Novel indole sulfides as potent HIV-1 NNRTIs

Article abstract of DOI:10.1016/j.bmcl.2016.02.006

In a previous communication we described a series of indole based NNRTIs which were potent inhibitors of HIV replication, both for the wild type and K103N strains of the virus. However, the methyl ether functionality on these compounds, which was crucial for potency, was susceptible to acid promoted indole assisted S_N1 substitution. This particular problem did not bode well for an orally bioavailable drug. Here we describe bioisosteric replacement of this problematic functional group, leading to a series of compounds which are potent inhibitors of HIV replication, and are acid stable.

Full text of DOI:10.1016/j.bmcl.2016.02.006

Accepted Manuscript
Novel Indole Sulfides as Potent HIV-1 NNRTIs
Siobhan Brigg, Nicole Pribut, Adriaan E. Basson, Moscos Avgenikos, Reinhardt
Venter, Margaret A. Blackie, Willem A.L. van Otterlo, Stephen C. Pelly
PII:
S0960-894X(16)30109-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.02.006
BMCL 23557
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 January 2016
2 February 2016
3 February 2016
Please cite this article as: Brigg, S., Pribut, N., Basson, A.E., Avgenikos, M., Venter, R., Blackie, M.A., van Otterlo,
W.A.L., Pelly, S.C., Novel Indole Sulfides as Potent HIV-1 NNRTIs, Bioorganic & Medicinal Chemistry Letters
(2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.02.006
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Novel Indole Sulfides as Potent HIV-1 NNRTIs
Stephen C. Pelly

Bioorganic & Medicinal Chemistry Letters
Novel Indole Sulfides as Potent HIV-1 NNRTIs
Siobhan Brigga, Nicole Pributa, Adriaan E. Bassonb, Moscos Avgenikosa, Reinhardt Ventera, Margaret A.
Blackiea, Willem A. L. van Otterloa and Stephen C. Pellya*.
a Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, 7602 Matieland, Western Cape, South Africa.
b National Institute for Communicable Diseases, Centre for HIV and STI: HIV Virology Section, Private Bag X4, Sandringham, Johannesburg, 2131, South
Africa.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
In a previous communication we described a series of indole based NNRTIs which were potent
inhibitors of HIV replication, both for the wild type and K103N strains of the virus. However,
the methyl ether functionality on these compounds, which was crucial for potency, was
susceptible to acid promoted indole assisted SN1 substitution. This particular problem did not
bode well for an orally bioavailable drug. Here we describe bioisosteric replacement of this
problematic functional group, leading to a series of compounds which are potent inhibitors of
HIV replication, and are acid stable.
Keywords:
HIV
NNRTI
Indole
2009 Elsevier Ltd. All rights reserved.
Sulfides
Human immunodeficiency virus type-1 (HIV-1) remains the
major cause of the life threatening condition known as acquired
immunodeficiency syndrome (AIDS). With no cure predicted for
the near future, this disease remains a significant pandemic with a
heavy socio-economic toll, especially for developing nations
where it is most prevalent.1 Fortunately, due to an extensive
amount of research in the area and the subsequent development
of numerous therapeutic agents, it is possible to control the viral
levels in afflicted individuals with chronic medication.2-4 Front
line anti-retroviral treatment usually consists of a cocktail of
three drug entities, all of which target the essential enzyme HIV
reverse transcriptase (RT).1 This enzyme is in fact unique in HIV
therapy in that it offers two sites for therapeutic intervention,
which have been well exploited. The first of these is at the actual
catalytic site and here several licensed inhibitors in the form of
DNA base mimics, or nucleoside reverse transcriptase inhibitors
(NRTIs), are highly effective inhibitors of HIV replication.
