Current Medicinal Chemistry, 2011, 18, 359-376 1
0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.
Recent Advances in DAPYs and Related Analogues as HIV-1 NNRTIs
Xuwang Chen1, Peng Zhan1, Dongyue Li1, Erik De Clercq2 and Xinyong Liu*,1
1Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,
250012, Jinan, Shandong, P.R. China
2Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Abstract: HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti-
AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specific-
ity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of
drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY)
derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have at-
tracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved
by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful
development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural bi-
ology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including
conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of
RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues
as promising anti-HIV drug candidates.
In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on
the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular
modeling. Other structural related NNRTI scaffolds will also be reviewed.
Keywords: HIV-1, NNRTIs, DAPY, TMC125, TMC278, drug design, drug-resistance.
Acquired immune deficiency syndrome (AIDS) is mainly
caused by human immunodeficiency virus type-1 (HIV-1),
and the lack of an effective vaccine remains a major obstacle
in the battle against HIV-1 infection. According to the statis-
tic data of AIDS epidemic in 2009 by WHO, there were 33.4
million people living with HIV, 2.7 million new HIV infec-
tions and 2 million AIDS-related deaths in 2008 . AIDS is
still one of the leading pandemic diseases worldwide. Since
1996, a combination of different inhibitors called highly ac-
tive antiretroviral therapy (HAART), has provided an effec-
tive way to treat AIDS patients, making AIDS a manageable
disease by dramatic reduction in viral loads and restoration
of the immune system . However, the treatment of AIDS
still faces the rapid emergence of drug resistance and serious
side effects during the long term drug use. Therefore, it is a
continuous need to design and develop new anti-AIDS drugs
that are active against HIV-1 mutants resistant to the avail-
HIV-1 non-nucleoside reverse transcriptase inhibitors
(HIV-1 NNRTIs) nowadays represent the most potent anti-
AIDS drugs that specifically inhibit HIV-1 reverse tran-
scriptase (RT). Due to their unique antiviral potency, high
specificity and low cytotoxicity, the NNRTIs have become
indispensable component of HAART regimen . Clinically,
*Address correspondence to this author at the Department of Medicinal
Chemistry, School of Pharmaceutical Sciences, Shandong University, 44,
West Culture Road, 250012, Jinan, Shandong, P.R. China; Tel: +86-531-
88380270; Fax: +86-531-88382731; E-mail: email@example.com
two types of RT inhibitors have been used: nucleoside re-
verse transcriptase inhibitors (NRTIs) and NNRTIs. NRTIs
compete as triphosphates with normal nucleoside substrates
for incorporation into the viral genome, behaving as chain
terminators. Whereas, NNRTIs bind in a flexible allosteric
pocket located at a distance of approximately 10 Å from the
DNA polymerizing processing site, known as NNRTI bind-
ing pocket (NNIBP), in a non-competitive manner, changing
the conformation and altering the ability and function of RT
Currently, four HIV-1 NNRTIs have been approved by
US FDA, namely, nevirapine (1), delavirdine (2), efavirenz
(3) and etravirine (4) (Fig. 1). The former three NNRTIs
could effectively inhibit the wild-type (WT) HIV-1, but are
less effective against common resistant mutants [6, 7]. As the
representative of next-generation HIV-1 NNRTIs, etravirine,
approved in January 2008, has attracted considerable atten-
tion due to its excellent potency against WT and NNRTI-
resistant HIV-1 strains [8-10]. However, its pharmacokinetic
profile is not satisfactory, as it must be administered twice
daily [11, 12]. Therefore, it remains necessary to improve the
pharmacokinetic profiles by modifying and optimizing di-
arylpyrimidine (DAPY) derivatives to which etravirine struc-
Although the crystal structures of the RT/NNRTI com-
plex are clearly illustrated in the literature, structure-based
design of innovative HIV-1 NNRTI scaffolds is still difficult
because of the following three aspects: (a) The NNIBP does
not really exist in the structure of RT (“closed pocket form”)
before HIV-1 NNRTI ligand binding. (b) The pocket is elas-
tic, and its spatial conformation depends on the molecular
2 Current Medicinal Chemistry, 2011 Vol. 18, No. 3
Chen et al.
size, specific chemical structure, and binding mode of the
ligand. (c) The NNRTI resistance mutations, such as K103N,
Y181C, L100I, V106A, Y188L and G190A, are frequently
observed and located in or around the NNIBP [13, 14].
These three factors make it laborious to identify NNRTI
leads with the strategy of de novo drug design. Thus, ligand-
based drug design, a frequently used principle in rational
drug design, is still the dominating approach, such as the
discovery of nevirapine, delavirdine and efavirenz. However,
the successful development of etravirine attributed to
multidisciplinary approach involving traditional medicinal
chemistry, structural biology, crystallography and computa-
In this review, we first make attempts to present a brief
historical account of the medicinal chemistry of DAPY-
based NNRTIs, then focus our main attention to the progress
of this unique class of NNRTIs, including extensive struc-
tural modifications, structure activity relationship (SAR)
studies, binding mode analysis based on crystallographic and
molecular modeling. Other structural related NNRTI scaf-
folds will be described, providing valuable avenues for the
future development of DAPY analogues as promising anti-
HIV drug candidates.
2. DISCOVERY AND DEVELOPMENT OF DAPY
In the search for compounds active against HIV-1, a se-
ries of tetrahydro-imidazo-[4,5,1-jk][l,4]-benzodiazepin-
2(1H)-one and -thione (TIBO) derivatives (5a-c), the origi-
nal NNRTIs, were found to inhibit the replication of HIV-1
in the MT-4 cell line assay (Fig. 2), which brightened the
outlook for anti-AIDS research [8, 15-17].
While TIBO compounds were being evaluated, a second
class of HIV-1 RT inhibitors was identified: ?-
anilinophenylacetamide (?-APA) series. The lead compound
R15345 (6a), exhibiting an EC50 value against WT HIV-1 of
610 nM, was originally synthesized in an unrelated medici-
nal chemistry project (Fig. 2). Subsequent lead optimization
resulted in the discovery of loviride (6b, R89439), a clinical
candidate at the time, with an EC50 value of 13 nM. How-
ever, the development of loviride was abandoned as it did
not offer sufficient advantages over nevirapine or delavirdine
[8, 18, 19].
Further chemical modifications of the ?-APA series, such
as increasing the spacer length between the two aryl groups,
led to imidoyl thiourea (ITU) derivatives (7, R93514; 8,
R100943), another series of HIV-1 NNRTIs. Compound 8
was surprisingly potent against both WT and clinically im-
portant mutant strains of HIV-1, comparable to the profiles
of nevirapine, delavirdine and loviride (Table 1). However, it
was prone to oxidative ring closure of the imidoyl thiourea,
and the product (9) was inactive (Fig. 3). From X-ray crystal
structure of the HIV-1 RT/8 complex, it appeared that the
conformation of the ligand resembled a horseshoe or “U”
shape in contrast to the butterfly-like shape of TIBO (5c), ?-
APA (6b), or nevirapine [8, 20, 21].
1 2 3 4
Nevirapine Delavirdine Efavirenz Etravirine
Fig. (1). The structures of the NNRTI drugs approved by US FDA.
5a 5b 5c 6a R1 = OMe, R2 = H, EC50 = 610 nM
R14458 R82913 R86183 6b R1 = COMe, R2 = Me, EC50 = 13 nM
EC50 = 62000 nM EC50 = 33 nM EC50 = 4.6 nM
Fig. (2). Structures of TIBO and ?-APA compounds with their activity in HIV-infected MT-4 cell line [8, 15-17].
Recent Advances in DAPYs and Related Analogues Current Medicinal Chemistry, 2011 Vol. 18, No. 3 3
Subsequently, the thione moiety of ITU series was substi-
tuted with an imino-cyano group, aiming to protect against
the ring closure and to improve the metabolic properties of
ITU series. Unexpectedly, instead of obtaining the intended
compound (10), a diaryltriazine (DATA) derivative (11,
R106168) was formed due to spontaneous closure of the
intermediate cyano-guanidino derivative (Fig. 3) [8, 22].
Surprisingly, compound 11 was highly potent against
WT HIV-1 (EC50 = 6.3 nM), nearly as active as compound 8
which was most potent of the ITU series. More importantly,
compound 11 was also highly potent against a number of
HIV-1 mutant strains (Table 2). The enhanced structural
stability and biological activity encouraged medicinal chem-
ists to continue to optimize DATA series [8, 22, 23].
In subsequent studies, the central triazine ring of DATAs
was replaced by a pyrimidine ring which resulted in three
isomers (12a-c). Compound 12a displayed promising activ-
ity, superior to compounds 11 and 12b-c against WT HIV-1
and single mutants thereof (Table 2). This led to the discov-
ery of DAPY NNRTIs, of which TMC120 (13, R147681)
was the prototype. Introduction of a bromine atom at the 5-
position and an amino group at the 6-position of the
pyrimidine ring afforded etravirine (4, TMC125, R165335),
which was approved by FDA with nanomolar potency
against WT HIV-1 and clinically relevant mutants as men-
tioned previously. Subsequent research resulted in the dis-
covery of rilpivirine (14, TMC278, R278474), a cyanovinyl
DAPY compound with an exceptional activity profile and
very desirable druglike properties (Table 3) [8, 23-25].
