL (10.0 mmol) of 3 M methyl magnesium

bromide in 40 mL dry ether was added a solution of 4-(N-

triphenylmethyl)-imidazole carboxaldehyde (1.69 g, 10 mmol) in

THF. After 1.5 h at ambient temperature, a concentrated solution

of 0.67 g (25 mmol) NH₄Cl in water was added to the reaction

mixture. The mixture was stirred for 1 h and filtered, and the solids

were washed with THF. The combined filtrate and washes were

washed with water and brine, dried over NaSO₄, and concentrated

in vacuo to afford the required compound.^{17 1}H NMR (300 MHz

CDCl₃) 7.42 (s, 1H), 7.30-7.39 (m, 9H), 7.10-7.21 (m, 6H), 6.85

(s, 1H), 4.85 (q, 1H), 1.5 (d, 3H). MS m/z 355.2 (M + H⁺).

d₄) δ 8.92 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.52 (dd, J ) 1.2, 8.4

Hz, 2H), 7.44 (s, 1H), 7.36 (t, J ) 7.5 Hz, 3H), 7.30-7.25 (m,

2H), 6.85 (d, J ) 8.7 Hz, 1H), 4.75 (d, J ) 16.8 Hz, 1H), 4.55 (d,

J ) 16.8 Hz, 1H), 4.50-4.40 (m, 1H), 4.15 (d, J ) 18.3 Hz, 1H),

4.08 (d, J ) 18.6 Hz, 1H), 3.95 (s, 3H), 3.80 (s, 3H), 3.70 (s, 3H),

3.55-3.45 (m, 2H), 3.05-2.90 (m, 2H). MS m/z 535.4 (M + H⁺).

General Procedure for the Synthesis of Compounds Accord-

ing to Scheme 7. General Procedure for the Conversion of

Nitrile (5) to Amide (28). To a stirred solution of nitrile 5 (441

mg, 1 mmol) in alcohol (8 mL) was slowly added concentrated

sulfuric acid (0.05 mL) at room temperature. The resulting solution

was stirred at 40 °C for 2 h. The mixture was poured into cold

aqueous 20% KHCO₃solution to neutralize the acid and precipitate

the product. The product was filtered, washed with cold water, and

dried under vacuum to give amides 28 (40-45%).

3-(1-Methyl-1H-imidazole-4-sulfonylamino)-1-(3-methyl-3H-

imidazol-4-ylmethyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic

1

Acid tert-Butylamide (28). H NMR (300 MHz, methanol-d₄) δ

8.90 (s, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.51 (dd, J ) 2.1, 8.7 Hz,

1H), 7.45 (s, 1H), 7.40 (d, J ) 2.1 Hz, 1H), 6.80 (d, J ) 8.7 Hz,

1H), 4.80 (d, J ) 16.8 Hz, 1H), 4.60 (d, J ) 16.8 Hz, 1H), 3.92 (s,

3H), 3.86-3.83 (m, 1H), 3.80 (s, 1H), 3.52-3.45 (m, 1H), 3.42-

3.35 (m, 1H), 3.0 (dd, J ) 4.8, 16.5 Hz, 1H), 2.74 (dd, J ) 6.3,

16.2 Hz, 1H), 1.45 (s, 9H) MS m/z 486.4 (M + H⁺).

3-[(tert-Butylcarbamoyl-methyl)-(1-methyl-1H-imidazol-4-sul-

fonyl)-amino]-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-

rahydro-quinolin-6-carboxylic Acid tert-Butylamide (285). The

compound was prepared using the general N-alkylation procedure

1

(5 to 2, Scheme 1). H NMR (300 MHz, methanol-d₄) δ 8.92 (s,

1H), 7.85 (s, 1H),7.80 (s, 1H), 7.52 (dd, J ) 2.1, 8.7 Hz, 1H), 7.43

(s, 1H), 7.40 (d, J ) 2.1 Hz, 1H), 6.79 (d, J ) 8.7 Hz, 1H), 4.75

(d, J ) 16.8 Hz, 1H), 4.63 (d, J ) 16.8 Hz, 1H), 4.33-4.25 (m,

1H), 3.92 (s, 3H), 3.87 (s, 2H), 3.81 (s, 3H), 3.57-3.51 (m, 1H),

3.44-3.40 (m, 1H), 3.03 (dd, J ) 4.5, 15.9 Hz, 1H), 2.80 (dd, J )

4.5, 15.9 Hz, 1H), 1.43 (s, 9H), 1.35 (s, 9H). MS m/z 599.5 (M +

H⁺).