Secondly, located just 10 Å from this catalytic site is a small cleft
in the enzyme which is amenable to the binding of small
hydrophobic inhibitors. These non-nucleoside reverse
transcriptase inhibitors (NNRTIs) cause an allosteric twist in the
enzyme, inactivating its DNA polymerase function, and these
compounds are also potent inhibitors of HIV replication.5 The
first-line highly active anti-retroviral therapy (HAART) regimen
usually consists of two NRTIs as well as an NNRTI, but
unfortunately all the drugs in these classes are susceptible to
resistance inactivation, and many of them display undesirable
side effects with long term use.6, 7 For this reason, until a cure for
the disease is found, there is a constant need to fill the drug
development pipeline with new inhibitors capable of tackling
problematic resistant strains of the virus. This is of particular
need in sub-Saharan Africa which has the highest incidence of
HIV, and where patient compliance, especially in rural areas, is
problematic due to a variety of logistical and socio-economic
reasons.8
In a previous communication, we discussed the design and
synthesis of several indole methyl ether derivatives (for example
1, Figure 1) which exhibited low nano-molar potency against
10
wild type and the problematic K103N strains of HIV-1.9,
Although the indole nucleus has been well validated as a scaffold
for the design of novel NNRTIs,11-18 we discovered a serious
problem with our particular compounds during acidic workup. In
this process, acid activation of the methyl ether would lead to the
elimination of methanol facilitated by the indole, and subsequent
attack by water would produce the corresponding alcohol 2
(Figure 1), which was poorly effective against HIV RT. In fact,
having discovered this instability we exploited it in our synthesis
of these analogues. Although this was convenient from a
synthetic chemistry perspective, it did not bode well for an orally
bioavailable drug. In this article we describe the preparation of a
bioisosteric replacement of the problematic labile methyl ether to
afford potent and stable HIV NNRTIs.

initially planned route followed a simple strategy outlined by
Hiremath et al.,20 involving a copper mediated coupling of
aniline to the appropriate 3-bromoindole. However, in our hands
this coupling could not be repeated and after a significant effort,
we reverted to the more complicated procedure shown in Scheme
1.21 To this end, commercially available 5-chloro-
anthranilonitrile 5 was converted into the carbamate 6 using ethyl
chloroformate. In the presence of sodium hydride, ethyl
chloroacetate was substituted onto the carbamate nitrogen with
concomitant intramolecular nucleophilic addition to the nitrile,
leading to the desired indole scaffold 7 in good yield.
Functionalization of the resulting amine however proved to be
problematic. In the end, the phenyl substituent was introduced by
way of a Buchwald coupling reaction, providing 8, albeit in poor
yield. Introduction of the ethyl substituent proved even more
troublesome and here we had to settle for a base promoted
substitution in very poor yield to afford 9. Part of the reason for
the poor yield was due to hydrolysis of the carbamate at the
indole nitrogen under these strongly basic conditions, which was
followed by the undesirable alkylation of the indole.
Figure 1. Our previously synthesized NNRTI 1 undergoes SN1 substitution in
the presence of aqueous acid leading to the alcohol 2 which is a poorly
effective NNRTI.
In our first attempt at synthesizing a more stable analogue, we
made use of a bioisosteric replacement of the labile methyl ether
3, opting instead for the ethyl amine analogue 4 (Figure 2). With
the nitrogen attached directly to the indole’s 3-position, acid
promoted elimination of this functional group would not be
possible. Molecular modelling of this compound indicated that it
would indeed be well accommodated in the non-nucleoside
inhibitor binding pocket (NNIBP),19 with the desired double
hydrogen bond interactions to the backbone of Lys101
maintained, as well as - interactions to Tyr181 and the
conserved residue, Trp229. Furthermore, the ethyl chain
extending off the nitrogen neatly occupied the small hydrophobic
pocket in the region of Val179. However, a concerning revelation
regarding the binding mode was that in order to adopt the perfect
binding conformation, the newly introduced nitrogen’s p-orbital
would be required to be almost transverse to both the phenyl and
indole aromatic ring systems. We anticipated that this may result
in poor p-orbital overlap and impede the desired sp2 trigonal
planar character of the nitrogen, lending itself more toward an sp3
trigonal pyramidal nitrogen. Although the change in geometry of
the newly introduced nitrogen system could also be well
accommodated in the NNIBP, the concern lay in the fact that a
nitrogen with more sp3 character would be basic, and susceptible
to protonation, resulting in a mismatch in terms of an ionized
nitrogen now being required to fill the hydrophobic Val179
pocket. Nevertheless, we felt that the elegant simplicity in this
design in terms of overcoming the acid lability problem
warranted an investigation. Furthermore, if this strategy proved
successful it would eliminate the complication of the stereogenic
carbon found in the methyl ether analogues.