Progress was laborious, costly and time-consuming. For-
tunately, the efforts proved to be worthwhile in the end.
DAPY derivatives were identified as a novel and potent fam-
ily of HIV-1 NNRTIs with one marketed anti-AIDS drug
etravirine and one promising clinical drug candidate ril-
pivirine (Fig. 4) [9, 24].
Table 1. Activity of Compound 8 and Reference NNRTIs versus WT HIV-1 and Selected Single Mutants 
EC50 (μM) in MT-4 cell line
LAI L100I K101E K103N V106A Y181C Y188L G190A
8 0.003 0.513 0.019 0.589 0.382 0.511 0.318 0.002
0.050 0.050 0.063 1.26 1.00 15.8 50.1 2.51
0.063 2.51 0.158 2.51 1.59 2.00 1.26 0.063
0.032 0.316 0.316 6.31 5.01 10.0 > 100.0 7.94
The LAI strain is the WT HIV-1. Other infecting viral strains with mutations in the RT are characterized according to the mutated amino acid position (one-letter codes). The first
amino acid is present in the WT HIV-1. The second amino acid is present in the mutated strain. For example, Y181C refers to replacement of the tyrosine at position 181 with cys-
teine. The EC50 is defined as the concentration of compound in cell culture required to block viral replication by 50%.
7 8 9
Fig. (3). The ring closure reactions of compound 8 [8, 20] and the intermediate 10 .
4 Current Medicinal Chemistry, 2011 Vol. 18, No. 3
Chen et al.
3. STRUCTURAL MODIFICATIONS OF DAPY
3.1. Modifications of the Left Wing
The initial DAPY derivatives which were 2,4,6-
trisubstituted on the left phenyl ring (13, 15a-c), displayed
high activity, especially with a cyano moiety at the 4-
position. Within this series, compounds 13 and 15a appeared
to be most appealing, as they were more potent against WT
HIV-1 and clinically relevant mutants, and comparable to
that of efavirenz (Table 4) .
Recently, a novel series of DAPY analogues featuring a
naphthyl moiety instead of the left phenyl ring were designed
and synthesized. Some of them (16a-b) exhibited strong ac-
tivity against WT HIV-1 and double mutant strain (K103N +
Y181C) with EC50 values in the low-nanomolar range and
low-micromolar range, respectively (Table 5) .
Subsequently, structural optimization of this naphthyl-
substituted DAPY family was pursued, with the aim to in-
hibit drug-resistant HIV-1 strains. Compounds 17a-d were
the representatives with their antiviral activity and cytotoxic-
ity listed in Table 5. Exceptionally, compound 17b, with a
Table 2. Activity of Compounds 11 and 12a-c versus WT HIV-1 and Selected Key Single Mutants [22, 23]
EC50 (μM) in MT-4 cell line.
Compds X Y Z
LAI L100I K103N Y181C Y188L
N N N 0.006 0.40 0.04 0.20 0.32
N CH N 0.001 0.30 0.012 0.18 0.071
CH N N 0.010 > 10 > 10 > 10 > 10
N N CH 0.45 > 10 > 10 > 10 > 10
Table 3. Activity of TMC120 (13), TMC125 (4) and TMC278 (14) against WT HIV-1 and Various Clinically Relevant Mutants [23-
EC50 (nM) in MT-4 Cell Line
LAI L100I K103N Y181C Y188L L100I + K103N
13 (TMC120) 1.0 18 4.3 7.5 4.8 > 10000 44
4 (TMC125) 1.4 3.3 1.2 7.0 4.6 19 4.3
14 (TMC278) 0.5 0.4 0.3 1.26 2.0 7.95 1.0
Recent Advances in DAPYs and Related Analogues Current Medicinal Chemistry, 2011 Vol. 18, No. 3 5
cyano group at the 6-position of the naphthalene ring, dem-
onstrated high potency against WT HIV-1 with an EC50
value of 2 nM, and against the K103N + Y181C mutant
strain with an EC50 value of 0.24 μM. The selectivity index
(SI) of compound 17b against WT HIV-1 was > 180,000, the
highest SI value among DAPY analogues. Compounds 17c-d
exhibited activity against the double mutant (103N + 181C)
strain at an EC50 of 0.16 and 0.15 μM. It was thus more ac-
tive than efavirenz [27, 28].
Molecular modeling studies showed that the naphthyl-
substituted compounds adopt a similar binding conformation
as TMC120 and TMC125 in the NNIBP. The left “wing”
bound in the hydrophobic sub-pocket, which was formed by
Fig. (4). Synopsis of the discovery and development of DAPY-based HIV-1 NNRTIs .
Table 4. Antiviral Activity of Compounds 13 and 15a-c against WT HIV-1 and Clinically Relevant Mutants 
EC50 (nM) in MT-4 cell line.
LAI L100I K103N Y181C Y188L
2,4,6-(Me)3 1.0 18 4.3 7.5 4.8 > 10000 44
2,6-(Me)2,4-CN 0.4 31 2.0 6.2 7.6 1000 31
2.0 199 12 19 100 > 10000 398
1.0 63 12 15 79 > 10000 nd
1.0 39 39 2.0 158 > 10000 39
nd: not determined
6 Current Medicinal Chemistry, 2011 Vol. 18, No. 3
Chen et al.
aromatic amino acid residues, and exhibited strong ?-? inter-
action with the residues of Y188, Y181 and F227 [27, 28].
3.2. Modifications of the Linker Between the Left Wing
and the Central Pyrimidine Ring
Further modulations were focused on the structural diver-
sity of the linker connecting the left wing and the central
pyrimidine ring. Structural variation from CH2 (12a), NH
(13) to oxygen (18a) or sulfur (18b) confirmed the superior
potency of compound 13 (TMC120) which is still under de-
velopment as a vaginal HIV microbicide [29, 30]. In general,
the NH-DAPYs showed the highest activity among DAPY
family such as TMC120 and TMC278 (Table 6). Besides,
methylation of the NH-linker also retained activity against
WT HIV-1 (compounds 13 and 18c). It should be noted that
the O-DAPY analogues are also highly potent in some cir-
cumstances (i.e. TMC125) .
Table 5. Antiviral Activity and Cytotoxicity of Compounds 16a-b, 17a-c and 18a-b in MT-4 Cell Line Infected with WT HIV-1 (LAI
strain IIIB) and the Double Mutant Strain (K103N + Y181C) [26-28]
WT(IIIB) K103N + Y181C
R1 = H, R2 = Me, R3 = Cl 3.83 7.55 > 323.14 > 84650
R1 = H, R2 = H, R3 = Br 2.35 6.57 153.5 65591
R1 = Me, R2 = Me, R3 = H 4 1.17 303.27 76436
R1 = Br, R2 = H, R3 = CN 2 0.24 282.63 181247
R1 = OMe, R2 = OMe, R3 = CN 5 0.16 > 118.44
R1 = Cl, R2 = OMe, R3 = CN 7 0.15 > 190.65
CC50 = 50% cytotoxic concentration; SI = CC50/EC50.
Table 6. Activity of Compounds 13, 18a-c Against WT HIV-1 and Clinically Relevant Mutants 
EC50 (nM) in MT-4 Cell Line
LAI L100I K103N Y181C Y188L L100I + K103N
NH 1.0 18 4.3 7.5 4.8 > 10000 44
O 4 20 3.2 40 50 7940 1000
S 3.2 50 10 25 20 5011 nd
NMe 6.3 126 79 100 398 nd nd
Recent Advances in DAPYs and Related Analogues Current Medicinal Chemistry, 2011 Vol. 18, No. 3 7
Recently, Fen-er Chen’s group reported the structural
modulations on the linker of CH2-DAPYs (19a-c, 20a-c),
containing a hydroxyimino group or a cyano substituent.
These novel DAPY analogues were assayed to examine
whether the introduction of the hydroxyimino or cyano
group could improve the antiviral activity and offer novel
scaffolds for the future development of HIV-1 NNRTIs.
Most of the hydroxyimino analogues demonstrated high po-
tency against WT virus in the nanomolar concentration range
(Table 7). Compound 19b was the most attractive of this new
series (EC50 = 25 nM, SI = 1223), exhibiting moderate po-
tency against K103N + Y181C double mutant strain (EC50 =
8.72 μM) and unexpected anti-HIV-2 activity (EC50 = 8.31
μM) . The cyano substituted compounds were potent
against the WT HIV-1, whereas, few were active against the
double mutant strain (K103N + Y181C). Among this series,
compound 20a displayed the highest potency (EC50 = 1.8
nM) and the greatest selectivity for the viral target (SI ?
118595). Molecular modeling studies were employed to bet-
ter understand the interactions between these inhibitors and
HIV-1 RT, guiding the SAR studies for further identification
of potent leads against HIV-1 .