General Procedure for the Conversion of Nitrile (5) to Acid

(27). A solution of 5 (441 mg, 1.0 m mol) in concentrated HCl (20

mL) was stirred at 80 °C for 2 h. The reaction mixture was cooled

to room temperature and then evaporated to dryness under reduced

pressure. The residue was dissolved in saturated LiOH solution (pH

9) and then evaporated to dryness under reduced pressure. The

residue was dissolved in 10% aqueous HCl solution (pH 2),

evaporated, and dried under vacuum to give the corresponding acid

27, which was used in the next step without further purification.

¹H NMR (300 MHz, methanol-d₄) δ 8.90 (s, 1H), 7.80 (s, 1H),

7.70 (s, 1H), 7.62 (dd, J ) 2.1, 8.7 Hz, 1H), 7.52 (d, J ) 2.1 Hz,

1H), 7.42 (s, 1H), 6.80 (d, J ) 8.7 Hz, 1H), 4.80 (d, J ) 16.8 Hz,

A mixture of 33 (47 mg, 0.1 mmol) and 1-(4-(N-triphenylmeth-

yl)imidazolyl)ethanol (17 mg, 0.05 mmol) in 5 mL of dry

acetonitrile was added methanesulfonyl chloride (34 mg, 0.3 mmol),

and the mixture was heated at 60 °C overnight under nitrogen.

Aqueous NaHCO₃and ethyl acetate were added. The organic layer

was washed with water and brine and dried over MgSO₄. The crude

product was purified by HPLC to give 34 as a mixture of isomers.¹⁸

¹H NMR (300 MHz, methanol-d₄) δ 8.95 (s, 1H), 8.94 (s, 1H),

8.72 (d, J ) 7.5 Hz, 1H), 8.68 (d, J ) 7.5 Hz, 1H), 7.90-8.10 (m,

4H), 7.59-7.70 (m, 4H), 7.31-7.48 (m, 4H), 6.95 (d, J ) 8.7 Hz,

1H), 6.91 (d, J ) 8.7 Hz, 1H), 5.50 (q, 1H), 5.40 (q, 1H), 4.38-

4.51 (m, 2H), 4.08-4.16 (m, 4H), 3.70 (s, 6H), 3.32-3.45 (m,

4604 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19

Bendale et al.

4H), 3.01-3.22 (m, 6H), 2.65-2.90 (m, 6H), 1.68-1.88 (m, 6H),

1.60 (d, 6H), 1.05-1.17 (m, 4H). MS m/z 564.6 (M + H⁺).

Resolution of Enantiomers (163 and 164). Enantiomerically

pure amines derived from racemic 6-cyano-1,2,3,4-tetrahydro-

quinolin-3-ylamine hydrochloride were obtained by coupling with

S-mandelic acid to form diastereomeric amides as described

previously.^5,10After resolution, the amines were converted to 163

and 164, as shown in Scheme 1.

Modeling Studies. We published a detailed procedure for

building a homology model of Pf-PFT.⁷Briefly, the model was

generated with MODELLER¹⁹by using the crystal structure of rat-

PFT complexed with the nonsubstrate tetrapeptide inhibitor CVFM

and farnesyl-pyrophosphate as the template structure (PDB entry

1JCR). The sequences of the two subunits (R and â) of Pf-PFT

were obtained from the PlasmoDB²⁰(R: PFL2050w and â:

