Design, Conformation, and Crystallography of 2-Naphthyl Phenyl Ethers as Potent Anti-HIV Agents

Article abstract of DOI:10.1021/acsmedchemlett.6b00390

Catechol diethers that incorporate a 7-cyano-2-naphthyl substituent are reported as non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Many of the compounds have 1-10 nM potencies toward wild-type HIV-1. An interesting conformational effect allows two unique conformers for the naphthyl group in complexes with HIV-RT. X-ray crystal structures for 4a and 4f illustrate the alternatives.

Full text of DOI:10.1021/acsmedchemlett.6b00390

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Letter
Design, Conformation, and Crystallography of 2-
Naphthyl Phenyl Ethers as Potent Anti-HIV Agents
Won-Gil Lee, Albert H. Chan, Krasimir A. Spasov, Karen S. Anderson, and William L Jorgensen
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00390 • Publication Date (Web): 31 Oct 2016
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Design, Conformation, and Crystallography of 2-Naphthyl Phenyl
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Won-Gil Lee,† Albert H. Chan,‡ Krasimir A. Spasov, ‡ Karen S. Anderson,‡,* and
William L. Jorgensen†,*
†Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, ‡Department of Pharmacology, Yale
University School of Medicine, New Haven, CT 06520-8066
.
KEYWORDS: Anti-HIV agents, NNRTIs, protein crystallography.
ABSTRACT: Catechol diethers that incorporate a 7-cyano-2-naphthyl substituent are reported as non-nucleoside inhibitors
of HIV-1 reverse transcriptase (NNRTIs). Many of the compounds have 1 – 10 nM potencies towards wild-type HIV-1. An
interesting conformational effect allows two unique conformers for the naphthyl group in complexes with HIV-RT. X-ray
crystal structures for 4a and 4f illustrate the alternatives.
Though significant advances have been made in the treat-
ment of HIV/AIDS, the rate of new infections has remained
constant near 2.5 million people per year, the number of
people living with the disease continues to increase and
now totals about 40 million, and the number of associated
deaths in 2015 was 1.2 million.1 Thus, there remains a
pressing need for new therapeutic agents, especially in
view of the uncertainties with mutation of the virus and
long-term use of the current approved drugs.2 To this end,
we have directed efforts towards the discovery of im-
proved non-nucleoside inhibitors of HIV-1 reverse tran-
scriptase (NNRTIs),3 which have been a central component
of anti-HIV chemotherapy.4,5 There are five FDA-approved
compounds in the class including efavirenz and rilpivirine,
which have particular importance since they are compo-
nents of the one-a-day oral therapies Atripla and Com-
plera, respectively.4
Though we have discovered new NNRTIs featuring sev-
eral different chemotypes, the most promising NNRTIs are
in the catechol diether class, which evolved from a docking
hit.6-9 The design 1 led to some extraordinarily potent
NNRTIs including the dichloro (R5, Y = Cl) and difluoro
analogues, which have EC50 values of 0.055 and 0.320 nM
in an assay using human MT-2 cells infected with wild-type
(WT) HIV-1.6 However, the cyanovinyl group in 1 may be
viewed as a potential liability in view of its possible partic-
ipation in Michael additions leading to off-target covalent
modifications. Though rilpivirine also has a cyanovinyl
group, another NNRTI, fosdevirine, was abandoned after
phase IIb clinical trials.10 Metabolites that arose from cys-
teine addition of glutathione to its cyanovinyl group were
implicated as the source of seizures in 5 of 20 patients.
In order to avoid the cyanovinyl group, results of free-
energy perturbation calculations led us to explore several
bicyclic replacements including the indolizine variant 2,
which provided very potent compounds.5 In particular, the
parent 2a (R5, Y = H) is impressive. In the standard MT-2
assay it has an EC50 of 0.38 nM towards WT HIV-1, while in
single-round infectivity assays with CD4+ T cells from
blood donors it gives EC50 values of 1, 2, and 3 nM towards
WT HIV-1, and the most common clinical variants bearing
the Y181C and K103N mutations in RT.9 For comparison,
the results for efavirenz are 15, 41, and 806 nM, and for
rilpivirine, 13, 51, and 13 nM, respectively.9 2a also re-
mains highly potent towards the K101P variant (1 nM),
while efavirenz and rilpivirine are not effective (870 and
1142 nM). In addition, 2a shows no cytotoxicity towards T
cells (CC50 > 100 µM), and it has good aqueous solubility,
38 µg/mL. Rilpivirine is significantly more cytotoxic (CC50
= 8 µM), and far less soluble (ca. 0.1 µg/mL). However,
oddly, in our MT-2 assays with virus containing the single
Y181C mutation, 2a has an EC50 of 310 nM, though it re-
mains potent towards the normally more challenging dou-
ble K103N/Y181C mutant at 11 nM.5 In the absence of an
explanation for the difference in results for Y181C, we
have explored additional bicyclic possibilities including 1-
naphthyl analogues 3.8 Though it was initially unclear if
their larger size would be accommodated in the NNRTI
binding site, compounds were obtained that performed
very well in the MT-2 assays such as 3b (R5 = H, Y = F) with
EC50s of 1, 8, and 6 nM towards the WT, Y181C, and
K103N/Y181C forms.