3.3. Modifications of 5,6-positions of the Central
Within the DAPYs we evaluated the effects on antiviral
activity of different substituents at the 5,6-positions of the
central pyrimidine ring. For example, 5,6-positions disubsti-
tuted analogues (4, 21) and bicyclic-heterocycle derivatives
(22a-d) demonstrated promising activity [9,3 3] (Fig. 5).
From molecular modeling studies on TMC125, an additional
hydrogen bond was predicted to occur between the C6 amino
group and the carboxylate of E138 . However, crystal
structure of WT RT/TMC125 revealed that the primary
amine and bromo moieties point to an opening in the pocket
between K101 and E138 . It was presumed that rational
modifications of this region might generate extra interactions
with solvent exposed region lined by V179.
TMC278, which is without 5,6-positions substituents,
showed an exceptional activity profile, that might result from
the existence of the cyanovinyl group which could compen-
sate for the absence of 5,6-positions substituents.
3.4. Substitutions at 4-position of the Right Wing
Introduction of a chlorine atom (23a), a carboxamide
moiety (23b), or other substituents instead of the 4-cyano
group (13) showed that the presence of a cyano moiety was
necessary for high potency against WT HIV-1 and clinically
relevant mutants (Table 8). The linear cyano group is posi-
tioned between F227, H235 and P236, undergoing a strong
dipole-dipole interaction with the backbone carbonyl of
H235 [9, 35].
Meanwhile, benzyl/phenyl-piperidine type of DAPY de-
rivatives (24a-d) also showed promising activity in a recom-
binant HIV-1 antiviral assay and RT assay (Fig. 6). Crystal
structure of WT RT/24a complex confirmed the edge-to-face
interaction with W229 and the hydrogen bond between the
piperidine-4-NH and K101. Exceptionally, a water-mediated
hydrogen bond linking the piperidine 1-nitrogen with the
backbone NH of K103 was revealed in the crystal structure.
The extended benzyl/phenyl moiety was located between
P236 and V106, and the sulfuryl substituents point directly
toward the solvent exposed region [36-38]. Taking advan-
tage of the solvent exposed region may be a means to further
optimize the pharmacokinetic profiles, or to construct a sec-
Table 7. Biological Activity of Compounds 19a-c and 20a-c Against WT HIV-1 and the Double Mutant Strain (K103N + Y181C) [31,
EC50 (nM) in MT-4 Cell Line
WT K103N + Y181C
CC50 (μM) SI
19a 4-Me 6 ? 5100 13.27 2394
19b 3-OMe 25 8720 30.51 1223
19c 4-OMe 13 10290 50.24 3791
20a 2-F 1.8 ? 41.1 ? 216.6 ? 118595
20b 3-Me 8.6 > 37.9 37.9 4441
20c 2-Me 7.1 > 249.9 ? 249.9 ? 35524
8 Current Medicinal Chemistry, 2011 Vol. 18, No. 3
Chen et al.
22a 22b 22c 22d
WT EC50 < 10 nM EC50 < 10 nM EC50 < 10 nM EC50 < 10 nM
L100I + K103N EC50 < 10 nM EC50 < 10 nM EC50 < 10 nM 10 nM < EC50 < 100 nM
Fig. (5). Structures of the novel DAPY derivatives with their antiviral activity [9, 33].
Table 8. Antiviral Activity of Compounds 13 and 23a-b Against WT HIV-1 and Clinically Relevant Mutants 
EC50 (nM) in MT-4 Cell Line
LAI L100I K103N Y181C Y188L
CN 1.0 18 4.3 7.5 4.8 > 10000 44
Cl 3.1 199 25 79 2511 > 10000 nd
CONH2 63 > 10000 > 10000 > 10000 > 10000 nd nd
24a 24b 24c 24d
EC50 = 3 nM EC50 = 2.2 nM EC50 = 0.4 nM EC50 = 1.1 nM
IC50 = 34.1 nM IC50 = 25.7 nM IC50 = 14.7 nM IC50 = 12 nM
Fig. (6). Substituted benzyl/phenyl-piperidine DAPY derivatives together with their anti-HIV-1 activity [36-38].
The structure is wrong, please replace it
with the new one in the enclosed file.
Recent Advances in DAPYs and Related Analogues Current Medicinal Chemistry, 2011 Vol. 18, No. 3 9
Table 9. Antiviral Activity of Compounds 14 and 25a-d Against HIV-1 According to the MTT Method 
EC50 (nM) in MT-4 Cell Line
LAI L100I K103N Y181C Y188L
CHCHCN (E) 0.5 0.4 0.3 1.26 2 7.95 1 60000
CH2CH2CN 0.63 7.95 0.4 12.5 20 31.6 2.51 4782
CHCHCN (Z) 0.6 6.3 1.6 5 31 794 39.8 50000
CHC(Me)CN (E) 0.8 0.6 0.6 1.6 3.16 31.6 2 25000
C(Me)CHCN (E) 1 0.8 1 2.51 4 25.1 2.51 30000
1 40 40 2 160 > 10000 40 10000
ond pharmacophore for the “designed multiple ligands
(DMLs)” strategy [39-41].
3.5. Variations on the 4-cyano of the Left Wing
In order to improve antiviral activity, modifications at the
para-position of the left phenyl ring were studied. Com-
pound 25a, with chain elongation with two carbons, exhib-
ited a remarkable enhanced activity in particular against the
single mutants (Table 9). Compound 14 (TMC278), with
insertion of a vinyl group between cyano group and phenyl
ring with E-geometry, showed greatly improved potency
against WT HIV-1 and its mutant stains comparable to com-
pound 15b (cyano moiety directly connecting to phenyl
ring). Moreover, in comparison of its activity spectrum with
that of efavirenz, compound 14 exhibited superior activity
against all HIV-1 strains tested. However, the corresponding
Z-isomer (25b) was less potent compared to the E-
enantiomer, but still better than efavirenz. Subsequently,
compounds 25c and 25d which were introduced a methyl
group at alpha or beta position of the cyano moiety respec-
tively, also showed high activity against all viruses within
the panel (Table 9) [9, 24, 25].
Furthermore, keeping 4-cyanovinyl group unchanged,
modifications at the 2,6-substituents of the left wing gener-
ated interesting TMC278 analogues (26a-b) which were
highly active against WT HIV-1 and common mutants clini-
cally (Table 10) . This confirmed the key interaction of
the 4-cyanovinyl moiety with the NNIBP; detailed analysis
will be described in the following section.
4. BINDING MODE ANALYSIS OF DAPYS BASED
ON CRYSTALLOGRAPHIC AND MOLECULAR
Crystal structures of HIV-1 RT/NNRTI complex and/or
molecular modeling studies have revealed important features
of enzyme-ligand interaction, including the details of action
First-generation HIV-1 NNRTIs, nevirapine [43, 44], de-
lavirdine  and efavirenz [46, 47], complexed in RT,
showed that structurally diverse inhibitors had similar bind-
ing patterns termed “butterfly-like” shape with one “body”
and two “wings” . These butterfly-like molecules also
shared a similar three-dimensional pharmacophore: hydro-
phobic center, hydrogen bond donor and acceptor [49-52].
The hydrophobic center which generally contained aromatic
rings, filled the hydrophobic pocket formed by the amino
acid residues Y181, Y188, F227 and W229. The hydrogen
bond donor and acceptor formed hydrogen bond with back-
bone carbonyl and amino of K101 (or K103), or with a struc-
tural water molecule .
X-ray crystallographic and molecular modeling studies
were carried out to understand how DAPYs interacted with
HIV-1 RT. The obtained results showed that DAPYs also
shared a similar pharmacophore as mentioned for the first-
generation HIV-1 NNRTIs, including hydrophobic center,
hydrogen bond donor and acceptor (Fig. 7a), whereas the
binding conformation resembled a horseshoe or “U” shape
on binding in the NNIBP (Fig. 7c, Fig. 8) [21, 35, 53]. Be-
sides, modeling studies revealed additional notable features
that may contribute to the robustness of DAPYs.
(1) Systematic crystallography and molecular modeling
studies of RT/DAPY complexes show that DAPY series can
bind into RT in different conformations through the follow-
ing ways: (a) The torsional flexibility (‘‘wiggling’’) can gen-
erate numerous conformational variants. (b) The compact
design of DAPYs permits significant repositioning and re-
orientation (translation and rotation) within NNIBP (“jig-
gling”) (Fig. 7b) . For instance, in the molecule
of TMC125, the ether and amino linkages of the two cya-
10 Current Medicinal Chemistry, 2011 Vol. 18, No. 3
Chen et al.
Table 10. The anti-HIV-1 Activity and Cytotoxicity of Compounds 26a-b Compared to TMC278 .
EC50 (nM) in MT-4 Cell Line
Compds R1, R2
LAI L100I K103N Y181C Y188L
CC50 (nM) SI
Me, Cl 0.8 0.4 0.1 2.3 2.3 6.6 4.1 2606 3316
OMe, Cl 0.1 0.2 0.3 1.0 2.5 15.8 2.0 398 3981
1.0 0.5 0.1 1.3 1.2 7.5 3.2 2000 2020
Fig. (7). (a) Schematic diagram of the binding mode for TMC125 in NNIBP. (b) Molecular torsion of TMC125 to accommodate different
conformations on binding into RT. (c) X-ray crystallographic structure of WT RT/TMC125 complex (PDB: 3MEC) [21,35] (The figure is
showed by PyMOL 0.99).