chr11.glm_528) and aligned with the template. Only regions with

reasonable reliability in the alignment were included. The model

of Pf-PFT comprises the following sequence segments (the residue

numbers of the corresponding segments of the rat-PFT subunits

are given in parentheses): R: 72-164 (87-179), 300-411 (184-

283); â: 421-677 (71-315), 806-896 (330-417). Note that the

Pf-PFT sequences (R: 497; â: 967) are much longer than the rat

ones (R: 377; â: 437)

by diluting 20 mM THQ PFTI in dimethylsulfoxide by 200-fold

with RP-20P for the highest concentration (100 µM stock gives

final assay concentration of 5 µM), then performing further serial

dilutions in RP-20P. Plates were flushed with 5% CO₂, 5% O₂,

and 90% N₂then incubated at 37 °C for 48 h. 8[³H]-Hypoxanthine

(0.3 µCi, 20 Ci/mmol, American Radiolabeled Chemicals) in 30

µL of RP-20P was added to cultures and incubated for an additional

24 h. Cells were harvested onto glass fiber filters by a cell harvester

(Inotech Biosystems International, Inc Rockville, MD), and the

radioactivity incorporated into the parasites was counted on a

Chameleon 425-104 multilabel plate counter (Hidex Oy Turku,

Finland). The background level detected with uninfected erythro-

cytes was subtracted from the data. The ³H-incorporation into

infected erythrocytes with 1 µL of DMSO vehicle alone represents

100% malaria growth. ED₅₀values, the effective dose that reduces

growth by 50%, were determined by linear regression analysis of

3

the plots of H-hypoxanthine incorporation versus concentration

of compound. Each compound was tested in duplicate, and the mean

value is shown; individual measurements differed by less than

3-fold.

Pf-PFT IC₅₀Determination. The PFT assay used to determine

the IC₅₀s (inhibitor concentration that causes 50% enzyme inhibi-

tion) of the compounds is based on a PFT [³H] scintillation

proximity assay (SPA; TRKQ7010 Amersham Biosciences Corp

Piscataway, NJ).³Assays were carried out in assay buffer (pH 7.5,

50 mM HEPES, 30 mM MgCl₂, 20 mM KCl, 5 mM DTT, 0.01%

Triton X-100), 1 µM human lamin-B carboxy-terminus sequence

peptide (biotin-YRASNRSCAIM), and 1 µCi ³H-farnesylpyrophos-

phate (Amersham specific activity 15 to 20 Ci/mM) in a total

volume of 50 µL, which included 1 µL of Pf-PFT inhibitor solution

in DMSO and 5 µL of partially purified Pf-PFT. Assays in the

absence of Pf-PFT inhibitor and Pf-PFT were included as positive

and negative controls, respectively. Reaction mixtures were incu-

bated at 37 °C for 60 min and terminated by the addition of 70 µL

of assay STOP solution and 5 µL of SPA beads. The assay mixture

was incubated at room temperature for 30 min. The assay was

counted on a plate Chameleon 425-104 multilabel counter (Hidex

Oy Turku, Finland). IC₅₀values were calculated using linear

regression analysis of the plots of the amount of radio-prenylation

versus the concentration of compound.

A small molecule crystal structure of 7-nitro-1,2,3,4-THQ,²¹with

R ) 0.034 at 0.77 Å resolution, shows that the tetrahydropyridine

ring adopts an envelope conformation, with atom C3 deviating by

0.66 Å from the mean plane through the other five atoms. Upon

substitution with an equatorial amino group, the deviation of the

methyl from the plane is 0.40 Å, implying that when the two

enantiomers are superimposed the amines are only 0.40 Å apart.

Both conformers of the molecule were built with Insight (Accelrys)

starting from the 7-nitro-1,2,3,4-THQ crystal structure, and the

energies were minimized with the CFF force-field; a 4rꢀ electrostat-

ics model was used. The energies were 54.28 kcal/mol (equatorial)

and 56.96 kcal/mol (axial).

