Potent non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase complex

Article abstract of DOI:10.1021/jm701239a

Measles virus (MV) is one of the most infectious pathogens known. In spite of the existence of a vaccine, approximately 350000 deaths/year result from MV or associated complications. Antimeasles compounds could conceivably diminish these statistics and pr

Full text of DOI:10.1021/jm701239a

J. Med. Chem. 2008, 51, 3731–3741
3731
Potent Non-Nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase
Complex
Aiming Sun,*,† Jeong-Joong Yoon,‡ Yan Yin,† Andrew Prussia,† Yutao Yang,† Jaeki Min,† Richard K. Plemper,‡ and
James P. Snyder*,†
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia 30322, Department of Pediatrics, DiVision of Pediatric
Infectious Diseases, Emory Children’s Center, Emory UniVersity School of Medicine, 2015 Uppergate DriVe, Atlanta, Georgia 30322
ReceiVed October 5, 2007
Measles virus (MV) is one of the most infectious pathogens known. In spite of the existence of a vaccine,
approximately 350000 deaths/year result from MV or associated complications. Antimeasles compounds
could conceivably diminish these statistics and provide a therapy that complements vaccine treatment. We
recently described a high-throughput screening hit compound 1 (16677) against MV-infected cells with the
capacity to eliminate viral reproduction at 250 nM by inhibiting the action of the virus’s RNA-dependent
RNA polymerase complex (RdRp). The compound, 1-methyl-3-(trifluoromethyl)-N-[4-sulfonylphenyl]-1H-
pyrazole-5-carboxamide, 1 carries a critical CF3 moiety on the 1,2-pyrazole ring. Elaborating on the
preliminary structure-activity (SAR) study, the present work presents the synthesis and SAR of a much
broader range of low nanomolar nonpeptidic MV inhibitors and speculates on the role of the CF3 functionality.
Introduction
mentally for the treatment of measles but with limited efficacy.9
More recently, benzimidazothiazole derivatives have been
reported to be more potent and less cytotoxic compared with
ribavirin against the Leningrad 16 strain, when assessed in Vero
(African green monkey kidney carcinoma) cells. The most active
compound in this series demonstrated a selectivity ratio (CC50/
EC50) of 245.5 compared with 14.4 for ribavirin.10
Paramyxoviruses are negative stranded RNA viruses, most
of which are highly contagious airborne pathogens that spread
via the respiratory route. Members of this viral family include
major human and animal pathogens such as measles virus
(MV),a human parainfluenza viruses (HPIV), mumps virus,
respiratory syncytial virus, and Newcastle disease virus.1 Despite
the existence of an effective live-attenuated vaccine,2 MV
remains a serious threat to human health globally, accounting
for approximately 0.35 million deaths annually.3 While most
of these cases occur in developing countries with limited access
to vaccination, measles outbreaks still occur in some developed
countries that have failed to maintain high vaccine coverage
rates. According to recent estimates, 20 million cases of measles
occur annually worldwide. Current outbreaks in the developed
world have affected Japan in the Western Pacific Region, Nova
Scotia, New Brunswick, Prince Edward Island, and Ontario,
Canada, and several parts of Western Europe.4,5a–c
This is partially due to declining herd immunity as a result
of reduced vaccination coverage resulting from parental concerns
about vaccination safety.6 Vaccination coverage below protective
levels in areas of the developing world and continued viral
activity in the developed world make desirable the development
of novel therapeutics that can be used for the rapid control of
local outbreaks and improved case management to limit severe
outcomes of infection.
In previous work, we reported the structure-based develop-
ment of a MV entry inhibitor, compound 30 (AS-4,11,12 Figure
1), with an EC50 of 260 nM against the MV-Edmonston (MV-
Edm) strain. Because this compound proved to be unstable, we
developed nitro analogue 31 (AS-48) with an EC50 of 0.6-3.0
µM (Figure 1) as a shelf-stable alternative.11b Further attempts
to increase the activity within this series of compounds proved
to be problematic. As a consequence, we broadened our search
by turning to cell-based high-throughput screening (HTS) to
capture small molecules capable of netting both entry inhibitors
as well as compounds operating against other proteins critical
for viral infection and reproduction. The exercise identified
1-methyl-3-(trifluoromethyl)-N-[4-(pyrrolidinylsulfonyl)phenyl]-
1H-pyrazole-5-carboxamide 1 (16677) (Figure 1) (EC50 ) 250
nM,) as a well-behaved, target-specific inhibitor of MV replica-
tion.13 Bypassing the fusion protein, 1 represents a first-in-class
non-nucleoside inhibitor of the MV RNA-dependent RNA
polymerase (RdRp) complex. Following resynthesis of the hit
compound 1, by coupling 1-methyl-3-trifluoro-pyrazole-5-acetyl
chloride with 4-amino-prolidinyl sulfonamide 7a in the presence
of pyridine,14,31 previous preliminary structural modifications
focused on the right side of the molecule as depicted in Figure
2(b).15 In the present work, we describe optimization of antiviral
activity for compound 1 scaffold by manipulation of the pyrazole
(A) and pyrrolidine (D) rings.
To date, ribavirin is the only drug available for the treatment
of some paramyxovirus infections7,8 It has been used experi-
* To whom correspondence should be addressed. Phone: 404-727-6689
(A.S.); 404-727-2415 (J.P.S.). Fax: 404-727-6689 (A.S.); 404-727-6586
(J.P.S.). E-mail: asun2@emory.edu (A.S.); jsnyder@emory.edu (J.P.S.).
†
Department of Chemistry, Emory University.
Department of Pediatrics, Division of Pediatric Infectious Diseases,
Preparation of Analogues around the HTS Hit Com-
pound 1. Modification of the Pyrazole Ring. The first stage
of hit optimization introduced a variety of aromatic rings as
1-methyl-3-trifluoromethyl pyrazole replacements. Com-
pounds 2a-o (Figure 2b, Table S1, Supporting Information)
can be readily prepared by coupling the corresponding acid
chlorides with 4-amino-prolidinyl sulfonamide 7a in the
presence of pyridine.15 Preliminary efforts were also devoted
‡
Emory Children’s Center, Emory University School of Medicine.
a Abbreviations: MV, measles virus; CPE, cytopathic effect; MTT,
[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]; MV-Edm,
measles virus Edmonston strain; RdRp, RNA-dependent RNA polymerase;
CC50, compound concentration that returns 50% cytotoxicity; EC50,
compound concentration that returns 50% inhibition; SI, selectivity index,
defined as CC50/EC50; SAR, structural activity relationship; QSAR, quantita-
tive structural activity relationship; MFTA, molecular field topology analysis.
10.1021/jm701239a CCC: $40.75
2008 American Chemical Society
Published on Web 06/05/2008

3732 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Sun et al.
Figure 1. Structures of previous measles virus entry inhibitors (30, 31) and hit compound 1.
disppearance of potency in the virus titer reduction assay.
While the N-ethyl pyrazole 9a demonstrates good activity
in (EC50 ) 55 nM), the compound is highly toxic. In a
previous limited exploration of the SAR of 1, we learned
that installing a piperidine ring instead of the pyrrolidine ring
on the left side of the molecule (Figure 2a, D ring) provided
a 100-fold boost in activity while simultaneously delivering
very low toxicity.15 To exploit this potency advantage, a
variety of alicyclic heterocyclic rings (15a-l) or dialkyl
amines (15m-r) were employed as pyrrolidine replacements
while retaining the remainder of compound 1 structure (see
Table 1).
Figure 2. (a) Sectors of compound 1 utilized as an SAR template. (b)
Aromatic ring analogues of the compound 1 pyrazole ring, 2a-o.
to modifying the 1-methyl-3-trifluoromethyl-pyrazole ring.
For example, the corresponding 4-bromo-1-methyl-3-(triflu-
oromethyl)-1H-pyrazole-5-carboxylic acid was prepared by
the protocol reported by Schlosser and treated with oxalyl
chloride to obtain acid chloride 3.14 The latter was further
coupled with sulfonamide 7a to give the 4-bromo-substituted
analogue 4 (Scheme 1).
In the present work, 3-trifluoromethyl pyrazole was treated
with NaH in DMF, followed by regioselective benzylation and
alkylation to obtain 1-benzyl or alkyl-3-trifluoromethylpyrazole.
The compound was then subjected to a routine deprotonation-
carboxylation sequence before coupling with aniline 7c to obtain
the desired compound 9 (Scheme 2).