Fig. (8). (a) X-ray crystallographic structure of WT RT/TMC120 complex (PDB: 1S6Q) . (b) X-ray crystallographic structure of WT
RT/TMC278 complex (PDB: 3MEE) [35,53] (The figures are showed by PyMOL 0.99).
Recent Advances in DAPYs and Related Analogues Current Medicinal Chemistry, 2011 Vol. 18, No. 3 11
Rigid inhibitorRigid inhibitor
Flexible inhibitorFlexible inhibitor
Fig. (9). Schematic diagram of the response of a rigid versus flexible inhibitor (light blue) in a WT (dark blue) or mutated (red) NNIBP [21,
nophenyl substituents provide sufficient flexibility to allow
favorable aryl-aryl interactions with Y181, Y188, F227 and
W229 [34, 35]. The flexible nature of the DAPY scaffold
appears to better compensate for the different structural
changes of amino acid residues arising in the NNIBP, which
is critical for DAPYs to retain their activity against WT
HIV-1 and a wide range of drug-resistant mutants. In con-
trast, highly rigid inhibitors (such as nevirapine) are less able
to adapt to conformation changes of NNIBP (Fig. 9), thus,
they display quite weak activity against HIV-1 mutants [21,
39]. Therefore, exploitation of molecule conformational
flexibility can be a powerful drug design concept, especially
for the design of drugs effective against rapidly mutating
(2) The left aryl wing, linked to the 4-position of
pyrimidine core, fits into the important hydrophobic sub-
pocket, where many key resistant mutations take place in-
cluding Y188L, Y181C and F227C. Detailed analysis shows
that the left phenyl ring is parallel to Y181 or Y188, and the
4-substituent (-CN or -Me) points towards the indole side
chain of the highly conserved W229 (Fig. 7c, Fig. 8a).
Among the conserved residues in RT, W229 is the priority
candidate for design of HIV-1 NNRTIs mainly because it
participates in creating the characteristic NNIBP, which
makes it feasible to target W229 with NNRTIs [21, 40, 54,
55]. Improving interaction with the highly conserved amino
acid residues in NNIBP contributes to the discovery of novel
HIV-1 NNRTIs that are potent against the common RT mu-
(3) The DAPY compounds form two hydrogen bonds
with K101 (Fig. 7c, Fig. 8), which is consistent with the high
activity of these compounds against the K101 mutant. The
NH linker connecting the central pyrimidine ring and the
right wing is responsible for a hydrogen bond interaction
27a X = O, IC50 < 1 nM 28a X = O, IC50 = 4 nM 29a R1 = Me, R2 = H
27b X = S, IC50 = 5 nM 28b X = SO2, IC50 = 5 nM 29b R1 = CN, R2 = Me
Fig. (10). Structures of the pyrazinone compounds and their potency against WT HIV-1 .
Table 11. The Potency of Pyrazinone Compounds Against WT HIV-1 (LAI Strain, IIIB) And Several Important Mutant Strains 
IC50 (μM) in MT-4 Cell Line
LAI L100I K103N Y181C Y188L L100I + K103N
29a 0.003 0.025 0.032 0.063 0.158 1.584 1.000
29b 0.006 0.006 0.006 0.025 0.006 0.158 0.063
0.001 0.040 0.040 0.002 0.158 > 10 0.040
12 Current Medicinal Chemistry, 2011 Vol. 18, No. 3
Chen et al.
with the backbone carbonyl of K101. And also, the
pyrimidine nitrogen at 1-position serves as hydrogen bond
acceptor with the backbone ?-amino of K101 [9, 21, 35].
The hydrogen bond interaction is unlikely to be disrupted by
mutations in the side chain and is able to reduce the free en-
ergy of binding for inhibitors .
(4) Compared with other DAPYs, the cyanovinyl group
of TMC278 is a main feature that contributes to its enhanced
potency. In the free TMC278 molecule, the cyanovinyl
group is expected to be coplanar with the dimethylphenyl
ring. However, when TMC278 binds into RT, the cyanovinyl
group will be inclined 50° to the plane of the dimethylphenyl
ring and be positioned in a hydrophobic tunnel connecting
the NNIBP to the nucleic acid binding cleft (Fig. 8b). The
extensive interaction of the cyanovinyl group with the tunnel
is conserved despite rearrangements in HIV-1 RT [24, 53,
(5) The size and volume of the NNIBP are greatly af-
fected by the movement of the P236 “hairpin loop” as well
as the repositioning of the ?10 strand (residues 232-234) and
the ?11 strand (residues 239-241). On binding of a larger
NNRTI, the P236 “hairpin loop” will tend to assume the apo
conformation, forming a more open pocket [58, 59]. Exploit-
ing the plasticity of this part of the pocket leads to an attrac-
tive target site: the protein/solvent interface, where rational
modifications can improve pharmacokinetic properties of
DAPYs, or to construct multi-target ligands as mentioned
above [39-41]. Additionally, V179 residue provides another
protein/solvent interface where structural modifications can
Detailed analysis of the unique binding mode and the de-
scriptions of SAR studies of DAPYs clarified why DAPYs
maintained high potency against a wide range of HIV-1 mu-
tants. Moreover, these studies could contribute to the modifi-
cations of the current HIV-1 NNRTIs and the discovery of
novel HIV-1 NNRTI scaffolds from different chemical se-
5. CONTRIBUTIONS OF DAPY FAMILY TO THE
DISCOVERY AND OPTIMIZATION OF OTHER
5.1. Scaffolds Transformation via Bioisosterism Strategy
The excellent pharmacological profiles of DAPY com-
pounds have encouraged medicinal chemists to explore HIV-
1 NNRTIs with novel scaffolds. On the basis of the knowl-
edge of binding mode and SAR studies of DAPYs, bioisos-
terism strategy is an excellent tool for the rational design of
new anti-AIDS drugs .
In 2005, Heeres J. et al.  reported the discovery of a
series of pyrazinones derivatives (27-29) as novel and potent
HIV-1 NNRTIs (Fig. 10). Compounds 29a-b were highly
Table 12. The Inhibitory Activity of 30a-b and 31a-b Against HIV-1 IIIB, NL4-3 and RTMDR1 in MT-2 Cell Line 
WT IIIB NL4-3 RTMDR1
EC50 (nM) SI EC50 (nM) SI EC50 (nM) SI
Me 118 4264 22.9 > 2335 55.2 > 969
CN 135 371 22.1 > 2351 21.1 > 2462
Me 58 182 1.67 11156 1.2 15525
CN 1.4 22700 0.68 13206 0.96 9354
0.62 > 490 0.298 > 1020
Favorable effect on
activity against mutants
Optimal for activity
Fig. (11). SAR analysis of the novel pyrazinone series .
Recent Advances in DAPYs and Related Analogues Current Medicinal Chemistry, 2011 Vol. 18, No. 3 13
active against WT HIV-1 and clinically relevant mutants,
even comparable to efavirenz (Table 11) . Thus, the
pyrazinone core was an acceptable isosteric replacement of
the pyrimidine ring in DAPYs, which could be inferred from
the following SAR analysis of the pyrazinone derivatives.
The pyrazinone molecules could also be dissected into
three parts: the central pyrazinone ring, the left ary-
loxy(sulfanyl) wing, and the right aniline wing. The cyano
moiety at the 4-position of the aniline ring was the optimal
choice, similar to that observed in DAPY compounds (Fig.
11). Molecular modeling studies revealed that the NH-
moiety, between the right wing and the central pyrazinone
core, formed a hydrogen bond with the backbone carbonyl of
K101, of which ?-amino formed a hydrogen bond with the 2-
carbonyl of the central pyrazinone ring. Substitutions of
methyl at the 1-position and/or 6-position on the pyrazinone
ring did not significantly increase potency against WT HIV-
1, whereas, there was a favorable activity against resistant
mutants. Similarly to DAPYs, methyl substituents at the 2,4-,
and 2,4,6-positions and/or cyano moiety at the 4-position of
the left phenyl ring generated high activity against HIV-1
including drug-resistant mutants .
Recent comparative molecular field analysis (CoMFA)
and comparative molecular similarity indices analysis
(CoMSIA) studies based on the docking conformation were
performed for 24 pyrazinone derivatives. Results obtained
from CoMFA and CoMSIA, powerful means of elucidating
the binding mode of pyrazinones, are suggesting the design
of novel potent HIV-1 NNRTIs .
Recently, two series of diarylpyridine derivatives (30a-b,
31a-b) designed by bioisosterism strategy were reported,
displaying promising potency against HIV-1, especially the
3-amino-diarylpyridine series with EC50 values in low-
nanomolar range (Table 12) .