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We have also reported numerous x-ray crystal struc-
tures for catechol diethers bound to WT HIV-RT and vari-
ants.7-9,11-13 Consistent with the high potencies, the com-
plexes are tightly packed with multiple protein-ligand aryl-
aryl interactions and hydrogen bonds. The point is illus-
trated in Figure 1, which has been rendered from the crys-
tal structure of 3a (R5 = Y = H) with WT RT. In particular,
the 1-naphthyl group is in well-packed aryl-aryl interac-
tions with Tyr181, Tyr188, and Trp229. In viewing this
structure, it is difficult to imagine that the alternative at-
tachment for the naphthyl substituent at the 2-position
would not lead to a serious steric clash with Trp229. Nev-
ertheless, structure building with the BOMB program fol-
lowed by energy minimizations with MCPRO using OPLS
force fields was carried out for 2-naphthyl alternatives.14
Surprisingly, the resultant structures appeared to be viable
as long as the cyano group was moved to the 7-position as
in 4. In addition, three possible conformers were suggest-
ed by BOMB for the parent 4a with the cyano group point-
ed towards Pro95, above Tyr181, and below Trp229 (Fig-
ure 2). Thus, motivation arose to pursue the 2-naphthyl
series 4.
Figure 2. Rendering of a computed structure for the third con-
former of 4a with wild type HIV-1 RT. Carbon atoms of 4a are
colored yellow.
Scheme 1. Synthesis of 2-Naphthyl Phenyl Ethers 4
Reagents: (a) CuI, Cs2CO3, 2,2,6,6-tetramethyl-3,5-heptanedione,
dioxane, 100 °C, 48 h; (b) BBr3, DCM, -78 °C  0 °C, 3 h; (c)
K2CO3, DMF, 60 °C, 3h; (d) NH4OH, DCM, 16 h.
As summarized in Scheme 1 and detailed in the Sup-
porting Information, synthesis of the 26 analogues of 4
listed in Table 1 proceeded in a manner similar to that for
3,8 though much effort was needed for the preparation of
the various 2-hydroxy-7-cyanonaphthalenes. The substi-
tuted 2-hydroxynaphthalenes underwent Cu(I)-catalyzed
addition to 2-bromoanisoles to yield 2-naphthyl phenyl
ethers. The methoxy group was unmasked with BBr3 to
yield phenols, which were alkylated with N-Bz-protected
1-bromoethyluracil. The identity of assayed compounds
was confirmed by 1H and 13C NMR and high-resolution
mass spectrometry; HPLC analyses established purity as
>95%. Aqueous solubilities were measured using a stand-
ard shake-flask procedure, as previously described.8,15 The
procedures for the human MT-2 T-cell assays have also
been described in detail.6-8,16,17 Triplicate assays using the
IIIB and variant strains of HIV-1 were performed yielding
EC50 values as the dose required to achieve 50% protection
of the infected MT-2 cells as well as CC50 values for inhibi-
tion of MT-2 cell growth by 50%.
The activity results for the 2-naphthyl ethers are sum-
marized in Table 1 along with corresponding data for key
compounds in the 1 - 3 series and for four FDA-approved
NNRTIs. The parent 4a did turn out to be a good inhibitor
of the WT virus with an EC50 of 22 nM, though it shows
only 2 – 4 µM potency towards the two variant strains. The
performance of the isomeric 3a is substantially better.
However, optimization of the substituents in 4 could be
expected to provide gains. For R5, the viable options were
Figure 1. Mixed rendering from the crystal structure of 3a with
wild type HIV-1 reverse transcriptase. Carbon atoms of 3a are
colored yellow. Some residues in front of the ligand have been
removed for clarity. The PDB code is 4WE1.