2-Methoxycarbonylphenyl and 2-carboxyphenyl analogues
were also prepared as outlined in Scheme 3. The furan precursor
10 was obtained as previously described16 and converted to ester
11 via the acid chloride/methylation method. Oxidation of the
furyl functionality afforded the desired carboxylic acid 12. The
latter as its acid chloride was coupled to aniline 7a to afford
compound 13. Saponification of ester 13 provided the corre-
sponding acid 14.
Syntheses of 23, 24, 28, and 29 proved to be straightfor-
ward by following standard procedures for sulfonamide
analogues as illustrated in Schemes 4 and 5. For example,
combination of 4-nitro-benzenesulfonyl chloride with pyr-
rolidine afforded 4-nitro-pyrrolidinyl sulfonamide 6. The
latter was reduced either with SnCl2 in EtOAc or by
hydrogenation over Pd/C (5%) to obtain 4-amino-prolidinyl
sulfonamide 7 in almost quantitative yield. Other secondary
amides behave similarly. Coupling of 7 with 1-methyl-3-
(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride obtained
compound 23. Deprotection of Boc-groups with a mixture
of TFA and CH2Cl2 (3:1) at room temperature for about 4 h
delivers free amines 24e and 24f. Compounds 29e and 29f
were obtained by hydrolysis of the corresponding esters 28
in 1 N HCl. Analogues 15a-r15 (See Table 1) were prepared
by using the same procedure as described in Scheme 4.
Qualitative SAR for Compound 1 Analogues. Disappoint-
edly, all attempts to replace the pyrazole ring with five- or
six-membered aromatic rings15 or to alter substitutents on
the pyrazole ring (e.g., 4, 13, and 14) led either to a decrease
or to a complete loss of activity. A striking example is the
inactivity of the series of N-alkyl analogues of 1 (EC50
30-150 nM15). Replacement of the N-methyl with N-
isopropyl or N-benzyl (9b and c, respectively) leads to
Piperidine analogues 15a-e and 15k exhibit significant
potency improvements by comparison with the original hit. All
yield EC50s in the low nM range. The 2-ethyl substitution on
the piperidine ring in 15e elicits 2-6-fold less activity than
methyl substitution (15b-15d). The seven-membered ring
variant 15f is 10-fold more potent than the azacyclooctane
analogue 15g and about 3-fold more active than the piperidine
15a. However, C2-substitution of the pyrrolidine ring with either
an ester or a carboxylic acid (15h and 15i, respectively) greatly
decreases activity by about 100-fold as does introduction of an
indole ring (15j). Interestingly, while the open-chain diethyl
amine compound 15n is highly active, the alkyl-enhanced di-
isopropyl, dipropyl, and diallyl variants 15o, 15p, and 15r lose
10-20 fold potency by comparison. Similarly, 15m and 15q,
the dimethyl and di-isobutyl analogues, respectively, exhibit
drops in activity.
Additional structural modifications of compound 1 included
synthesis of 16-20, compounds that examine structural
environments around a six-membered ring. (Figure 3)
Analogue 16 moves the nitrogen out of the piperidine ring
of 15a and introduces a secondary amine as an H-bond donor,
while 17 incorporates a sulfonate moiety instead of a
sulfonamide group. Compound 18 incorporates a methyl
group on the amide and eliminates possible hydrogen bonding
of NH with a nearby amino acid residue. All three compounds
16, 17, and 18 occasion a complete loss of activity.
Compounds 19 and 20 switch the sulfonamide para-amide
linker in sector C to the meta- and ortho-positions, respec-
tively. Both compounds 19 and 20 similarly show no
detectable activity below 75 µM (Table 1).
Discovery of four highly active piperidine analogues in the
D-sector of 1 (15a-d, see Table 1 for biological data)
encouraged us to further examine this center in an effort to retain
nM potency while improving solubility within the series. Thus,
morpholine derivative 23a, piperazines 23b-d, 24e, and pip-
eridine rings decorated with hydrophilic groups 24f, 28a-d,
and 29e-f were prepared. Unfortunately, with the exception
of 28c bearing a CH2OH group alpha to nitrogen (EC50 850
nM), none of the compounds are significantly active. Clearly,
the incorporation of a hydrophilic group in this sector is
detrimental to MV blockade (Table 1). This may reflect impaired
passive diffusion through the plasma membrane because inhibi-
tors of the RdRp complex activity need access to the cytosol of
the infected cells.

Non-Nucleoside Inhibitors of the Measles Virus RdRp Complex
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3733
Scheme 1. Synthesis of 1-Methyl-3-(trifluoromethyl)-4-bromo-N-[4-(pyrrolidinylsulfonyl)-phenyl]-1H-pyrazole-5-carboxamide (4)a
Scheme 2. Synthesis of 1-Alkyl-3-(trifluoromethyl)-5-carboxamide 9a
Scheme 3. Synthesis of 1-[2-Carboxy-phenyl]-3-trifluoromethyl-pyrazole Analoguesa
a Reagents: (a) oxalyl chloride; (b) MeOH; (c) KMnO4, H2O, acetone; (d) (COCl)2, DMF (cat.), CH2Cl2, 0°C-rt, then py, 7a, CH2Cl2, rt; (e) 50% NaOH,
MeOH/H2O (5:1), room temperature, 5 h, then 1 N HCl.
Molecular Field Topology Analysis (MFTA) QSAR. The
SAR discussion in the previous section is based on qualitative
observations. In an effort to put this on a more quantitative
footing, the MFTA method developed by Palyulin et al.17,18 was
applied to the MV RdRp complex inhibitor series to generate a
quantitative structure-activity relationship (QSAR). MFTA
performs a topological analysis for a compound series, generates
a molecular supergraph with descriptor values for each com-
pound mapped at each atom vertex, and finishes with PLS-based
correlation statistics to generate predictive QSAR models. In
the present case, the log(1/EC50) values for CPE inhibition
without standard deviations were used as the numerical biologi-
cal end points. To incorporate the virus titer data into the
correlation, the titer values of compounds with CPE inhibitory
activities less than 2.3 µM were scaled to an equivalent CPE
EC50 by a conversion factor of 10 µM EC50 per 1 µM virus
titer. The latter was based on the EC50s and virus titers for 15o
and 28d. Where compounds exhibit activities greater than 75
µM, a value of 150 µM was assigned. Compounds with a
cytoxicity greater than 300 µM or a theraputic index greater
than 4 were selected for MFTA. To simplify the analysis within
a congeneric series, only compounds with a scaffold similar to
the pyrazole ring A, amide linker B, and sulfonamide linker C
were included. Thus, the training set consisted of 26 compounds:
1, 2j, 2o, 9a, 13, 14, 15a, 15c-15i, 15k, 15m, 15o, 15p, 15r,
23a, 23d, 28c, and 28d. Three compounds from a previous
publication15 were also included because they are instructive
members of this congeneric series (cf. S5, S7, and S8, Figure
S1, Supporting Information). On the other hand, 9b, 23c, 24f,
29e, and 29f were inactive and consistent outliers. Thus, these
compounds were excluded from the training set. For the test
set, seven compounds were used 2n, 2k, 15b, 15n, 24e, 28a,
and S6 (Figure S1, Supporting Information).15
A variety of single local descriptors and sets of local
descriptors were applied to the training set, generating a series
of different models with varying predictive Q2 values based on
MFTA’s leave-25% cross-validation. The best results were
obtained with descriptors for Gasteiger-Marsili atomic charge

3734 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Scheme 4. Synthesis of Derivatives 23 and 24a
Sun et al.
a Reagents: (a) Py/CH2Cl2; (b) Pd/C (10%), H2 (50 psi), 1 h; (c)Py, CH2Cl2, 1-methyl-3-trifluoro-pyrazole-5-acetyl chloride, 2 h; (d) TFA/CH2Cl2 (3:1),
4 h.
Scheme 5. Synthesis of Substituted Piperidine Derivatives 28 and 29a
a Reagents: (a) Py/CH2Cl2; (b) Pd/C (10%), H2 (50 psi), 1 h; (c)Py, CH2Cl2, 2 h; (d) 50% NaOH, MeOH/H2O (5:1), room temperature, 5 h, then 1 N HCl.
(Q), the effective environment van der Waal radius (Re), and
group lipophilicity based on the sum of the Ghose-Crippen
atomic contributions for an atom and attached hydrogens (Lg).