Preliminary SAR studies have revealed that (1) the pyri-
dine core is a rational isosteric replacement for the
pyrimidine ring in DAPYs, (2) 3-nitro or 3-amino group of
the pyridine core is crucial for the enhanced activity, as it
can provide potential H-bond with K101, similar to the 1-
position nitrogen of pyrimidine ring in DAPY derivatives,
and (3) the R group on the phenoxy wing is also an impor-
tant moiety affecting anti-HIV-1 potency .
The discovery of the diarylpyridine-3-amine series as a
novel HIV-1 NNRTI scaffold with high potency against both
NNRTI-sensitive (IIIB and NL4-3) and drug-resistant
(RTMDR1) HIV-1 strains, resulted from the understanding
32a X = CH2; R = N(Me)2
32b X = CH2; R = N(Me)(Et)
32c X = CO; R = N(Me)2
32d X = O; R = I
X = CH2, CO, O
Fig. (12). Schematic structure of pyridin-2(1H)-one-DAPY hybrid.
Table 13. Antiviral Activity of Compounds 32a-d Against WT HIV-1 and Clinically Relevant Mutants [70-72]
EC50 (nM) in MT-4 Cell Line
LAI L100I K103N Y181C Y188L L100I + K103N
32a 0.4 10 2 16 158 32 32
1 8 6 32 251 200 199
32c 1 6 2 16 158 25 40
0.8 2 1 4 200 8 4
14 Current Medicinal Chemistry, 2011 Vol. 18, No. 3
Chen et al.
the notable features of highly potent DAPYs. Further struc-
tural optimization is likely to yield novel HIV-1 NNRTIs
with dramatically improved potency .
5.2. Scaffold Transformation via Molecular Hybridization
Molecular hybridization is a new approach in drug design
and development based on the combination of privileged
bioactive sub-unities of known prototypes to produce a new
hybrid compound with improved affinity and efficacy [65,
66]. The conceptual strategy was illustrated by NNRTI hy-
brids such as the pyridin-2(1H)-one-DAPY hybrid and aryl
phosphinate indole-DAPY hybrid.
Pyridin-2(1H)-ones, a class of potent NNRTIs, were dis-
covered in an enzyme-based screening program conducted
by Merck . Subsequent systematic synthetic efforts led to
several promising clinical candidates such as L-697,661,
however, resistant strains of the virus emerged rapidly (at
K103 and Y181) [68, 69]. Thus, extensive structural modifi-
cations have been done to optimize Merck’s pyridones
against resistant strains, such as incorporating the acryloni-
trile group of TMC278 (Fig. 12). Activity evaluation of these
analogues showed that the acrylonitrile substituent substan-
tially improved the potency against WT HIV-1 and several
mutant strains (Table 13). The X-ray crystal structure of
34a X = H
34b X = F
Fig. (13). Strategy for aryl phosphinate-indole NNRTI discovery.
36a R = 3,4-Cl2, EC50 = 310 nM
36b R = 4-CN, EC50 = 130 nM
38a R = CH2O-4-Pyridinyl, EC50 = 30 nM
38b R = O-3-Pyridinyl, EC50 = 31 nM
37a X = Cl, EC50 = 22 nM
37b X = F, EC50 = 13 nM
Fig. (14). Oxadiazole and oxazole derivatives with their anti-HIV-1 potency in MT-2 cell line assay [78-82].
Recent Advances in DAPYs and Related Analogues Current Medicinal Chemistry, 2011 Vol. 18, No. 3 15
RT/32d complex (PDB: 2B5J) revealed that the acrylonitrile
moiety extended into a “tunnel” that led out of the NNIBP
toward the catalytic site and interacted with the conserved
W229, similar to the parent compound TMC278 [70-72].
Aryl Phosphinate indole-DAPY Hybrid
The aryl phosphinate-indoles 34a (IDX-899) and 34b
were discovered through coordinated medicinal chemistry
principles involving bioisosterism with sulfonylindole
NNRTI (33) and molecular hybridization with DAPYs
(TMC278) (Fig. 13). These aryl phosphinate-indole deriva-
tives showed promising potency against WT HIV-1 and sev-
eral mutant strains, and IDX899 has been advanced into
phase II clinical trials with favorable safety profile and pre-
dictable pharmacokinetic properties. X-ray crystal structure
of RTK103N/Y181C/34b complex demonstrated that the newly
introduced 3-substituent “-CH=CH-CN” of the phenyl ex-
tended towards the channel lined by W229 and F227 in a
very similar manner as the same functional group in the
RT/TMC278 complex, which contributed to its high potency
to a great extent [73-75].
6. OTHER NEWLY EMERGING ANALOGUES WITH
SIMILAR BINDING MODE AS DAPYS
Free energy perturbation(FEP)-guided lead optimization
was confirmed as a valuable tool for molecular design in-
cluding drug discovery [76, 77]. In 2007, efficient optimiza-
tion of an inactive parent compound (35) guided by FEP
calculations led to the identification of oxadiazole deriva-
tives (36a-b) as potent NNRTIs. Compound 36b showed an
EC50 value as low as 130 nM in the WT MT-2 cell line as-
say, meanwhile, nevirapine yielded an EC50 of 110 nM in the
same assay (Fig. 14) [5, 78-80].
Subsequent structural modifications readily led to the ox-
azole derivatives (37a-b), which were confirmed as highly
potent anti-HIV-1 agents with EC50 values in the 10-20 nM
range. Moreover, variations of the benzylic linker, C4-
substitution of the oxazole, and replacement of the amino-
phenyl ring were considered and deemed to be less promis-
ing [5, 80, 81].
Recently, research of this series was pursued, extending
the aniline group into the distal region of the NNIBP that is
lined by V106, F227 and P236. For example, introduction of
pyridinyl with a linker on the para position of aniline led to
the novel oxazole derivatives 38a-b with high activity to-
wards WT HIV-1 and clinically relevant variants .
Currently, AIDS remains to be one of the leading pan-
demic diseases worldly, mainly because of the lack of vac-
cine, and the limited use of multi-drug regimen of HAART
that can suppress the HIV-1 viral load (often to an undetect-
able level), but cannot eradicate the virus from the organism.
In addition, drug resistance and side effects caused by use of
HAART regimen often compromise clinical treatment by
poor patient compliance. Thus, discovery and development
of novel anti-HIV drugs efficient to inhibit WT and resistant
viral strains is of significance for providing drug therapy.
Among the research of novel HIV-1 NNRTIs progress
has been made in the DAPY NNRTIs, brightening the out-
look for an improved treatment of HIV infection. Foremost
amon ghte DAPYs are the newly approved etravirine
(TMC125) and clinical candidate rilpivirine (TMC278). Ril-
pivirine will soon be added to the list of licensed HIV-1
NNRTIs because of its high antiviral potency, satisfactory
oral bioavailability and minimal side effects.
Unlike the first-generation NNRTIs which are structur-
ally highly rigid, DAPYs display sufficient flexibility
through ‘‘wiggling’’ and “jiggling”. The flexible nature of
DAPY scaffold could better compensate for the different
structural changes of the key residues within the NNIBP,
which clearly demonstrated why DAPYs retain high activity
against WT HIV-1 and a wide range of drug-resistant mu-
tants, offering great value in the design of further DAPYs
and other related NNRTIs from different chemical series as
promising anti-HIV drug candidates. Recently, good exam-
ples have been set in identification of new DAPY NNRTIs
based on their crystal structures with RT, SAR analysis and
molecular modeling studies. Also, novel scaffolds of HIV-1
NNRTIs have been discovered via the bioisosterism princi-
ple or molecular hybridization concept. The excellent phar-
macological profiles and characteristic molecular binding
mode of DAPYs will continue to encourage medicinal chem-
ists to find more potent HIV-1 NNRTIs.
The authors thank the National Natural Science Founda-
tion of China (NSFC No.30873133, No.30772629,
No.30371686), Key Project of NSFC for International Coop-
eration (30910103908), Research Fund for the Doctoral Pro-
gram of Higher Education of China (070422083) and Inde-
pendent Innovation Foundation of Shandong University
LIST OF ABBREVIATIONS
HIV(-1) = Human immunodeficiency virus (type-
AIDS = Acquired immune deficiency syndrome
Highly active antiretroviral therapy
NRTIs = Nucleoside reverse transcriptase inhibi-
NNRTIs = Non-nucleoside reverse transcriptase
NNIBP = NNRTIs binding pocket
SAR = Structure activity relationship
TIBO = Tetrahydroimidazobenzodiazepinone or
ITU = Imidoyl thiourea
16 Current Medicinal Chemistry, 2011 Vol. 18, No. 3
Chen et al.
DATA = Diaryltriazine
SI = Selectivity index
Comparative molecular field analysis
Comparative molecular similarity indi-
FEP = Free energy perturbation
UNAIDS, global AIDS report, 2009.
Hirschel, B.; Francioli, P. Progress and problems in the fight
against AIDS. N. Engl J. Med., 1998, 338, 906-908.
De Clercq, E. New developments in anti-HIV chemotherapy. Curr.
Med. Chem., 2001, 8, 1543-1572.