Nevertheless, following
a potassium phosphate mediated
deprotection of the indole which proceeded smoothly, the desired
3-amino indole derivative 4 was in hand and could be evaluated
in our HIV-1 assay to establish proof of concept. To this end, we
utilized an in vitro single-cycle, non-replicative phenotypic assay
to determine IC50 values,22, 23 and toxicity values were determined
using HEK293T cells and a tetrazolium-based colorimetric
assay.24 Disappointingly, this compound performed poorly with
an IC50 = 1.2 M. Possible explanations for this severe decrease
in potency could firstly be associated with the aforementioned
problem regarding the hybridization state of the nitrogen and
secondly, the presence of this electron rich nitrogen at the 3-
position of the indole could in fact weaken the hydrogen bond
donor character of the indole NH, a crucial interaction on our
compound design strategy. Therefore, we abandoned this scaffold
as a viable option to overcome the acid lability problem.
Scheme 1. Reagents and conditions: a) ethyl chloroformate, 93°C, 18 h,
85%; b) ethyl chloroacetate, NaH, DMF, 0°C
– r.t, 18 h, 82%; c)
bromobenzene, Pd(dba)2, Xphos, K3PO4, toluene, 130°C, 48 h, 32%; d)
NaOtBu, EtI, DMF, 0°C – r.t, 18 h, 11%; e) K3PO3, EtOH, 70°C, 4 h, quant.
We now turned our attention to a new strategy, that being to
install a poorer Lewis base in the form of a methyl sulfide 10
rather than the methyl ether 3 (Figure 3). Molecular modelling of
the methyl sulfide derivatives indicated that there was indeed
enough room to accommodate the larger sulfur atom, with its
methyl substituent extending into the small hydrophobic Val179
pocket. In addition, the desired double hydrogen bonding
interactions to the backbone of Lys101 were maintained, as well
as  interactions to the side chains of Tyr181 and the important
conserved residue, Trp229. Molecular modelling using Discovery
Studio’s CDocker suggested that although the sulfide analogues
could be accommodated in the pocket, they would be slightly
Figure 2. Bioisosteric replacement of the acid labile methyl ether 3 provided
compound 4 which modelled equally well.
Synthesis of the amine derivative 4 however, turned out to be
significantly more challenging than originally anticipated. The

poorer inhibitors, as attested to by slightly poorer energy scores
(Table 1). There are two possible reasons as to why this may be
the case, the first of which is simply that the larger methyl sulfide
may not be as well accommodated in the small hydrophobic
Val179 pocket. Secondly, the more electronegative ether located
at the three position of the indole draws more electron density
from the indole scaffold, rendering the indole N-H a better
hydrogen bond donor than is the case when the methyl sulfide is
located at this same position. It should also be mentioned that in
general, the R-enantiomers scored just slightly better according to
CDocker, however at this stage our assay tests were performed
on the racemates for all compounds.
on the phenyl ring system (compound 37), we decided to expand
upon this and synthesize the bromo derivative 40. To this end we
followed a very similar synthetic route although we utilized a
Boc protecting group and not the tosyl as had been employed for
the other methyl ether derivatives. In summary, the Boc protected
indole 33 was subjected to the acid promoted SN1 substitution
reaction in the presence of methanol. Similarly to the chloro-
derivative 28, this reaction was particularly reluctant to proceed
and the large excess of toluene sulfonic acid employed in the
procedure resulted in simultaneous removal of the Boc protecting
group, leading directly to the desired methyl ether indole 40.
Figure 3. Replacement of the methyl ether 3 with methyl sulfide 10 was
envisaged to lead to a more stable compound given the poorer Lewis basicity
of the sulfur. Modelling indicated that the larger sulfide group could still be
well accommodated in the small Val179 pocket.
To evaluate the effectiveness of this strategy, a small library of
methyl sulfide compounds was synthesized, as well as the
corresponding methyl ether compounds for comparative purposes
(Scheme 2). To this end, commercially available ethyl 5-chloro-
2-indole-carboxylate was acylated in the presence of aluminium
trichloride thereby affording the 3-acyl derivatives 11-15.
Subsequent protection of the indole nitrogen using either toluene
sulfonyl chloride or Boc anhydride afforded compounds 16-24.
Simple reduction of the ketone using sodium borohydride
provided the alcohols 25-33. For the synthesis of the methyl ether
analogues, the alcohols 25-28 were subjected to an acid catalyzed
SN1 substitution, facilitated by the indole, leading to compounds
34-37. This reaction proved to be particularly difficult for
compounds bearing an electron withdrawing group on the phenyl
ring (e.g. 37) no doubt due to the higher energy transition state
leading to the required SN1 intermediate. This interesting
revelation provided some insight into a possible means of
overcoming the acid lability of these methyl ether derivatives.