This QSAR model generated a correlation (Figure 6) with the
following statistics: N ) 26, number of PLS factors NF ) 2, R
) 0.88, R2 ) 0.77, RMSE ) 0.49, and Q2 ) 0.66. Adding
additional descriptors did not substantially improve the correla-
tion. To verify that MFTA has not simply fortuitously found a
nonpredictive model, a Y-randomization test38 was performed
on the training set data in ten separate trials. In each trial, the
activity data was randomly reordered, and a QSAR model
generated. Each random data set delivered the same mean,
variance, and molecular supergraph, but no real correlation of
activity to structure. The resulting QSAR models generally had
a good correlation (Ravg ) 0.83, Rmax ) 0.92) but poor predictive
ability (Q2avg ) 0.21, Q2max ) 0.42). This lends confidence that
the experimental model with Q2 ) 0.66 is not an artifact of the
method.
Predictions for the seven compound test set with the present
model were made by first using MFTA to map the test set
compounds with assigned descriptor values to the previously
generated molecular supergraph, followed by prediction with
the PLS model based on the training set (Figure 5). Test set
activities are predicted reasonably well with R ) 0.67 and R2
) 0.45. For three of the compounds, the errors are somewhat
substantial (about 30-40% of the training set activity span in
log units), but for the other four compounds, the error is less
than 20%. The mean absolute error for the complete test set is
0.74 log units, and the rms error of prediction is 0.86 log units.
MFTA was used to visualize the descriptors’ contributions
to the correlation by means of a color-coded molecular super-
graph (Figure 6). Positions colored brown and red suggest that
an increase in descriptor property in that part of the molecule
would increase activity, red positions having more effect than
brown. Conversely, light blue and blue positions suggest that
an increase in descriptor property would decrease activity, blue
positions having more effect than light blue. At uncolored
positions, either the descriptor property is not correlated to
activity or there is insufficient diversity in the training set for
MFTA to develop correlation to activity. The reader should note
that the attempt to display the range of substituents in 2D in
sector D in Figure 6 leaves the impression of disorder around
the sulfonyl amine group. This is inaccurate and misleading
because the correlation of descriptor property to activity is
limited by the property range of the substituents in the training
set. The graph accurately reflects how subtle changes in the
atoms’ properties affect activity within the bounds of diversity
in the training set.
Interpreting the descriptor impact graphs supports qualitative
trends in the structure-activity data. Substituted rings and alkyl
chains attached to the sulfonamide have a positive impact on
activity if they increase the lipophilicity and decrease the charge

Non-Nucleoside Inhibitors of the Measles Virus RdRp Complex
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3735
Table 1. Antiviral MV EC50’s, Cytotoxicities, and Selectivity Indices for 1-Methyl-N-(4-(piperidin-1-ylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-
5-carboxamide (15a) and other sulfonamide analogues
EC50 (µM) (MV-Alaska)
CPE inhibitiona virus titer reductionc
CC50 (µM) (Vero cells)
MTT cytotoxicityd Trypan blue exclusion assaye
SI (CC50/EC50)
entry ID no.
CPE + MMT
titer + trypan
4
>75
ND
95 ( 20
30 ( 2.4
>300
ND
ND
ND
<1.3
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
14214
1862
1514
23429
160.9
85,000
ND
ND
ND
ND
ND
ND
ND
14737
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
9a
<2.3
0.055 ( 0.013
9b
>75
ND
9c
>19c
>19b
ND
19 ( 1
>300
>300
199 ( 27
54 ( 3
53 ( 4
328 ( 28
14 ( 2
425 ( 65
ND
ND
ND
ND
ND
ND
ND
280 ( 90
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
13
>75
>75
ND
ND
14
>75
>75
ND
15af
15b
15c
15d
15e
15f
15g
15hf
15if
15jf
15k
15l
15m
15n
15o
15p
15q
15r
16
<2.3
0.014 ( 0.02
>300
>130
>130
>130
>130
>130
>130
>7
7.1
>13
ND
69.1
<1.2
>47.6
>130
>85.7
>130
ND
10.3
ND
ND
<3.8
<1.1
ND
>7
ND
<2.3
0.029 ( 0.031
>300
<2.3
0.035 ( 0.035
>300
<2.3
0.014 ( 0.013
>300
<2.3
0.087 ( 0.116
>300
<2.3
0.005 ( 0.0003
>300
<2.3
0.045 ( 0.034
16 ( 0.8
100
14 ( 2
23 ( 10
>13b
ND
ND
ND
>300
13 ( 0.7
159 ( 12
92 ( 9.3
>300
2.3 ( 0.7
>75
0.02 ( 0.02
ND
ND
6.3 ( 0.6
<2.3
0.019 ( 0.019
>300
3.5 ( 0.4
<2.3
0.53 ( 0.02
0.19 ( 0.32
ND
>300
>300
>13.8b
3.3 ( 1.4
>15b
13.8 ( 0.7
34 ( 0.9
15 ( 0.6
>300
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
0.85 ( 0.05
0.57 ( 0.04
ND
17
>75
18
>75
286 ( 17
84 ( 23
>300
19
>75
20
>75
23af
23b
23c
23d
24e
24ff
28a
28b
28c
28d
29e
29f
43 ( 24
>75
>300
>300
>75
>300
ND
>21.3
4.5
ND
13.6
ND
>69
40.2
ND
14.1 ( 6.6
28 ( 9
>75
>300
126 ( 7
>300
ND
ND
ND
ND
ND
ND
ND
10 ( 5.6
136 ( 3
38 ( 1
159 ( 40
274 ( 19
>300
>38b
<2.3
6.8 ( 0.9
>75
>75
ND
>300
ND
a EC50not determined (ND) when CC50 e 15 µM. Values represent averages of four experiments ( SD; highest concentration assessed 75 µM, lowest
concentration assessed 2.3 µM. b No virus inhibition detected at CC50 concentration. c Determined only when CPE inhibition-based EC50 concentration <2.3
µM. Values represent averages of two to four experiments ( SEM; highest concentration assessed 1 µM. (ND: not determined) d Values represent averages
of at least three experiments ( SD; highest concentration assessed 300 µM. e Determined only when virus titer reduction was assessed and MTT-assay based
cytotoxicity >300 µM. (ND: not determined) f Published results.15

3736 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Sun et al.
Figure 3. Variation scaffolds of piperidine analogues.
positively or negatively effect activity, depending on the
substituent position.
Discussion
Mechanistic and functional characterization of the high-
throughput screening hit 1 has demonstrated that the compound
represents a first-in-class non-nucleoside inhibitor of MV RdRp
complex activity.13 We have developed an SAR by structural
manipulation of 1 within the four sectors highlighted in Figure
2a. As an extension of previously published work15 mainly
focusing on the phenyl sulfonamide unit, the amide linker, and
the pyrazole ring in sector A, the current modification within
sector A–C either essentially abolish anti-MV activity or result
in high cytotoxicity. However, a highly potent analogue has
been identified by replacing the pyrrolidine ring in compound
1 with a piperidine. Subsequent SAR development of the current
series was centered on modification of the heterocyclic rings in
sectors A and C. Disappointedly, all attempts to replace the
N-methyl group on the pyrazole ring (9a-c, 13, and 14) or to
add other functionality on the same ring leads to complete loss
of activity or high toxicity (9a). Furthermore, replacement of
the pyrazole ring CF3 group with Me or t-Bu also causes
significant loss of activity, a factor explained below by the
beneficial electrostatic properties of the CF3 group.
Figure 4. MFTA molecular supergraph (left) formed by the 26
compounds of the training set. The superposition of compound 1 (right)
is highlighted to exemplify the alignment.
Intriguingly, maintaining the structure of the hit molecule 1
in sectors A-C, while modifying the pyrrolidine ring in D,
delivers highly active and noncytotoxic compounds. (Table 1,
15a-g, 15k) The seven-membered ring analogue 15f was the
most potent series member with an EC50 around 5 nM and no
detectable cytotoxicity at concentrations below 300 µM as
determined by two independent assays (reflected by an ap-
proximate selectivity index (CC50/EC50) of 85000). Further
increases in the ring size, however, resulted in a reduction of
antiviral activity by about 10-fold (Table 1, 15g). The open-
chain diethyl amine analogue 15n also exhibited excellent
antiviral activity. However, other amine substitutions (15o and
15q) caused a complete loss of activity.
Further optimization of the lead compound sought to increase
solubility and improve cellular bioavailability. Such structural
changes may, of course, reduce membrane permeability and
consequently compromise antiviral activity. In attempts to
resolve the conflicting structural requirements, compounds with
a piperazine ring (24e) and polar groups on the piperidine (e.g.,
24d,f and 28a-f, Figure 2a, sector D) were prepared. Indeed,
assessment of biological activity returned a correlation between
increasing hydrophilicity and decreasing inhibitory potency.