Martins, S.; Ramos, M.J.; Fernandes, P.A. The current status of the
NNRTI family of antiretrovirals used in the HAART regime
against HIV infection. Curr. Med. Chem., 2008, 15, 1083-1095.
Zhan, P.; Liu, X.Y.; Li, Z.Y. Recent advances in the discovery and
development of novel HIV-1 NNRTI platforms: 2006-2008 update.
Curr. Med. Chem., 2009, 16, 2876-2889.
Ilina, T.; Parniak, M.A. Inhibitors of HIV-1 reverse transcriptase.
Adv. Pharmacol., 2008, 56, 121-167.
Jochmans, D. Novel HIV-1 reverse transcriptase inhibitors. Virus
Res., 2008, 134, 171-185.
De Corte, B.L. From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-
jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine(TMC125):
fifteen years of research on non-nucleoside inhibitors of HIV-1 re-
verse transcriptase. J. Med. Chem., 2005, 48, 1689-1696.
Heeres, J.; Lewi, P.J. The medicinal chemistry of the DATA and
DAPY series of HIV-1 non-nucleoside reverse transcriptase inhibi-
tors (NNRTIs). Adv. Antiviral Drug Des., 2007, 5, 213-242.
De Clercq, E. The design of drugs for HIV and HCV. Nat. Rev.
Drug Discov., 2007, 6, 1001-1018.
Sax, P.E. FDA approval: etravirine. AIDS Clin. Care, 2008, 20, 17-
Seminari, E.; Castagna, A.; Lazzarin, A. Etravirine for the treat-
ment of HIV infection. Expert Rev. Anti Infect. Ther., 2008, 6, 427-
Hsiou, Y.; Ding, J.; Das, K.; Clark, A.D.; Hughes, S.H.; Arnold, E.
Structure of unliganded HIV-1 reverse transcriptase at 2.7 ? reso-
lution: implications of conformational changes for polymerization
and inhibition mechanisms. Structure, 1996, 4, 853-860.
Sarafianos, S.G.; Marchand, B.; Das, K.; Himmel, D.M.; Parniak,
M.A.; Hughes, S.H.; Arnold, E. Structure and function of HIV-1
reverse transcriptase: molecular mechanisms of polymerization and
inhibition. J. Mol. Biol., 2009, 385, 693-713.
Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla, M.J.;
Breslin, H.J.; Raeymaekers, A.; Van Gelder, J.; Woestenborghs, R.;
Heykants, J.; Schellekens, K.; Janssen, M.A.C.; De Clercq, E.;
Janssen, P.A.J. Potent and selective inhibition of HIV-1 replication
in vitro by a novel series of TIBO derivatives. Nature, 1990, 343,
Kukla, M.J.; Breslin, H.J.; Diamond, C.J.; Grous, P.P.; Ho, C.Y.;
Miranda, M.; Rodgers, J.D.; Sherrill, R.G.; De Clercq, E.; Pauwels,
R.; Andries, K.; Moens, L.J.; Janssen, M.A.C.; Janssen, P.A.J. Syn-
thesis and anti-HIV-1 activity
derivatives 2. J. Med. Chem., 1991, 34, 3187-3197.
Kukla, M.J.; Breslin, H.J.; Pauwels, R.; Fedde, C.L.; Miranda, M.;
Scott, M.K.; Sherrill, R.G.; Raeymaekers, A.; Van Gelder, J.; An-
dries, K.; Janssen, K.; Janssen, M.A.C.; De Clercq, E.; Janssen,
P.A.J. Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-
(1H)-one (TIBO) derivatives. J. Med. Chem., 1991, 34, 746-751.
Pauwels, R.; Andries, K.; Debyser, Z.; Van Daele, P.; Schols, D.;
Stoffels, P.; De Vreeze, K.; Woestenborghs, R.; Vandamme, A.M.;
Janssen, C.G.M.; Anne, J.; Cauwenbergh, G.; Desmyter, J.;
Heykants, J.; Janssen, M.A.C.; De Clercq, E.; Janssen, P.A.J. Po-
tent and highly selective human immunodeficiency virus type 1
(HIV-1) inhibition by a series of ?-anilinophenylacetamide deriva-
tives targeted at HIV-1 reverse transcriptase. Proc. Natl. Acad. Sci.
USA, 1993, 90, 1711-1715.
 Romero, D.L.; Morge, R.A.; Genin, M.J.; Biles, C.; Busso, M.;
Resnick, L.; Althaus, I.W.; Reusser, F.; Thomas, R.C.; Tarpley,
W.G. Bis(heteroaryl)piperazine (BHAP) reverse transcriptase in-
hibitors: structure-activity relationships of novel substituted indole
analogues and the identification of 1-[(5-methanesulfonamido-1H-
pyridinyl]piperazine monomethanesulfonate (U-90152S), a sec-
ondgeneration clinical candidate. J. Med. Chem., 1993, 36, 1505-
Ludovici D.W.; Kukla M.J.; Grous P.G.; Krishnan, S.; Andries, K.;
de Béthune, M.-P.; Azijn, H.; Pauwels, R.; De Clercq, E.; Arnold,
E.; Janssen, P.A. Evolution of anti-HIV drug candidates. part 1:
from ?-anilinophenylacetamide (?-APA) to imidoyl thiourea (ITU).
Bioorg. Med. Chem. Lett., 2001, 11, 2225-2228.
Das, K.; Clark, A.D.; Lewi, P.J.; Heeres, J.; De Jonge, M.R.; Koy-
mans, L.M.; Vinkers, H.M.; Daeyaert, F.; Ludovici, D.W.; Kukla,
M.J.; De Corte, B.; Kavash, R.W.; Ho, C.Y.; Ye, H.; Lichtenstein,
M.A.; Andries, K.; Pauwels, R.; de Béthune, M.-P.; Boyer, P.L.;
Clark, P.; Hughes, S.H.; Janssen, P.A.; Arnold, E. Roles of con-
formational and positional adaptability in structure-based design of
TMC125-R165335 (etravirine) and related non-nucleoside reverse
transcriptase inhibitors that are highly potent and effective against
wild-type and drug-resistant HIV-1 variants. J. Med. Chem., 2004,
Ludovici, D.W.; Kavash, R.W.; Kukla, M.J.; Ho, C.Y.; Ye, H.; De
Corte, B.L.; Andries, K.; de Béthune, M.-P.; Azijn, H.; Pauwels,
R.; Moereels, H.E.; Heeres, J.; Koymans, L.M.; de Jonge, M.R.;
Van Aken, K.J.; Daeyaert, F.F.; Lewi, P.J.; Das, K.; Arnold, E.;
Janssen, P.A. Evolution of anti-HIV drug candidates part 2: diaryl-
triazine (DATA) analogues. Bioorg. Med. Chem. Lett., 2001, 17,
Ludovici, D.W.; De Corte, B.L.; Kukla, M.J.; Ye, H.; Ho, C.Y.;
Lichtenstein, M.A.; Kavash, R.W.; Andries, K.; de Béthune, M.-P.;
Azijn, H.; Pauwels, R.; Lewi, P.J.; Heeres, J.; Koymans, L.M.H.;
de Jonge, M.R.; Van Aken, K.J.A.; Daeyaert, F.F.D.; Das, K.;
Arnold, E.; Janssen, P.A.J. Evolution of anti-HIV drug candidates.
part 3: diarylpyrimidine (DAPY) analogues. Bioorg. Med. Chem.
Lett., 2001, 11, 2235-2239.
Janssen, P.A.J.; Lewi, P.J.; Arnold, E.; Daeyaert, F.; de Jonge, M.;
Heeres, J.; Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.;
Kukla, M.; Ludovici, D.; Andries, K.; de Béthune, M.-P.; Pauwels,
R.; Das, K.; Clark, A.D.; Jr.; Frenkel, Y.V.; Hughes, S.H.; Medaer,
B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.; Williams,
P.; Stoffels, P. In search of a novel anti-HIV drug: multidiscipli-
nary coordination in the discovery of 4-[[4-[[4-[(1E)-2-
2pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J. Med.
Chem., 2005, 48, 1901-1909.
Guillemont, J.; Pasquier, E.; Palandjian, P.; Vernier, D.; Gaurrand,
S.; Lewi, P.J.; Heeres, J.; de Jonge, M.R.; Koymans, L.M.H.; Dae-
yaert, F.F.D.; Vinkers, M.H.; Arnold, E.; Das, K.; Pauwels, R.;
Andries, K.; de Béthune, M.-P.; Bettens, E.; Hertogs, K.; Wiger-
inck, P.; Timmerman, P.; Janssen, P.A.J. Synthesis of novel di-
arylpyrimidine analogues and their antiviral activity against human
immunodeficiency virus type 1. J. Med. Chem., 2005, 48, 2072-
Feng, X.Q.; Liang, Y.H.; Zeng, Z.S.; Chen, F.E.; Balzarini, J.;
Pannecouque, C.; De Clercq, E. Structural modifications of DAPY
analogues with potent anti-HIV-1 activity. Chem. Med. Chem.,
2009, 4, 219-224.