2
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Table 1. Inhibitory Activity (EC50, nM)a for HIV-1 and Cyto-
1
2
3
4
5
6
7
8
toxicity (CC50, µM) in MT-2 Cell Assays
K103N/
R5
F
H
H
F
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
Z
-
-
-
-
-
-
-
Y
F
Cl
H
F
H
F
F
H
Cl
Me
F
F
WT
0.32
0.31
0.38
0.40
0.53
1.1
1.9
22
Y181C Y181C
CC50
45
18
>100
50
>100
>100
>100
15
12
6
>100
>100
>100
>100
>100
12
15
9
13
16
85
1a
1b
2a
2b
3a
3b
3c
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
46
24
310
250
19
11
10
15
binding site where there is limited space, though Z = Cl and
CH3 could be accommodated with the latter generally pre-
ferred as in 4f and 4g, and 4t and 4u. For Y, a range of op-
tions was explored in 4h – 4o with Z = CH3. There was op-
timism that larger groups for Y would benefit the activity
towards the variant viral strains as the group might occupy
some of the space vacated by the Y181C mutation. Though
this strategy had worked for another NNRTI series,18 CH3
emerged as the best choice for Y, and the larger options in
4j – 4o showed a narrow range of WT activities, 6 – 21 nM,
and poorer performance for the variant HIV strains. It ap-
pears that the substituent Y is directed more towards
Pro95 and is not optimally oriented to fill the Y181C void.
The analyses above are also consistent with x-ray crystal
structures that were obtained for 4a and 4f with WT RT
(Figure 3). The procedures were similar to those in previ-
ous reports7-9,11-14 and are detailed in the Supporting In-
formation.19 Strikingly, 4a is in the conformation with the
cyano group projecting over Tyr181. This conformation is
only possible when Z = H to avoid a steric clash between
8.0
5.6
2600
890
800
90
60
58
42
62
150
630
400
900
670
200
690
NA
NA
1200
1100
72
31
1200
27
28
330
6.0
21
9
4000
890
2900
310
890
280
120
150
300
990
100
1200
1600
800
790
1700
790
9400
4100
1600
980
3800
500
410
NA
5600
NA
30
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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53
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58
59
60
14
4.9
5.0
7.8
6.2
5.0
3.5
6.0
21
16
18
17
10
Cl
Me
Me
Cl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Cl
Me
Me
Et
Pr
iPr
cPrCH2
MeO
EtO
MOM
3-Me
3,4-Me
H
Cl
F
F
Me
Cl
>100
>100
16
15
160
580
26
5
>100
>100
>100
28
>100
45
82
>100
6
24
F
F
F
F
F
F
Cl
H
H
4s
4t
7.0
3.0
58
3.6
1.9
18
1300 NA
110
2
Cl
Me
F
Me
Me
Me
H
4u
4v
4w
4x
4y
4z
Me
F
6-CNc
9
nevd
efvd
etvd
rpvd
NA
10
>100
15
11
1
0.67
8
5
0.65
2
8
a For 50% protection in MT-2 cells; NA for EC50 > CC50 or > 100
µM. b For 50% inhibition of MT-2 cell growth. c 6-CN rather than
d
7-CN analogue. nevirapine (nev); efavirenz (efv); etravirine
(etv); rilpivirine (rpv)
known to be limited8 such that R5 = F yields similar poten-
cies as R5 = H, e.g., 4a and 4r, and R5 = Cl is already too
large (4y vs. 4u). Overall, the SAR data are consistent with
the structure in Figure 2. For example, a substituent, even
CH3, at C3 of the naphthyl group as in 4p and 4q is disfa-
vored since the substituent would be placed over the cen-
tral phenyl ring. For 2-methyldiphenyl ether such a con-
formation is not an energy minimum with the OPLS-AA
force field; the only two minima are I and II in which a
phenyl hydrogen atom is over a ring center. Furthermore,
shift of the cyano group to C6 leads to a 60-fold reduction
in WT potency (4a vs. 4z) owing to the expected steric
conflict with Trp229.
The structure in Figure 2 and modeling of derivatives
did indicate that there should be a wider range of options
for Z and especially Y. Z points into the center of the NNRTI
Figure 3. Renderings from the crystal structures of 4a (top) and
4f (bottom) with wild type HIV-1 reverse transcriptase.
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Table 2. Experimental Aqueous Solubility at pH 6.5 (S in
µg/mL) and Computed ClogP
* william.jorgensen@yale.edu
1
2
3
4
5
6
7
8
Notes
Cmpd
1a
1b
2a
2b
3a
3b
3c
S
ClogP
3.09
3.38
2.70
3.14
3.30
3.59
3.73
Cmpd
4e
4f
nev
efv
etv
rpv
rpv
S
28.2
ClogP
3.95
4.52
2.65
4.67
5.22
5.75
5.75
The authors declare no competing financial interests.