Within this series, all compounds were completely inactive with
the exception of piperidines 28c and 28d, which harbor
2-CH2OH and 4-OH groups, respectively; both returning only
moderate activity.
Figure 5. MFTA correlation for the 26 compounds of the training set
(blue) and the seven compounds of the test set (red) based on charge
(Q), effective vdW radius (Re), and lipophilicity (Lg) descriptors.
Figure 6. Descriptor impact on activity shown on the molecular
supergraph. The QSAR model predicts that increasing the descriptor
property at the red and blue positions results in an increase and decrease
in activity, respectively.
on this part of the molecule. However, the QSAR model is able
to parse some additional complexity in the structure-activity
data by noting that increasing charge in the 3- and 4-positions
of the pyrrolidine ring, as well as the para-position of the six-
membered ring, has a favorable effect on activity. In general,
substituents connected to the pyrazole ring have a favorable
impact on activity if they contribute an increase in size and
lipophilicity. Increasing charge at the pyrazole ring can either

Non-Nucleoside Inhibitors of the Measles Virus RdRp Complex
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3737
Figure 9. A trifluoromethyl ketone inhibitor of human leukocyte
elastase (1EAS) illustrating an FsHS hydrogen bond and a charge
dipole interaction between a ligand C-F bond and His57. Units for
numerical values are Å.
Figure 7. The 1,2,4-oxadiazole terminus of the rhinovirus blocker
pleconaril sited in a hydrophobic pocket as determined by X-ray
crystallography (1NCR). One of the CF3 fluorine atoms engages in a
slightly elongated hydrogen bond with the backbone NH of Tyr144.
Figure 8. H-Ras 166 in 50% 2,2,2-triflouroethanol (1P2S) sequesters
the CF3 group of a solvent molecule between Arg97 and Lys101 side
chains by bidentate and monodentate hydrogen bonds, respectively.
Distances are between FsN atoms. Units for numerical values are Å.
Figure 10. Porcine factor IXa complexed to 1-{3-[amino(imino)-
methyl]phenyl}-N-[4-(1H-benzimidazol-1-yl)-2-fluorophenyl]-3-(triflu-
oromethyl)-1H-pyrazole-5-carboxamide) (1 × 7A). The CF3 of the
pyrazole ligand interacts tightly with the cationic terminus of the Arg143
side chain. Units for numerical values are Å.
Interactions between Ligand CF3 Groups Associated
Proteins. Compound 1, the most potent high-throughput screen-
ing (HTS) inhibitor against MV,13 identified from a 34000
compound pool,19 carries a trifluoromethyl group on the pyrazole
ring. Substitution of the CF3 with a methyl or a t-butyl group
completely abrogates the inhibitory activity of the compound.15
To gain insight into the possible role of the pyrazole CF3 as an
enhancer of MV inhibition and to investigate more generally
the structural influence of CF3 groups in protein-bound ligands,
we searched the Protein Data Bank (PDB) for such protein-ligand
complexes using Relibase+ and ReliView. A total of 132 CF3-
complemented ligands was returned from the search. Less than
a dozen trifluoromethyl groups are located in hydrophobic
environments, while 15 are directed into the aqueous layer
surrounding the proteins. Carbon-fluorine bonds in 117 com-
plexes were judged to participate in at least one CF-HX (X )
O, N, or S, r(F-H) 1.8-2.0 Å) interaction in which FsX
distances range from 2.7-3.6 Å. It has been argued that fluorine
rarely engages in hydrogen bonds in small molecule X-ray
crystal structures.20 However, in protein pockets where ligands
are immobilized by a variety of forces, they appear to be more
common. FsX distances beyond 3.0 Å can be regarded as
dipole-dipole interactions that most likely provide small
stabilizing contributions (<1 kcal/mol) for the observed binding
poses. An example is presented in Figure 7 showing the
heterocyclic terminus of the rhinovirus blocker pleconaril
encased in a hydrophobic pocket (PDB code 1NCR21). One of
the CF3 fluorine atoms experiences a short contact with the
backbone NH of Tyr144.
associates with one fluorine in the same pair, all of which
involve FsH distances of 2.6-2.7 Å. The latter are 0.3-0.4 Å
smaller than the sum of the van der Waals radii (N 1.55, F 1.47
Å).23 These charge-dipole interactions are well-known to
operate as controlling forces in the conformational preferences
of fluorinated piperidines. In particular, the fluorine in protonated
3-fluoropiperidines universally adopts an axial orientation
contrary to intuition based on cyclohexane conformational
analysis.24,25
Figure 9 depicts a trifluoromethyl ketone inhibitor of human
leukocyte elastase (1EAS26). The compound enjoys a weak
interaction with the SH of Cys42 and a stronger association
with His57. Intriguingly, four protein-ligands incorporate CF3-
subsituted pyrazole rings, very similar to that found in compound
1. Three of these (1 × 7A,27 1CX2,28 and 6COX29) juxtapose
the CF3 fluorines and a single Arg residue located among
hydrophobic residues. This observation has been exploited to
explain the activity of a series of anti-inflammatory COX
inhibitors.30 Porcine factor IXa complexed to 1-{3-[amino(imi-
no)methyl]phenyl}-N-[4-(1H-benzimidazol-1-yl)-2-fluorophe-
nyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide) (1 × 7A)
is illustrative (Figure 10). The fourth CF3-substituted pyrazole
ligand, a nanomolar inhibitor of carbonic anhydrase (1OQ530)
positions the trifluoromethyl group in a hydrophobic cavity on
the surface of the protein partially exposed to the aqueous layer
surrounding the protein.
If the binding site for pyrazole in the MV RNA-dependent
RNA polymerase were hydrophobic or solvent exposed, then
substitution of CF3 in compound 1 with CH3 (Figure 2b, 2n) is
unlikely to cause complete loss of activity as observed.
Consequently, we conclude that the pyrazole-CF3 in the highly
active MV blockers examined in this work (Table 1, 15a-g,
15k, 15n) is likely docked in a pocket that houses either a
cationic Arg, His, or Lys. This prediction is being actively
A subset of 28 cases involve cationic Arg, Lys, and His
residues that direct N-H bonds toward fluorine. One interesting
CF3-protein association (1P2S22) locates the fluorinated moiety
of 2,2,2-trifluoroethanol (CF3CH2OH) between Arg and Lys side
chains in H-Ras 166 as shown in Figure 8.
The topographical representation shows that Arg97 forms a
bidentate contact with two fluorine atoms, while Lys101

3738 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Sun et al.
8.14 (s, 1H). Anal. Calcd for C18H17F3N2O3S: C, 54.27; H, 4.30;
N, 7.03. Found: C, 54.01; H, 4.37; N, 7.10.
Compound 2d (as-36b). H NMR (600 MHz, CDCl3) δ: 1.77
pursued to identify MV blockers that maintain potency but carry
improved solubility and bioavailability properties.
1
(4H, t, J ) 7.2 Hz), 3.25 (4H,t, J ) 6.6 Hz), 4.65 (2H, s), 7.55
(2H, d, J ) 7.8 Hz), 7.82 (2H, d, J ) 8.4 Hz), 7.85 (2H, d, J ) 7.8
Hz), 7.89 (2H, d, J ) 7.8 Hz), 7.96 (s, 1H). Anal. Calcd for
C18H19ClN2O3S: C, 57.06; H, 5.05; N, 7.39. Found: C, 56.21; H,
5.18; N, 7.57.
Conclusions
High throughput screening followed by chemical synthesis
has provided the first highly potent small molecule blockers of
the measles virus accompanied by low cell toxicity. Synthetic
modification of the 1 lead reveals that both potency gains and
structural diversity resides primarily in sector D (Figure 2a).
This behavior is captured by a three-descriptor QSAR model
developed using molecular field topology analysis (MFTA) and
implies the sector D sulfonyl amines reside in a rather tight
hydrophobic cavity. Behavior at the other end of the molecule
(sector A) suggests that the pyrazole-CF3 most likely sits in a
pocket housing cationic Arg, His, or Lys. These speculations
are being actively pursued in an effort to identify MV blockers
that maintain potency but carry improved solubility and bio-
availability properties suitable for evaluating various MV strains
and closely related viruses in animal models.
1
Compound 2e (as-60a). H NMR (400 MHz, CDCl3) δ: 1.61
(4H, m), 3.09(4H, m), 7.05-7.11 (4H, m), 7.64-7.76 (5H, m).