Liang, Y.H.; Feng, X.Q.; Zeng, Z.S.; Chen, F.E.; Balzarini, J.;
Pannecouque, C.; De Clercq, E. Design, synthesis, and SAR of
naphthyl-substituted diarylpyrimidines as non-nucleoside inhibitors
of HIV-1 reverse transcriptase. Chem. Med. Chem., 2009, 4, 1537-
Liang, Y.H.; Zeng, Z.S.; Liu, Z.Q.; Feng, X.Q.; Chen, F.E.; Balza-
rini, J.; Pannecouque, C.; De Clercq, E. Synthesis and anti-HIV ac-
tivity of 2-naphthyl substituted DAPY analogues as non-nucleoside
reverse transcriptase inhibitors. Bioorg. Med. Chem., 2010,
Di Fabio, S.; Van Roey, J.; Giannini, G.; van den Mooter, G.;
Spada, M.; Binelli, A.; Pirillo, M.F.; Germinario, E.; Belardelli, F.;
de Bethune, M.-P.; Vella, S. Inhibition of vaginal transmission of
HIV-1 in hu-SCID mice by the non-nucleoside reverse tran-
scriptase inhibitor TMC120 in a gel formulation. AIDS, 2003, 17,
Recent Advances in DAPYs and Related Analogues Current Medicinal Chemistry, 2011 Vol. 18, No. 3 17
 Van Herrewege, Y.; Vanham, G.; Michiels, J.; Fransen, K.; Ke-
stens, L.; Andries, K.; Janssen, P.; Lewi, P. A series of diaryltriazi-
nes and diarylpyrimidines are highly potent non-nucleoside reverse
transcriptase inhibitors with possible applications as microbicides.
Antimicrob. Agents Chemother., 2004, 48, 3684-3689.
Feng, X.Q.; Zeng, Z.S.; Liang, Y.H.; Chen, F.E.; Pannecouque, C.;
Balzarini, J.; De Clercq, E. Synthesis and biological evaluation of
4-(hydroxyimino)arylmethyl diarylpyrimidine analogues as poten-
tial non-nucleoside reverse transcriptase inhibitors against HIV.
Bioorg. Med. Chem., 2010, 18, 2370-2374.
Zeng, Z.S.; Liang, Y.H.; Feng, X.Q.; Chen, F.E.; Pannecouque, C.;
Balzarini, J.; De Clercq, E. Lead optimization of diarylpyrimidines
as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Chem.
Med. Chem., 2010, 5, 837-840.
Girardet, J.L.; Koh, Y.H.; Shaw, S.; Kin, H.W. Diaryl-purine,
azapurines and -deazapurines as non-nucleoside reverse tran-
scriptase inhibitors for treatment of HIV. Patent WO 2006122003,
Udier-Blagovi?, M.; Tirado-Rives, J.; Jorgensen, W.L. Validation
of a model for the complex of HIV-1 reverse transcriptase with
non-nucleoside inhibitor TMC125. J. Am. Chem. Soc., 2003, 125,
Lansdon, E.B.; Brendza, K.M.; Hung, M.; Wang, R.; Mukund, S.;
Jin, D.; Birkus, G.; Kutty, N.; Liu, X.H. Crystal structures of HIV-1
reverse transcriptase with etravirine (TMC125) and rilpivirine
(TMC278): implications for drug design. J. Med. Chem., 2010, 53,
Brotherton-Pleiss, C.E.; Kertesz, D.J.; Yang, M.M. Non-nucleoside
reverse transcriptase inhibitors. Patent WO 2008071587, 2008.
Kertesz, D.J.; Brotherton-Pleiss, C.; Yang, M.M.; Wang, Z.G.; Lin,
X.F.; Qiu, Z.X.; Hirschfeld, D.R.; Gleason, S.; Mirzadegan, T.;
Dunten, P.W.; Harris, S.F.; Villaseñor, A.G.; Hang, J.Q.; Heilek,
G.M.; Klumpp, K. Discovery of piperidin-4-yl-aminopyrimidines
as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with
broad potency against resistant mutant viruses. Bioorg. Med. Chem.
Lett., 2010, 20, 4215-4218.
Tang, G.; Kertesz, D.J.; Yang, M.; Lin, X.; Wang, Z.; Li, W.; Qiu,
Z.; Chen, J.; Mei, J.; Chen, L.; Mirzadegan, T.; Harris, S.F.; Vil-
laseñor, A.G.; Fretland, J.; Fitch, W.L.; Hang, J.Q.; Heilek, G.;
Klumpp, K. Exploration of piperidine-4-yl-aminopyrimidines as
HIV-1 reverse transcriptase inhibitors. N-Phenyl derivatives with
broad potency against resistant mutant viruses. Bioorg. Med. Chem.
Lett., 2010, 20, 6020-6023.
Zhan, P.; Liu, X.Y.; Li, Z.Y.; Pannecouque, C.; De Clercq, E.
Design strategies of novel NNRTIs to overcome drug resistance.
Curr. Med. Chem., 2009, 16, 3903-3917.
Morphy, R.; Rankovic, Z. Designing multiple ligands-medicinal
chemistry strategies and challenges. Curr. Pharm. Des., 2009, 15,
Zhan, P.; Liu, X.Y. Designed multiple ligands: an emerging anti-
HIV drug discovery paradigm. Curr. Pharm. Des., 2009, 15, 1893-
Mordant, C.; Schmitt, B.; Pasquier, E.; Demestre, C.; Queguiner,
L.; Masungi, C.; Peeters, A.; Smeulders, L.; Bettens, E.; Hertogs,
K.; Heeres, J.; Lewi, P.; Guillemont J. Synthesis of novel di-
arylpyrimidine analogues of TMC278 and their antiviral activity
against HIV-1 wild-type and mutant strains. Eur. J. Med. Chem.,
2007, 42, 567-579.
Kohlstaedt, L.A.; Wang, J.; Friedman, J.M.; Rice, P.A.; Steitz, T.A.
Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase
complexed with an inhibitor. Science, 1992, 256, 1783-1790.
Smerdon, S.J.; Jager, J.; Wang, J.; Kohlstaedt, L.A.; Chirino, A.J.;
Friedman, J.M.; Rice, P.A.; Steitz, T.A. Structure of the binding
site for non-nucleoside inhibitors of the reverse transcriptase of
human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA,
1994, 91, 3911-3915.
Esnouf, R.M.; Ren, J.; Hopkins, A.L.; Ross, C.K.; Jones, E.Y.;
Stammers, D.K.; Stuart, D.I. Unique features in the structure of the
complex between HIV-1 reverse
bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mu-
tations for this non-nucleoside inhibitor. Proc. Natl. Acad. Sci.
USA, 1997, 94, 3984-3989.
Ren, J.; Milton, J.; Weaver, K.L.; Short, S.A.; Stuart, D.I.; Stam-
mers D.K. Structural basis for the resilience of efavirenz (DMP-
266) to drug resistance mutations in HIV-1 reverse transcriptase.
Struct. Fold Des., 2000, 8, 1089-1094.
transcriptase and the
 Lindberg, J.; Sigurdsson, S.; Lowgren, S.; Andersson, H.O.; Sahl-
berg, C.; Noréen R.; Fridborg K.; Zhang H.; Unge T. Structural ba-
sis for the inhibitory efficacy of efavirenz (DMP-266), MSC194
and PNU142721 towards the HIV-1 RT K103N mutant. Eur. J.
Biochem., 2002, 269, 1670-1677.
Ren, J.; Stammers, D.K. Structural basis for drug resistance
mechanisms for non-nucleoside inhibitors of HIV reverse tran-
scriptase. Virus Res., 2008, 134, 157-170.
Daeyaert, F.; de Jonge, M.; Heeres, J.; Koymans, L.; Lewi, P.;
Vinkers, M.H.; Janssen, P.A. A pharmacophore docking algorithm
and its application to the cross-docking of 18 HIV-NNRTI's in their
binding pockets. Proteins, 2004, 54, 526-533.
Daszykowski, M.; Walczak, B.; Xu, Q.S.; Daeyaert, F.; de Jonge,
M.R.; Heeres, J.; Koymans, L.M.; Lewi, P.J.; Vinkers, H.M.; Jans-
sen, P.A.; Massart, D.L. Classification and regression trees-studies
of HIV reverse transcriptase inhibitors. J. Chem. Inf. Comput. Sci.,
2004, 44, 716-726.
Barreca, M.L.; Rao, A.; De Luca, L.; Zappal, M.; Monforte, A.M.;
Maga, G.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Chimirri,
A.; Monforte, P. Computational strategies in discovering novel
non-nucleoside inhibitors of HIV-1 RT. J. Med. Chem., 2005, 48,
Barreca, M.L.; De Luca, L.; Iraci, N.; Rao, A.; Ferro, S.; Maga, G.;
Chimirri, A. Structure-based pharmacophore identification of new
chemical scaffolds as non-nucleoside reverse transcriptase inhibi-
tors. J. Chem. Inf. Model., 2007, 47, 557-562.