Finally, deprotection of the indole using potassium hydroxide
furnished the methyl ether indoles 1, 3, 38 and 39. For the
synthesis of the sulfide analogues, the Boc-protected alcohols 29-
32 were treated with Lawesson's reagent thereby converting the
alcohol into the corresponding thiol. Unfortunately, this reaction
proved to be somewhat low yielding throughout the series.
Nevertheless, methylation of the thiol provided the sulfides 45-48
and finally potassium phosphate mediated Boc deprotection
furnished the desired sulfides 10 and 49-51. In addition, having
stumbled upon a possible method of stabilizing the methyl ether
derivatives by incorporating an electron withdrawing substituent
Scheme 2. Reagents and conditions: a) aryl acid chloride, AlCl3, DCE, 2 h,
0°C - 85°C, 47% - 65%; b) p-TsCl, NaH, DMF, 18 h, 0°C - r.t., 42% - 79%;
c) Boc2O, DMAP, THF, 3 h, r.t., 63% - 94%; d) NaBH4, EtOH, THF, 3 h,
0°C - r.t., 75% - 99%; e) p-TsOH, MeOH, 18 h, r.t., 11% - 63%; f) KOH,
EtOH, THF, 4 h, r.t., 72% - 100%; g) Lawesson's Reagent, toluene, 3 h,
reflux, 27% - 53%; h) MeI, Et3N, DCM, 18 h, r.t., 76% - 85%; i) K3PO4,
EtOH, 1 h, 70°C, 67% - quant.
To evaluate the importance of the ester functionality at the
indole’s 2-position on the sulfide compounds, an analogue was
synthesized lacking this group (Scheme 3). As would be
expected, molecular modelling indicated that this compound
would be a significantly less effective inhibitor of HIV RT. To
this end, commercially available 5-chloroindole 52 was acylated
using benzoyl chloride and then the indole was protected as the
Boc carbamate, affording 53. Reduction of the ketone proceeded
smoothly giving alcohol 54 which was converted into the thiol 55

using Lawesson’s reagent. Finally, methylation of the thiol
afforded the sulfide 56 and following a Boc-deprotection
facilitated by potassium phosphate, the desired sulfide 57 was in
hand ready for testing.
Having synthesized a small library of methyl ether and methyl
sulfide analogues, we were now in a position to compare their
anti-viral efficacy in our phenotypic assay (Table 1).22-24
Consistent with our previous results,9 the methyl ether derivatives
were all very effective low nano-molar inhibitors of HIV-1
replication. Interestingly, the modelling results correlated well
with the observed HIV assay data. In general, the methyl sulfide
compounds obtained slightly poorer CDocker Energy values in
comparison to the methyl ether derivatives (Table 1), and
similarly, their IC50 values were all just slightly less potent than
their corresponding methyl ether analogues. Nevertheless, the
methyl sulfide compounds remained potent inhibitors of HIV-1
replication with the exception of compound 57, which lacks the
ester group at the 2-position of the indole. Since this compound
cannot form a second hydrogen bond to Lys101 it scores
significantly less well in the CDocker docking protocol, and as
expected, also performs significantly more poorly in the HIV
assay.
Scheme 3. Reagents and conditions: a) aryl acid chloride, AlCl3, DCE, 2 h,
0°C - 85°C, 47%; b) Boc2O, DMAP, THF, 3 h, r.t., 83%; c) NaBH4, EtOH,
THF, 3 h, 0°C - r.t., 90%; d) Lawesson's Reagent, toluene, 3 h, reflux, 46%;
e) MeI, Et3N, DCM, 18 h, r.t., 71%; f) K3PO4, EtOH, 1 h, 70°C, 72%.
Table 1. Modelling data and HIV-1 phenotypic assay data and toxicity data
Compound
R1
R2
R3
R4
IC50
/M
CC50
/M
26.7
35.9
27.4
26.8
26.4
26.1
32.0
29.6
28.6
52.7
CDocker
Energy
-OMe
-OMe
-OMe
-OMe
-OMe
-SMe
-SMe
-SMe
-SMe
-SMe
-CO2Et
-CO2Et
-CO2Et
-CO2Et
-CO2Et
-CO2Et
-CO2Et
-CO2Et
-CO2Et
-H
-H
-CH3
-CH3
-Cl
-H
-CH3
-H
-49.8
-51.8
-53.1
-51.1
-50.6
-43.7
-41.5
-44.5
-41.9
-30.0
0.016
0.034
0.020
0.033
0.020
0.039
0.060
0.038
0.042
9.95
3
1
38
39
40
10
49
50
51
57
-H
-Br
-H
-H
-H
-CH3
-CH3
-Cl
-CH3
-H
-H
-H
-H
Note: CDocker Energy score values (KCal.mol-1) are calculated using the CDocker docking protocol,25 launched from within Biovia Discovery studio 2016.