Anal. Calcd for C17H17FN2O3S: C, 58.61; H, 4.92; N, 8.04. Found:
C, 58.14; H, 5.12; N, 8.08.
1
Compound 2f (as-36a). H NMR (600 MHz, CDCl3) δ: 1.77
(4H, t, J ) 6.6 Hz), 3.25 (4H, t, J ) 6.6 Hz), 7.66 (2H, d, J ) 8.4
Hz), 7.76 (2H, d, J ) 7.8 Hz), 7.80-7.84 (4H, m), 8.0 (1H, s).
Anal. Calcd for C17H17BrN2O3S: C, 49.89; H, 4.19; N, 6.84. Found:
C, 49.75; H, 4.23; N, 6.84.
Compound 2g (as-40). 1H NMR (400 MHz, CDCl3) δ: 1.79
(4H, m), 3.23(4H, m), 7.37 (1H, dd, J ) 20 Hz, J ) 11.2 Hz),
7.83-7.89 (4H, m), 8.50 (1H, dd, J ) 2.4 Hz, 6.0 Hz), 8.57 (1H,
d, J ) 11.2 Hz). Anal. Calcd for C18H16F4N2O3S: C, 51.92; H,
3.87; N, 6.73. Found: C, 51.69; H, 3.98; N, 6.57.
1
Compound 2h (as-60b). H NMR (400 MHz, CDCl3) δ: 1.78
(4H, t, J ) 6.4 Hz), 3.25 (4H, t, J ) 6.8 Hz), 6.92 (1H, dd, J ) 3.2
Hz, 8.8 Hz), 7.23 (1H, d, J ) 3.2 Hz), 7.53 (1H, d, J ) 9.2 Hz),
7.80-7.87 (4H, m), 7.96 (s, 1H). Anal. Calcd for C18H19BrN2O4S:
C, 49.21; H, 4.36; N, 6.38. Found: C, 49.18; H, 4.29; N, 6.42.
Compound 2i (as-61d). 1H NMR (400 MHz, DMSO-d6) δ: 1.78
(4H, t, J ) 6.4 Hz), 3.12 (4H, t, J ) 6.4 Hz), 6.55 (1H, dd, J ) 2.0
Hz, 8.4 Hz), 6.65 (1H, d, J ) 8.4 Hz), 7.75 (2H, d, J ) 8.8 Hz),
7.92 (4H, d, J ) 8.8 Hz), 10.53 (s, 1H). Anal. Calcd for
C17H18ClN3O3S: C, 53.75; H, 4.78; N, 11.06. Found: C, 53.38; H,
4.79; N, 10.44.
Experimental Section
General Chemistry. Routine proton and carbon NMR spectra
measured during synthesis were obtained on a Varian Inova-400
(400 MHz). Solvents for NMR were deuteriochloroform (CDCl3)
(residual shifts: δ 7.26 for H and δ 77.7 for 13C) and deuteriom-
1
ethyl sulfoxide (DMSO-d6; residual shift: δ 2.5 for 1H). The residual
shifts were taken as internal references and reported in parts per
million (ppm). TLC and preparative thin-layer chromatographies
(PTLC) were performed on precoated, glass-backed plates (silica
gel 60 F254; 0.25 mm thickness) from EM Science and were
visualized by UV lamp. Column chromatography was performed
with silica gel (230-400 mesh ASTM) using the “flash” method.
Elemental analyses were performed by Atlantic Microlab Inc.
Norcross, Georgia. All solvents and other reagents were purchased
from Aldrich Chemical Co., Milwaukee. The reagents were used
as received. All reactions were performed under anhydrous nitrogen
atmosphere in oven-dried glassware.
Compound 4 (as-101). 1H NMR (400 MHz, CDCl3) δ:
1.74-1.78 (4H, m), 3.21-3.24 (4H, m), 4.25 (3H, s), 7.79-7.84
(4H, m), 8.66 (1H, s). 13C NMR (100 MHz, CDCl3, ppm): 25.41,
42.04, 48.15, 92.22, 120.32, 129.07, 133.34, 135, 20, 140.62,
155.94. Anal. Calcd for C16H16BrF3N4O3S: C, 39.93; H, 3.35; N,
11.64. Found: C, 40.20; H, 3.36; N, 11.21.
1
Compound 9a (jm1-98). H NMR (400 MHz, CDCl3) δ: 1.07
(3H, d, J ) 7.0 Hz), 1.49-1.60 (9H, m), 2.98 (1H, td, J ) 13.3,
2.3 Hz), 3.69 (1H, bd, J ) 13.3 Hz), 4.23 (1H, m), 4.65 (2H, q, J
) 7.8 Hz), 6.94 (1H, s), 7.70 (2H, d, J ) 8.8 Hz), 7.81 (2H, d, J
) 8.8 Hz), 7.82 (1H, s). Anal. Calcd for C16H16BrF3N4O3S: C,
51.34; H, 5.22; N, 12.61. Found: C, 51.88; H, 5.54; N, 12.22.
Compound 9b (jm1-89b). 1H NMR (400 MHz, CDCl3) δ: 1.06
(3H, d, J ) 7.0 Hz), 1.30-1.45 (2H, m), 1.53 (6H, d, J ) 7.0 Hz),
1.55-1.60 (4H, m), 2.97 (1H, td, J ) 13.3, 2.3 Hz), 3.66 (1H, bd,
J ) 13.3 Hz), 4.21 (1H, m), 5.48 (1H, m), 6.98 (1H, s), 7.68 (2H,
d, J ) 8.6 Hz), 7.74 (2H, d, J ) 8.6 Hz), 8.12 (1H, s). Anal. Calcd
for C16H16BrF3N4O3S: C, 52.39; H, 5.50; N, 12.22. Found: C, 52.44;
H, 5.51; N, 11.79.
General Procedures for Synthesis of 4-Amino-sulfonamide
7. Pyridine (11.0 mmol, 1.1eq) was added to a solution of 4-nitro-
benzenesulfonyl chloride (10.0 mmol, 2.22 g) and amine (11.0
mmol, 1.1eq) in CH2Cl2 (20 mL) at 0 °C. The reaction mixture
was allowed to warm up to room temperature and stirred for 10 h.
The reaction was quenched by addition of 1N HCl (15 mL) and
extracted with CH2Cl2 (3 × 15 mL). The organic solution was dried
(Na2SO4) and evaporated to obtain 4-nitro-sulfonamide. The latter
was subjected to reduction without further purification.
4-Nitro-sulfonamide (1.0 mmol) in EtOAc was stirred with
SnCl2.2H2O (5.0 mmol) at room temperature for at least 8 h until
starting material disappeared by TLC. The reaction mixture was
poured into saturated aqueous NaHCO3 (10 mL) and extracted with
EtOAc (3 × 20 mL). The EtOAc extracts were washed with
saturated aqueous NaHCO3 (10 mL) a second time and dried
(Na2SO4). Products were purified by chromatography over silica
gel.
1
Compound 9c (as-252). H NMR (400 MHz, CDCl3) δ: 1.78
(4H, t, J ) 6.4 Hz), 3.24(4H, t, J ) 6.8 Hz), 5.84 (2H, s), 7.01
(1H, s), 7.28-7.35 (5H, m), 7.70 (2H, d, J ) 8.8 Hz), 7.74 (1H,s),
7.83 (2H, d, J ) 8.8 Hz). Anal. Calcd for C24H25F3N4O3S: C, 56.91;
H, 4.97; N, 11.06. Found: C, 56.95; H, 5.09; N, 11.06.
Compound 13 (as-73b). 1H NMR (400 MHz, CDCl3) δ:
1.71-1.74 (m, 4H), 3.19 (t, 4H, J ) 6.8 Hz), 3.76 (s, 3H), 7.10 (s,
1H), 7.48 (dd, 1H, J ) 1.6 Hz, 7.8 Hz), 7.57 (d, 2H, J ) 8.8 Hz),
7.62 (dd, 1H, J ) 1.2 Hz, 7.6 Hz), 7.67 (dd, 1H, J ) 1.6 Hz, 7.6
Hz), 7.75 (d, 2H, J ) 8.8 Hz), 8.04 (dd, 1H, J ) 1.6 Hz, 8.0 Hz),
8.30 (s, 1H). Anal. Calcd for C23H21F3N4O5S: C, 52.87; H, 4.05.
Found: C, 52.63; H, 4.60.
Compounds 2a-o were synthesized by the same procedure as
compound 1.