All molecular docking calculations of the THQ compounds were

carried out using the FLO/QXP v.6.02 package²⁴with as start model

162, as observed in the rat-PFT crystal structure transferred by

superposition into the comparative model of Pf-PFT. THQ com-

pounds were built with the FLO BUILDER module, specifically

taking care to assign the mixed sp2/sp3 N atom type of the

sulfonamide and allowing for mild pyramidalization. Monte Carlo

searches were carried out for the THQ substituents, using 50 cycles

per rotatable bond, while keeping the THQ scaffold fixed.

Subsequently, the best solutions were minimized, allowing also for

spatial freedom to the scaffold. Because the force-field has not been

parametrized for transition metal complexes, the inhibitor N atom

that coordinates the Zn²⁺atom was spatially constrained as well

as all other atoms of the Zn²⁺-binding imidazole ring.

Plasmodium Strains. The P. falciparum strains used in this study

were 3D7 (Netherlands [airport-associated malaria], chloroquine

sensitive) and K1 (Thailand, chloroquine resistant, pyrimethamine

resistant). Strain 3D7 was provided by Dr. Pradipsinh Rathod from

the University of Washington. P. falciparum strain K1 and P.

berghei isolate NK65 (used for rodent malaria experiments) were

obtained from the MR4 unit of the American Type Culture

Collection (ATCC, Manassas, VA).

P. falciparum Culture. Strains of P. falciparum were cultured

in vitro using experimental techniques described by Trager and

Jensen.²²Cultures were maintained in RPMI-1640 (Sigma, St.

Louis, MI) with 2 mM L-glutamine, 25 mM HEPES, 33 mM

NaHCO₃, 20 µg/mL gentamicin sulfate, and 20% (v/v) heat-

inactivated human plasma type A+ (RP-20P). Type A+ erythro-

cytes were obtained from lab donors, washed three times with RPMI

1640, resuspended in 50% RPMI-1640, and stored at 4 °C. Parasites

were grown in 10 mL of a 2% hematocrit/RP-20P (v/v) in 50 mL

flasks under a 5% CO₂, 5% O₂, and 90% N₂atmosphere.

P. falciparum ED₅₀Determination. A total of 10 µL of PFTI

in solution was added to each well of a 96-well plate followed by

the addition of 190 µL of an asynchronous P. falciparum culture

at parasitemia and hematocrit of 0.5%. PFTI solutions were prepared

Mammalian-PFT IC₅₀Determination. The PFT assay used to

determine the IC₅₀s of the compounds is based on a farnesyl

transferase [³H] SPA enzyme assay (TRKQ7010 Amersham Bio-

sciences Corp Piscataway, NJ). Rat PFT was prepared as de-

scribed.²³Assays were carried out in assay buffer pH 7.5 (50 mM

HEPES, 30 mM MgCl₂, 20 mM KCl, 5 mM DTT, 0.01% Triton

X-100) and 1 µM human lamin-B carboxy-terminus sequence

peptide (biotin-YRASNRSCAIM) in a total volume of 50 µL, which

included 1 µL of PFT inhibitor solution in DMSO and 5 µL of

partially purified rat-PFT. Assays in the absence of PFT inhibitor

and rat-PFT were included as positive and negative controls,

respectively. Reaction mixtures were incubated at 37 °C for 15 min

and terminated by the addition of 70 µL of assay STOP solution

and 5 µL of SPA beads. The assay is incubated at room temperature

for 30 min. The assay was counted on a plate Chameleon 425-104

multilabel counter (Hidex Oy Turku, Finland). IC₅₀values were

3

calculated using linear regression analysis of the plots of H-FPP

prenylation versus concentration of compounds.

Note Added after ASAP Publication. This manuscript was

released ASAP on August 28, 2007, with errors in the compound

numbers in Schemes 5 and 7 and with an error in the structure

for compound 119 in Table 2. The correct version was posted

on September 13, 2007.

Supporting Information Available: HPLC traces of key

compounds 6, 162, 110, 191, and 234. This material is available

free of charge via the Internet at http://pubs.acs.org.

Protein Farnesyltransferase Inhibitors Antimalarials

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JM0703340

Article Doi

Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials

DOI: 10.1021/jm0703340

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Article abstract of DOI:10.1021/jm0703340

Full text of DOI:10.1021/jm0703340

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