10.8
510
37.9
43.8
4.3
20.6
ACKNOWLEDGMENT
167a
68.0
Gratitude is expressed to the National Institutes of Health
(AI44616, GM32136, GM49551) for research support and for
a fellowship for AHC (AI122864). Crystal screening was con-
ducted with support in the Yale Macromolecular X-ray Core
Facility (1S10OD018007-01). This work is based upon re-
search conducted at the Northeastern Collaborative Access
Team beamlines, which are funded by the National Institute of
General Medical Sciences from the National Institutes of
Health (P41 GM103403). This research used resources of the
Advanced Photon Source, a U.S. Department of Energy (DOE)
Office of Science User Facility operated for the DOE Office of
Science by Argonne National Laboratory under Contract No.
DE-AC02-06CH11357.
<<1a
0.02a,b
0.24a,c
9.1
82.9
a See Ref. 8. b pH 7. c pH 7.4.
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Z and the central phenyl ring, e.g., 4a, 4b, 4c, 4r, and 4s. In
these cases, the EC50 values for the two variant HIV strains
are relatively high, which likely arises from loss of the
greater contact between the inhibitors and Tyr181 in this
conformation. When the 1-position is substituted, the con-
formation with the cyano group projecting below Trp229
(Figure 2) is expected to be preferred as found for 4f in
Figure 3. Overall, the parent and fluoro-substituted 1-
naphthyl analogues 3a – 3c have significantly greater po-
tency than the 2-naphthyl compounds 4a and 4r. In view-
ing the crystal structures and computed ones, a simple
explanation is not obvious. However, when one optimizes
the complexes with the OPLS/CM1A force field14 for 3a as
in Figure 1 and 4a as in Figure 2, the protein-ligand inter-
action energy is lower for 3a than 4a by 2.6 kcal/mol. This
arises mostly from improved interactions for 3a with
Tyr181, Tyr188, and Trp229 by 0.3, 0.3, and 1.2 kcal/mol,
respectively. The preference carries over to the mutant
strains, and substitutions at R5, Y, and Z in 4 were not able
to compensate in full.
Overall, 4d - 4i are the most promising NNRTIs in the 2-
naphthyl series. 4g and 4h have activities of 5.0 and 3.5 nM
towards WT HIV-1, ca. 50 nM towards the Y181C strain,
and 120-150 nM toward the double mutant. They also
exhibit no T-cell cytotoxicity, CC50 > 100 µM. In addition,
aqueous solubilities were measured for 4e and 4f and fall
in the acceptable range for oral drugs (Table 2).20 The cyto-
toxicities and solubilities of the approved NNRTIs etraviri-
ne and rilpivirine are much less favorable. Previously un-
reported solubility results for 3b and 3c are also provided
in Table 2 and with 3a show the seemingly unconventional
pattern of increasing solubility with increasing fluorina-
tion. However, similar boosts have been found previously
for other cases with fluorine separated from an oxygen
atom by 3 carbons.21,22
ABBREVIATIONS
HIV, human immunodeficiency virus; HIV-RT, HIV reverse
transcriptase; NNRTI, non-nucleoside inhibitor of HIV-RT; Bz,
benzoyl; DCM, dichloromethane; DMF, dimethylformamide;
HPLC, high-performance liquid chromatography.
REFERENCES
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ASSOCIATED CONTENT
Supporting Information. Synthetic procedures, NMR and
HRMS spectral data for compounds 4a-z, and crystallographic
details. The crystal structure data for the complexes of 4a and
4f with HIV-RT have been deposited in the RCSB Protein Data
Bank with the PDB codes 5TEP and 5TER. This information is
available free of charge via the Internet at http://pubs.acs.org
.
AUTHOR INFORMATION
(10) Castellino, S.; Groseclose, M. R.; Sigafoos, J.; Wagner, D.; de
Serres, M.; Polli, J. W.; Romach, E.; Myer, J.; Hamilton, B. Central
Nervous System Disposition and Metabolism of Fosdevirine
(GSK2248761), a Non-Nucleoside Reverse Transcriptase Inhibi-
Corresponding Authors
* karen.anderson@yale.edu
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MS Investigation into Central Nervous System Toxicity. Chem.
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do-Macias, R.; Jorgensen, W. L.; Anderson, K. S. Crystal Structures
of HIV-1 Reverse Transcriptase with Picomolar Inhibitors Reveal
Key Interactions for Drug Design. J. Am. Chem. Soc. 2012, 134,
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