Lower values imply a better docking. All CDocker Energy values are for the R-enantiomers, which generally score just slightly better than the S-enantiomers.
The IC50 and CC50 describe the concentration of each compound that inhibits viral infection by 50% or decreases cell viability by 50%, respectively. These assays
were performed on the racemates in each case. Compounds 1 and 3 have been reported in a previous communication,9 but are included here for comparative
purposes to the sulfide analogues.
Having established that the methyl sulfide compounds were
potent inhibitors of HIV-1 replication, we now set about
investigating whether these compounds would be less susceptible
to acid promoted degradation by way of the indole assisted SN1
mechanism discussed earlier. To this end, the methyl ether 38,
and its sulfide analogue, 50 were suspended in equivalent
amounts of ethanol and the solutions were spiked with equivalent
amounts of concentrated sulfuric acid. Under these identical
conditions, the reactions were stirred and sampled at regular
intervals in order to monitor the progress of the SN1 substitution
by HPLC. Interestingly, within two hours, the methyl ether 38
had been fully consumed, yet the methyl sulfide remained
essentially unreacted showing no conversion to the ethyl ether
over this time period (Chart 1). In fact, after 72 hours there was
less than 5% conversion of the sulfide 50 to the ethyl ether. As
per our hypothesis, the sulfide was indeed a far poorer Lewis
base and therefore resulted in significantly more stable
compounds than the ether derivatives. Also of interest was
compound 40, a methyl ether derivative with a bromine
substituent on the phenyl ring system. We noticed during the
synthetic campaign that it was particularly difficult to convert
from the alcohol 33 into the methyl ether 40 (Scheme 2).
Therefore, we were similarly interested to see how this
compound would fair in our stability test. Although this
compound is also a methyl ether derivative it was significantly
more stable than its analogue 38, with only 17% conversion to
the corresponding ethyl ether over a four-hour period. This
enhanced stability for a methyl ether derivative can be explained
by virtue of the fact that the bromine on the phenyl ring decreases
the electron density in this ring system resulting in a much higher
energy transition state leading towards the SN1 intermediate. It
was however, not nearly as stable as the sulfide derivative 50.

7.
8.
9.
Mehellou, Y.; De Clercq, E. J. Med. Chem. 2010, 53, 521-
538.
Peltzer, K.; Friend-du Preez, N.; Ramlagan, S.; Anderson,
J. BMC Public Health 2010, 10.
Müller, R.; Mulani, I.; Basson, A. E.; Pribut, N.; Hassam,
M.; Morris, L.; van Otterlo, W. A. L.; Pelly, S. C. Bioorg.
Med. Chem. Lett. 2014, 24, 4376-4380.
Pelly, S. C.; van Otterlo, W. A. L.; Muller, R.; Basson, A.
Patent WO2015044928 A1, 2014.
Ragno, R.; Artico, M.; De Martino, G.; La Regina, G.;
Coluccia, A.; Di Pasquali, A.; Silvestri, R. J. Med. Chem.
2004, 48, 213-223.
Ragno, R.; Coluccia, A.; La Regina, G.; De Martino, G.;
Piscitelli, F.; Lavecchia, A.; Novellino, E.; Bergamini, A.;
Ciaprini, C.; Sinistro, A.; Maga, G.; Crespan, E.; Artico,
M.; Silvestri, R. J. Med. Chem. 2006, 49, 3172-3184.
Silvestri, R.; Artico, M. Curr. Pharm. Des. 2005, 11, 3779-
806.
Silvestri, R.; Artico, M.; De Martino, G.; La Regina, G.;
Loddo, R.; La Colla, M.; La Colla, P. J. Med. Chem. 2004,
47, 3892-3896.
Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.;
Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.;
La Colla, P. J. Med. Chem. 2003, 46, 2482-2493.
Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.;
Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.;
Goldman, M. E.; Greenlee, W. J. J. Med. Chem. 1993, 36,
1291-1294.