Compound 2a(ns-8). 1H NMR (400 MHz, CDCl3) δ: 1.79 (4H,
t, J ) 6.8 Hz), 3.26(4H,t, J ) 6.8 Hz), 7.60-7.69 (4H, m),
7.76-7.86 (5H, m). Anal. Calcd for C18H17F3N2O3S: C, 54.27; H,
4.30; N, 7.03. Found: C, 54.26; H, 4.64; N, 7.74.
Compound 2b (ns-9). 1H NMR (400 MHz, CDCl3) δ: 1.78 (4H,
t, J ) 6.8 Hz), 3.26(4H,t, J ) 6.8 Hz), 7.79-7.87 (6H, m), 8.0-8.02
(3H, m), 7.84-7.87 (3H, m). Anal. Calcd for C18H17F3N2O3S: C,
54.27; H, 4.30; N, 7.03. Found: C, 54.20; H, 4.32; N, 7.04.
Compound 2c (ns-10). 1H NMR (400 MHz, CDCl3) δ:
1.76-1.80 (4H, m), 3.26 (4H,t, J ) 6.8 Hz), 7.69 (1H, t, J ) 8.0
Hz)), 7.82-7.88 (5H, m), 8.0 (1H, s), 8.08 (1H, d, J ) 7.6 Hz),
Compound 14 (as-77). 1H NMR (400 MHz, CDCl3) δ: 1.74
(4H, t, J ) 6.8 Hz), 3.2 (4H, t, J ) 6.8 Hz), 7.15 (s, 1H), 7.52
(1H, d, J ) 8.0 Hz), 7.59 (2H, d, J ) 8.8 Hz), 7.64 (1H, d, J ) 6.8
Hz), 7.71 (2H, d, J ) 8.4 Hz), 7.75 (1H, dd, J ) 1.6 Hz, 7.8 Hz),
8.11 (1H, dd, J ) 1.2 Hz, 7.8 Hz), 8.33 (1H, s). Anal. Calcd for
C22H19F3N4O5S·H2O: C, 50.19; H, 4.02; N, 10.64. Found: C, 50.80;
H, 4.20; N, 10.13.

Non-Nucleoside Inhibitors of the Measles Virus RdRp Complex
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3739
Compound 15a (as-136a). 1H NMR (400 MHz, CDCl3) δ:
1.43-1.44 (m, 2H), 1.63-1.66 (m, 4H), 3.02 (t, 2H, J ) 3.6 Hz),
4.28 (s, 3H), 6.98 (s, 1H), 7.75 (d, 1H, J ) 6.0 Hz), 7.78 (d, 1H,
J ) 6.0 Hz), 7.84 (s, 1H). Anal. Calcd for C17H19F3N4O3S: C, 49.03;
H, 4.60; N, 13.45. Found: C, 49.14; H, 4.64; N, 13.40.
Compound 15b (as-125c). 1H NMR (400 MHz, CDCl3) δ: 1.07
(d, 3H, J ) 4.8 Hz), 1.30-1.37 (m, 1H), 1.43 (d, 1H, J ) 6.0 Hz),
1.51-1.56 (m, 1H), 2.98 (dt, 1H, J1 ) 8.8 Hz, J2 ) 1.6 Hz), 3.64
(d, 1H, 8.0 Hz), 7.16 (s, 1H), 7.78-7.81 (m, 4H), 8.57 (br, 1H).
13C NMR (100 MHz, CDCl3, ppm): 15.61, 18.23, 25.33, 30.47,
40.54, 40.59, 48.91, 105.98, 120.02, 120.62, 121.81, 128.22, 136.38,
136.79, 141.00, 157.38. Anal. Calcd for C18H21F3N4O3S: C, 50.23;
H, 4.92; N, 13.02. Found: C, 50.34; H, 5.00; N, 12.71.
Compound 15c (as-127). 1H NMR (400 MHz, CDCl3) δ: 0.99
(d, 3H, J ) 3.6 Hz), 1.33-1.36 (m, 4H), 1.76 (d, 2H, J ) 7.6 Hz),
2.36 (t, 2H, J ) 7.8 Hz), 3.79 (d, 2H, J ) 8.0 Hz), 4.35 (s, 3H),
7.26 (s, 1H), 7.76 (d, 2H, J ) 6.0 Hz), 7.89 (d, 2H, J ) 5.6 Hz),
8.73 (br, 1H). 13C NMR (100 MHz, CDCl3, ppm): 21.58, 30.20,
33.35, 40.60, 46.64, 106.03, 120.52, 128.92, 131.32, 141.54, 157.47.
Anal. Calcd for C18H21F3N4O3S: C, 50.23; H, 4.92; N, 13.02. Found:
C, 50.14; H, 4.99; N, 12.86.
(1H, s). Anal. Calcd for C14H15F3N4O3S: C, 44.68; H, 4.02; N,
14.89. Found: C, 44.86; H, 4.04; N, 14.62.
Compound 15n (as-154). 1H NMR (600 MHz, CDCl3) δ: 1.14
(t, 6H, J ) 7.2 Hz), 3.24 (q, 4H, J ) 7.2 Hz), 4.27 (s, 3H), 7.0 (s,
1H), 7.70 (d, 1H, J ) 8.4 Hz), 7.79 (d, 1H, J ) 9.0 Hz), 7.92 (s,
1H). Anal. Calcd for C16H19F3N4O3S: C, 47.52; H, 4.74; N, 13.85.
Found: C, 47.41; H, 4.72; N, 13.81.
Compound 15o (yy-0213a). 1H NMR (400 MHz, CDCl3) δ:
1.27 (12H, d, J ) 7.2 Hz), 3.68-3.71 (2H, m), 4.27 (3H, s), 7.05
(1H, s), 7.64 (2H, d, J ) 8.8 Hz), 7.80 (2H, d, J ) 8.8 Hz), 8.02
(1H, s). Anal. Calcd for C18H23F3N4O3S: C, 49.99; H, 5.36; N,
12.96. Found: C, 50.18; H, 5.38; N, 12.86.
1
Compound 15p (yy-0237a). H NMR (400 MHz, CDCl3) δ:
0.88 (6H, t, J ) 7.6 Hz), 1.53-1.59 (4H, m), 3.06-3.10 (4H, m),
4.27 (3H, s), 7.00 (1H, s), 7.71 (2H, d, J ) 8.8 Hz), 7.80 (2H, d,
J ) 8.8 Hz), 7.89 (1H, s). Anal. Calcd for C18H23F3N4O3S: C, 49.99;
H, 5.36; N, 12.96. Found: C, 50.03; H, 5.40; N, 12.86.
1
Compound 15q (yy-0215a). H NMR (400 MHz, CDCl3) δ:
0.88 (12H, d, J ) 6.4 Hz), 1.88-1.91 (2H, m), 2.86 (4H, d, J )
7.6 Hz), 7.02 (1H, s), 7.69 (2H, d, J ) 8.8 Hz), 7.76 (2H, d, J )
8.8 Hz), 7.96 (1H, s). Anal. Calcd for C20H27F3N4O3S: C, 52.16;
H, 5.91; N, 12.17. Found: C, 52.18; H, 6.01; N, 12.04.
Compound 15d (as-125b). 1H NMR (400 MHz, CDCl3) δ: 1.35
(6H, d, J ) 7.2 Hz), 1.45-1.55 (m, 6H), 4.17-4.22 (m, 2H), 4.27
(s, 3H), 6.97 (s, 1H), 7.70 (d, 2H, J ) 8.8 Hz), 7.80 (s, 1H), 7.83
(d, 2H, J ) 8.8 Hz). Anal. Calcd for C19H23F3N4O3S: C, 51.34; H,
5.22; N, 12.61. Found: C, 51.41; H, 5.34; N, 12.15.
Compound 15r (yy-0247a). 1H NMR (400 MHz, CDCl3) δ:
3.82 (4H, d, J ) 6.8 Hz), 4.28 (3H, s), 5.14-5.18 (4H, m),
5.57-5.65 (2H, m), 6.99 (1H, s), 7.34 (2H, d, J ) 8.8 Hz), 7.83
(2H, d, J ) 8.8 Hz), 7.88 (1H, s). Anal. Calcd for C18H19F3N4O3S:
C, 50.46; H, 4.47; N, 13.08. Found: C, 50.33; H, 4.44; N, 12.83.