Chart 1: Acid lability studies
100
90
80
70
60
50
40
30
20
10
0
10.
11.
12.
0
30
60
90
120
150
180
210
240
13.
14.
Suspension of the methyl ether 38 and methyl sulfide 50 in acidic ethanol
shows rapid degradation of the methyl ether, yet the methyl sulfide remains
stable under these conditions. Interestingly, the methyl ether 40, with the
electron withdrawing bromine on the phenyl ring system is also more stable
than 38, but not as stable as the sulfide 50.
15.
16.
In conclusion, we have prepared a series of methyl sulfide
indole based NNRTIs compounds, which, like their methyl ether
analogues, are potent inhibitors of HIV replication. However,
unlike the methyl ether analogues, these sulfides are stable under
acidic conditions.
17.
Zhao, Z.; Wolkenberg, S. E.; Lu, M.; Munshi, V.; Moyer,
G.; Feng, M.; Carella, A. V.; Ecto, L. T.; Gabryelski, L. J.;
Lai, M.-T.; Prasad, S. G.; Yan, Y.; McGaughey, G. B.;
Miller, M. D.; Lindsley, C. W.; Hartman, G. D.; Vacca, J.
P.; Williams, T. M. Bioorg. Med. Chem. Lett. 2008, 18,
554-559.
Acknowledgments
This study was supported by the University of Stellenbosch,
the National Research Foundation (NRF), the National Institute
for Communicable Diseases (NICD), the Medical Research
Council (MRC), and the National Health Laboratory Service
(NHLS) Research Trust. We express our gratitude to the Centre
for High Performance Computing (CHPC) for access to
Discovery Studio.
18.
19.
Klibanov, O.; Kaczor, R. Curr. Opin. Investig. Drugs
2010, 11, 237-245.
Docking studies were carried out with Biovia Discovery
Studio 2016, using the CDcocker docking tool. The RT
receptor was obtained from the PDB with ID 2RF2.
Hiremath, S. P.; Hiremath, D. M.; Purohit, M. G. Indian
Journal of Chemistry, Section B: Organic Chemistry
Including Medicinal Chemistry 1987, 26, 1042-1046.
Romagnoli, R.; Baraldi, P. G.; Sarkar, T.; Carrion, M. D.;
Cara, C. L.; Cruz-Lopez, O.; Preti, D.; Tabrizi, M. A.;
Tolomeo, M.; Grimaudo, S.; Di Cristina, A.; Zonta, N.;
Balzarini, J.; Brancale, A.; Hsieh, H.-P.; Hamel, E. J. Med.
Chem. 2008, 51, 1464-1468.
20.
21.
Supplementary Material
Detailed experimental conditions as well as compound
characterization data can be found in the supplementary
information (PDF file).
22.
23.
Parry, C. M.; Kohli, A.; Boinett, C. J.; Towers, G. J.;
McCormick, A. L.; Pillay, D. J. Virol. 2009, 83, 9094-
9101.
Gupta, R. K.; Kohli, A.; McCormick, A. L.; Towers, G. J.;
Pillay, D.; Parry, C. M. AIDS 2010, 24, 1651-1655.
Tim, M. J. Immunol. Methods 1983, 65, 55-63.
Wu, G.; Robertson, D. H.; Brooks, C. L.; Vieth, M. J.
Comput. Chem. 2003, 24, 1549-1562.
Author Information
*E-mail: scpelly@sun.ac.za. Telephone: +27-21-808-2180.
Fax +27-21-808-3360.
24.
25.
References and notes
1.
Reynolds, C.; de Koning, C. B.; Pelly, S. C.; van Otterlo,
W. A. L.; Bode, M. L. Chem. Soc. Rev. 2012, 41, 4657-
4670.
2.
3.
Li, D.; Zhan, P.; De Clercq, E.; Liu, X. J. Med. Chem.
2012, 55, 3595-3613.
Peng, Z.; Xinyong, L.; Zhenyu, L.; Pannecouque, C.; De
Clercq, E. Curr. Med. Chem. 2009, 16, 3903-3917.
De Clercq, E. Int. J. Antimicrob. Agents 2009, 33, 307-320.
Hsiou, Y.; Ding, J.; Das, K.; Clark, J. A. D.; Hughes, S. H.;
Arnold, E. Structure 1996, 4, 853-860.
4.
5.
6.
Zhan, P.; Pannecouque, C.; De Clercq, E.; Liu, X. J. Med.
Chem. 2015.