Compound 16 (as-140). 1H NMR (400 MHz, CDCl3) δ:
1.13-1.27 (m, 4H), 1.54-1.56 (m, 2H), 1.64-1.66 (m, 2H),
1.76-1.78(m, 2H), 3.15-3.16 (m, 1H), 4.27 (s, 3H), 4.34 (d, 1H,
J ) 5.2 Hz), 6.99 (s, 1H), 7.73 (d, 2H, J ) 5.6 Hz), 7.87-7.90(m,
3H). Anal. Calcd for C18H21F3N4O3S: C, 50.23; H, 4.92; N, 13.02.
Found: C, 50.27; H, 5.03; N, 12.99.
Compound 15e (yy-0169a). 1H NMR (400 MHz, CDCl3) δ:
0.87 (3H, t, J ) 7.2 Hz), 1.41-1.69 (8H, m), 2.96-3.03 (1H, m),
3.73-3.77 (1H, m), 3.91-3.96 (1H, m), 4.27 (3H, s), 7.01 (1H,
s), 7.70 (2H, d, J ) 8.8 Hz), 7.82 (2H, d, J ) 8.8 Hz), 7.95 (1H,
s). Anal. Calcd for C19H23F3N4O3S: C, 51.34; H, 5.22; N, 12.61.
Found: C, 51.36; H, 5.24; N, 12.50.
Compound 15f (as-124a). 1H NMR (400 MHz, CDCl3) δ:
1.56-1.59 (m, 4H), 1.66-1.70 (m, 4H), 3.26 (4H, t, J ) 6.0 Hz),
4.26 (s, 3H), 7.10 (s, 1H), 7.69-7.73 (m, 4H), 8.27 (s, 1H). 13C
NMR (100 MHz, CDCl3, ppm): 27.07, 29.28, 40.68, 48.45, 120.62,
128.32, 135.52, 136.31, 140.73, 157.28. Anal. Calcd for
C18H21F3N4O3S: C, 50.23; H, 4.92; N, 13.02. Found: C, 49.71; H,
4.92; N, 12.78.
Compound 17 (as-155). 1H NMR (400 MHz, CDCl3) δ:
1.22-1.31 (3H, m), 1.45-1.55 (3H, m), 1.68-1.78 (4H, m), 4.26
(3H, s), 4.51 (m, 1H), 7.1 (s, 1H), 7.77 (d, 1H, J ) 8.0 Hz), 7.83
(d, 1H, J ) 8.0 Hz), 8.30 (br, 1H). Anal. Calcd for C18H20F3N3O4S:
C, 50.11; H, 4.67; N, 9.74. Found: C, 50.11; H, 4.58; N, 9.59.
Compound 18 (as-627-03). 1H NMR (400 MHz, CDCl3) δ:
1.38-1.42 (2H, m), 1.58-1.64 (4H, m), 2.88 (4H, t, J ) 5.2 Hz),
3.49 (3H, s), 4.15 (3H, s), 5.59 (1H, s), 7.23-7.26 (2H, m),
7.70-7.72 (2H, d, J ) 8.4 Hz). Anal. Calcd for C18H21F3N4O3S:
C, 50.23; H, 4.92; N, 13.02. Found: C, 50.32; H, 4.90; N, 12.78.
Compound 19 (yy-0131b). 1H NMR (400 MHz, CDCl3) δ: 1.05
(3H, d, J ) 7.2 Hz), 1.25-1.56 (6H, m), 2.96-3.04 (1H, m),
3.71-3.74 (1H, m), 4.22-4.27 (4H, m), 7.19 (1H, s), 7.50-7.54
(1H,m), 7.58-7.60 (1H, d, J ) 8.0 Hz), 7.93-7.97 (1H, m), 8.18
(1H, d, J ) 8.0 Hz), 8.64 (1H, br). Anal. Calcd for C18H21F3N4O3S:
C, 50.23; H, 4.92; N, 13.02. Found: C, 50.29; H, 4.95; N, 13.05.
Compound 20 (yy-0131c). 1H NMR (400 MHz, CDCl3) δ: 1.11
(3H, d, J ) 7.2 Hz), 1.25-1.55 (6H, m), 2.99-3.06 (1H, m),
3.60-3.63 (1H, m), 4.16-4.18 (1H, m), 4.31 (3H, s), 7.06 (1H,
s), 7.26 (1H, t, J ) 8.4 Hz), 7.60 (1H, t, J ) 8.4 Hz), 7.86 (1H, d,
J ) 8.4 Hz), 8.56 (1H, d, J ) 8.4 Hz), 10.43 (1H, br). Anal. Calcd
for C18H21F3N4O3S: C, 50.23; H, 4.92; N, 13.02. Found: C, 50.00;
H, 4.92; N, 12.92.
Compound 15g (as-124f). 1H NMR (400 MHz, CDCl3) δ:
1.62-1.71 (m, 10H), 3.12 (4H, t, J ) 4.0 Hz), 4.25 (s, 3H), 7.14
(s, 1H), 7.65-7.69 (m, 4H), 8.42 (br, 1H). 13C NMR (100 MHz,
CDCl3, ppm): 25.19, 26.71, 27.88, 40.61, 48.95, 105.91, 120.81,
121.80, 128.37, 134.54, 136.34, 140.86, 157.36. Anal. Calcd for
C19H23F3N4O3S: C, 51.34; H, 5.22; N, 12.61. Found: C, 51.43; H,
5.27; N, 12.29.
1
Compound 15j (as-103). H NMR (400 MHz, CDCl3) δ: 2.91
(t, 2H, J ) 8.0 Hz), 3.93 (t, 2H, J ) 8.6 Hz), 4.24 (s, 3H), 6.96 (d,
1H, J ) 7.2 Hz), 7.0 (dd, 1H, J ) 1.2 Hz, 7.6 Hz), 7.09 (d, 1H, J
) 7.6 Hz), 7.20 (t, 1H, J ) 7.6 Hz), 7.62 (d, 1H, J ) 8.4 Hz),
7.66-7.69 (m, 2H), 7.78-7.81 (m, 2H), 7.87 (s, 1H). 13C NMR
(100 MHz, CDCl3, ppm): 28.07, 40.61, 50.21, 105.34, 115.17,
120.14, 124.22, 125.45, 128.02, 128.97, 131.96, 141.35. Anal. Calcd
for C20H17F3N4O3S: C, 53.33; H, 3.80; N, 12.44. Found: C, 52.92;
H, 3.57; N, 12.18.
Compound 15k (yy-0187a). 1H NMR (400 MHz, CDCl3) δ:
1.63-1.66 (1H, m), 1.84-1.87 (1H, m), 1.99-2.04 (1H, m),
2.19-2.25 (2H, m), 2.23-2.25 (1H, m), 3.79-3.82 (1H, m),
3.96-3.98 (1H, m), 4.21-4.23 (1H, m), 4.26 (3H, s), 7.05 (1H,
s), 7.73 (2H, d, J ) 8.8 Hz), 7.81 (2H, d, J ) 8.8 Hz), 8.20 (1H,
s). Anal. Calcd for C18H18F6N4O3S: C, 44.63; H, 3.75; N, 11.57.
Found: C, 44.70; H, 3.76; N, 11.32.
Compound 23a (as-236). 1H NMR (400 MHz, CDCl3) δ: 3.02
(4H, t, J ) 4.8 Hz), 3.76 (4H, t, J ) 4.8 Hz), 4.28 (s, 3H), 7.0 (s,
1H), 7.82-7.79 (m, 4H), 7.86 (s, 1H). Anal. Calcd for
C16H17F3N4O4S: C, 45.93; H, 4.10; N, 13.39. Found: C, 45.92; H,
4.19; N, 13.17.
Compound 23b (as-270). 1H NMR (400 MHz, CDCl3) δ:
2.59-2.63 (6H, m), 3.05 (4H, br), 3.53-3.62 (6H, m), 4.27 (3H,
s), 7.14 (1H, s), 7.65 (2H, d, J ) 8.8 Hz), 7.75 (2H, d, J ) 8.8
Hz), 8.69 (1H, s). 13C NMR (100 MHz, CDCl3, ppm): 40.74, 46.02,
52.40, 54.19, 57.49, 61.93, 67.48, 72.14, 105.88, 120.17, 129.13,
130.72, 136.36, 141.90, 157.30. Anal. Calcd for C20H26F3-
N5O5S·H2O: C, 45.88; H, 5.39; N, 13.38. Found: C, 46.40; H, 5.08;
N, 13.30.
1
Compound 15l (as-625). H NMR (400 MHz, CDCl3) δ: 2.43
(2H, t, J ) 6.0 Hz), 2.67 (2H, t, J ) 6.0 Hz), 3.14 (2H, t, J ) 6.0
Hz), 3.21 (2H, t, J ) 6.0 Hz), 3.78 (3H, s), 4.27 (3H, s), 7.0(1H,
s), 7.77 (4H, br), 7.88 (1H, s). HRMS calcd for C18H20F3N5O4S,
457.12831; found, 458.11204 M + 1. Anal. Calcd for C18H20-
F3N5O4S: C, 47.06; H, 4.39; N, 15.24. Found: C, 46.51; H, 4.39;
N, 14.57.
1
Compound 15m (yy-0233a). H NMR (400 MHz, CDCl3) δ:
Compound 23c (as-254). 1H NMR (400 MHz, DMSO) δ: 1.33
(9H, s), 2.84-2.85 (4H, m), 3.38 (4H, m), 4.17 (3H, s), 7.56
2.72 (6H, s), 4.28 (3H, s), 7.01 (1H, s), 7.76-7.80 (4H, s), 7.95

3740 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Sun et al.
(1H, s), 7.75 (2H, d, J ) 8.8 Hz), 8.01 (2H, d, J ) 8.8 Hz),
(compounds 2n, 2k, 15b, 15n, 24e, and 28a; plus 6 from a previous
publication). These compounds were selected based on their range
of activities and diversity of structures. MFTA was used to map
the test set to the previously generated molecular supergraph and
to calculate their descriptor values. Then these values were applied
to the previously generated QSAR equation and the test set activities
predicted. The validity of the correlation was further checked by
randomizing the data and structures. MFTA was also used to
generate color-coded molecular supergraphs, reflecting the quantita-
tive effect on activity of each descriptor in each position.
CF3-Bearing Ligands Bound to Proteins. Identification of CF3-
substituted ligands was achieved by searching the Protein Data Bank
(PDB32) with Relibase+.33–35 The resulting 132 hits were individu-
ally inspected in ReliView and catalogued for the presence of
protein side-chains, water, ions or other small molecules within 4
Å of the fluorine atoms. Selected examples were examined further
with DeepView36 and displayed with PyMOL37 in the construction
of Figures 7–10.
10.80 (1H, s).
1
Compound 23d (yy-0168a). H NMR (400 MHz, CDCl3) δ:
1.25-1.34 (2H, m), 1.43(9H, s), 1.75-1.80 (2H, m), 2.76-2.86
(2H, m), 3.30-3.33 (1H, m), 3.90-3.97 (2H, s), 4.28 (3H, s), 4.36
(1H, d, J ) 8 Hz), 6.97 (1H, s), 7.76 (2H, d, J ) 7.2 Hz), 7.89
(1H, s), 7.91 (2H, d, J ) 7.2 Hz).
Compound 24e (as-244). 1H NMR (400 MHz, CDCl3) δ:
2.90-2.92 (4H, m), 2.96-2.98 (4H, m), 4.25 (3H, s), 5.28 (1H,
s), 7.04 (1H, s), 7.71 (2H, d, J ) 9.2 Hz), 7.76 (2H, d, J ) 9.2
Hz), 8.17 (1H, s). Anal. Calcd for C16H18F3N5O3S: C, 46.04; H,
4.35; N, 16.78. Found: C, 45.58; H, 4.36; N, 16.26.
1
Compound 24f (yy-0251). H NMR (400 MHz, Actone-d6) δ:
1.33-1.42 (2H, m), 1.65-1.69 (2H, m), 2.49-2.55 (2H, m),
2.93-2.97 (2H, m), 3.14-3.21 (1H, m), 4.25 (3H, s), 7.42 (1H,
s), 7.88 (2H, d, J ) 8.4 Hz), 7.98 (2H, d, J ) 8.4 Hz), 9.96 (1H,
s). Anal. Calcd for C17H20F3N5O3S·0.5EtOAc: C, 47.99; H, 5.09;
N, 14.73. Found: C, 48.30; H, 5.19; N, 15.21.
Compound 28a (yy-0150a). 1H NMR (400 MHz, CDCl3) δ:
1.48-1.49 (1H, m), 1.58-1.77 (3H, m), 2.05-2.13 (1H, m),
3.16-3.24 (1H, m), 3.58 (3H, s), 3.75-3.77 (1H, m), 4.25 (3H,
s), 4.75-4.77 (1H, m), 6.99 (1H, s), 7.22 (2H, d, J ) 6.8 Hz),
7.78 (2H, d, J ) 6.8 Hz), 7.91 (1H, s). Anal. Calcd for
C19H21F3N4O5S: C, 48.10; H, 4.46; N, 11.81. Found: C, 48.14; H,
4.50; N, 11.66.
Acknowledgment. This work was supported by a research
grant from the American Lung Association, and Public Health
Service grants AI056179 and AI071002 from NIH/NIAID (to
R.K.P.) and by the National Institutes of Health 1 U54
HG003918 (to J.P.S.). We are grateful to Ernest Murray for
synthetic assistance.
Compound 28b (as-248). 1H NMR (400 MHz, CDCl3) δ: 1.38
(9H, s), 1.48-1.78 (5H, m), 2.12 (1H, d, J ) 13.6 Hz), 3.27 (1H,
dt, J ) 12.8 Hz, 3.2 Hz), 3.74 (1H, d, J ) 9.2 Hz), 4.27 (3H, s),
4.65 (1H, d, J ) 5.2 Hz), 9.96 (1H, s), 7.71 (2H, d, J ) 8.8 Hz),
7.81 (2H, d, J ) 8.8 Hz).
Supporting Information Available: Elemental analyses. Com-
pounds S5, S6, S7, and S8 were reported previously and are pictured
here for the reader’s convenience.) This material is available free
of charge via the Internet at http://pubs.acs.org.
Compound 28c (as-267). 1H NMR (400 MHz, CDCl3) δ:
1.23-1.62 (6H, m), 2.20 (1H, m), 3.08 (1H, t, J ) 13.2 Hz),
3.53-3.59 (1H, m), 3.77 (1H, d, J ) 14.0 Hz), 3.84 (1H, t, J )
10.4 Hz), 4.00-4.06 (1H, m), 4.26 (3H, s), 7.11 (1H, s), 7.74-7.81
(4H, m), 8.48 (1H, s). Anal. Calcd for C18H21F3N4O4S: C, 48.43;
H, 4.74; N, 12.55. Found: C, 48.33; H, 4.84; N, 12.23.
References
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1
Compound 28d (yy-0194a). H NMR (400 MHz, DMSO-d6)
δ: 1.38-1.41 (2H, m), 1.70-1.72 (2H, m), 2.66-2.70 (2H, m),
3.07-3.15 (2H, m), 3.45-3.52 (2H, m), 4.64 (1H, d, J ) 3.6 Hz),
7.52 (1H, s), 7.72 (2H, d, J ) 8.8 Hz), 7.96 (2H, d, J ) 8.8 Hz),
10.74 (1H, s). Anal. Calcd for C17H19F3N4O4S: C, 47.22; H, 4.43;
N, 12.96. Found: C, 47.43; H, 4.41; N, 12.72.
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Compound 29e (as-251). 1H NMR (400 MHz, CDCl3) δ:
1.23-1.62 (6H, m), 2.20 (1H, m), 3.08 (1H, t, J ) 13.2 Hz),
3.53-3.59 (1H, m), 3.77 (1H, d, J ) 14.0 Hz), 3.84 (1H, t, J )
10.4 Hz), 4.00-4.06 (1H, m), 4.26 (3H, s), 7.11 (1H, s), 7.74-7.81
(4H, m), 8.48 (1H, s). Anal. Calcd for C18H19F3N4O5S: C, 46.95;
H, 4.16; N, 12.17. Found: C, 47.10; H, 4.33; N, 11.54.
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Compound 29f (yy-0173a). 1H NMR (400 MHz, CDCl3) δ:
1.55-1.70 (2H, m), 1.81-1.96 (2H, m), 2.63-2.74 (2H, m),
2.84-2.89 (1H, m), 3.42-3.45 (1H, m), 3.65-3.67 (1H, m), 4.27
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Computational Methods. QSAR by Molecular Field
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the training set structures (compounds 1, 2j, 2o, 9a, 13, 14, 15a,
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3s, 5, 7, and 8 from a previous publication) to construct a molecular
supergraph, providing a common reference framework for the
chosen descriptor set. Then MFTA’s PLS (partial least-squares)
regression function was used to build statistical models, the
predictivity of which was assessed by the leave-25%-out cross-
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charge (Q), the effective environment van der Waal radius (Re),
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