Das, K.; Bauman, J.D., Clark Jr., A.D., Frenkel, Y.V., Lewi, P.J.,
Shatkin, A.J., Hughes, S.H., Arnold, E. High-resolution structures
of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexi-
bility explains potency against resistance mutations. Proc. Natl.
Acad. Sci. USA, 2008, 105, 1466-1471.
Fattorusso, C.; Gemma, S.; Butini, S.; Huleatt, P.; Catalanotti, B.;
Persico, M.; De Angelis, M.; Fiorini, I.; Nacci, V.; Ramunno, A.;
Rodriquez, M.; Greco, G.; Novellino, E.; Bergamini, A.; Marini,
S.; Coletta, M.; Maga, G.; Spadari, S.; Campiani, G. Specific tar-
geting highly conserved residues in the HIV-1 reverse transcriptase
primer grip region. design, synthesis, and biological evaluation of
novel, potent, and broad spectrum NNRTIs with antiviral activity.
J. Med. Chem., 2005, 48, 7153-7165.
Butini, S.; Brindisi, M.; Cosconati, S.; Marinelli, L.; Borrelli, G.;
Coccone, S.S.; Ramunno, A.; Campiani, G.; Novellino, E.; Zanoli,
S.; Samuele, A.; Giorgi, G.; Bergamini, A.; Mattia, M.D.; Lalli, S.;
Galletti, B.; Gemma, S.; Maga, G. Specific targeting of highly con-
served residues in the HIV-1 reverse transcriptase primer grip re-
gion. 2. stereoselective interaction to overcome the effects of drug
resistant mutations. J. Med. Chem., 2009, 52, 1224-1228.
Ren, J.; Nichols, C.; Bird, L.E.; Fujiwara, T.; Sugimoto, H.; Stuart,
D.I.; Stammers, D.K. Binding of the second generation non-
nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves
extensive main chain hydrogen bonding. J. Biol. Chem., 2000, 275,
Fang, C.; Bauman, J.D.; Das, K.; Remorino, A.; Arnold, E.;
Hochstrasser, R.M. Two dimensional infrared spectra reveal relaxa-
tion of the non-nucleoside inhibitor TMC278 complexed with HIV-
1 reverse transcriptase. Proc. Natl. Acad. Sci. USA, 2008, 105,
Hopkins, A.L.; Ren, J.; Milton, J.; Hazen, R.J.; Chan, J.H.; Stuart,
D.I.; Stammers, D.K. Design of non-nucleoside inhibitors of HIV-1
reverse transcriptase with improved drug resistance properties 1. J.
Med. Chem., 2004, 47, 5912-5922.
Hopkins, A.L.; Ren, J.; Esnouf, R.M.; Willcox, B.E.; Jones, E.Y.;
Ross, C.; Miyasaka, T.; Walker, R.T.; Tanaka, H.; Stammers, D.K.;
Stuart, D.I. Complexes of HIV-1 reverse transcriptase with inhibi-
tors of the HEPT series reveal conformational changes relevant to
the design of potent non-nucleoside inhibitors. J. Med. Chem.,
1996, 39, 1589-1600.
Lima, L.M.; Barreiro, E.J. Bioisosterism: a useful strategy for
molecular modification and drug design. Curr. Med. Chem., 2005,
Heeres, J.; de Jonge, M.R.; Koymans, L.M.H.; Daeyaert, F.F.D.;
Vinkers, M.; Van Aken, K.J.A.; Arnold, E.; Das, K.; Kilonda, A.;
Hoornaert, G.J.; Compernolle, F.; Cegla, M.; Azzam, R.A.; An-
dries, K.; de Be´thune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P.J.;
Janssen, P.A.J. Design, synthesis, and SAR of a novel pyrazinone
series with non-nucleoside HIV-1 reverse transcriptase inhibitory
activity. J. Med. Chem., 2005, 48, 1910-1918.
18 Current Medicinal Chemistry, 2011 Vol. 18, No. 3 Download full-text
Chen et al.
 Silvestri, R.; Maga, G. Current state-of-the-art in preclinical and
clinical development of novel non-nucleoside HIV-1 reverse tran-
scriptase inhibitors. Expert Opin. Ther. Pat., 2006, 16, 939-962.
Saparpakorn, P.; Thammaporn, R.; Hannongbua, S. Use of 3D
QSAR to investigate the mode of binding of pyrazinones to HIV-1
RT. Monatsh. Chem., 2009, 140, 587-594.
Tian, X.T.; Qin, B.J.; Lu, H.; Lai,W.H.; Jiang, S.B.; Lee, K.H.;
Chen, C.H.; Xie, L. Discovery of diarylpyridine derivatives as
novel non-nucleoside HIV-1 reverse transcriptase inhibitors.
Bioorg. Med. Chem. Lett., 2009, 19, 5482-5485.
Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro,
E.J.; Fraga C.A. Molecular hybridization: a useful tool in the de-
sign of new drug prototypes. Curr. Med. Chem., 2007, 14, 1829-
Terasaka, T.; Kinoshita, T.; Kuno, M.; Nakanishi, I. A highly po-
tent non-nucleoside adenosine deaminase inhibitor: efficient drug
discovery by intentional lead hybridization. J. Am. Chem. Soc.,
2004, 126, 34-35.
Goldman, M.E.; Nunberg, J.H.; O’Brien, J.A.; Quintero, J.C.;
Schleif, W.A.; Freund, K.F.; Gaul, S.L.; Saari, W.S.; Wai, J.S.;
Hoffman, J.M.; Anderson, P.S.; Hupe, D.J.; Emini, E.A.; Stern,
A.M. Pyridinone derivatives: specific human immunodeficiency vi-
rus type 1 reverse transcriptase inhibitors with antiviral activity.
Proc. Natl. Acad. Sci. USA, 1991, 88, 6863-6867.
Davey Jr, R.T.; Dewar, R.L.; Reed, G.F.; Vasudevachari, M.B.;
Polis, M.A.; Kovacs, J.A.; Falloon, J.; Walker, R.E.; Masur, H.;
Haneiwich, S.E.; O’Neill, D.G.; Decker, M.R.; Metcalf, J.A.; Delo-
ria, M.A.; Laskin, O.L.; Salzman, N.; Lane, H.C. Plasma viremia as
a sensitive indicator of the antiretroviral activity of L-697 661.
Proc. Natl. Acad. Sci. USA, 1993, 90, 5608-5612.
Saag, M.S.; Emini, E.A.; Laskin, O.L.; Douglas, J.; Lapidus, W.I.;
Schleif, W.A.; Whitley, R.J.; Hildebrand, C.; Byrnes, V.W.; Kap-
pes, J.C.; Anderson, K.W.; Massari, F.E.; Shaw, G.M. A short-term
clinical evaluation of L-697,661, a non-nucleoside inhibitor of
HIV-1 reverse transcriptase. N. Engl. J. Med., 1993, 329, 1065-
Benjahad, A.; Courté, K.; Guillemont, J.; Mabire, D.; Coupa, S.;
Poncelet, A.; Csoka, I.; Andries, K.; Pauwels, R.; de Béthune,
M.P.; Monneret, C.; Bisagni, E.; Nguyen, CH.; Grierson, DS. 4-
benzyl- and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones, a new
family of potent anti-HIV agents: optimization and in vitro evalua-
tion against clinically important HIV mutant strains. J. Med.
Chem., 2004, 47, 5501-5514.
Benjahad, A.; Croisy, M.; Monneret, C.; Bisagni, E.; Mabire, D.;
Coupa, S.; Poncelet, A.; Csoka, I.; Guillemont, J.; Meyer, C.; An-
dries, K.; Pauwels, R.; de Béthune M.P.; Himmel, D.M.; Das, K.;
Arnold, E.; Nguyen, C.H.; Grierson. D.S. 4-Benzyl and 4-benzoyl-
3-dimethylaminopyridin-2(1H)-ones: in vitro evaluation of new C-
3-amino-substituted and C-5,6-alkyl-substituted analogues against
clinically important HIV mutant strains. J. Med. Chem., 2005, 48,
 Himmel, D.M.; Das, K.; Clark Jr, A.D.; Hughes, S.H.; Benjahad,
A.; Oumouch, S.; Guillemont, J.; Coupa, S.; Poncelet, A.; Csoka,
I.; Meyer, C.; Andries, K.; Nguyen, C.H.; Grierson, D.S.; Arnold,
E. Crystal structures for HIV-1 reverse transcriptase in complexes
with three pyridinone derivatives: a new class of non-nucleoside
inhibitors effective against a broad range of drug-resistant strains.
J. Med. Chem., 2005, 48, 7582-7591.
Storer R.; Alexandre F.R.; Dousson C.; Moussa A.M.; Bridges E.;
Enantiomerically pure phosphoindoles as HIV inhibitors. Patent
WO 2008042240, 2008.
Zhou X.J.; Pietropaolo K.; Damphousse D.; Belanger B.; Chen J.;
Sullivan-Bólyai J.; Mayers, D. Single-dose escalation and multiple-
dose safety, tolerability, and pharmacokinetics of IDX899, a candi-
date human immunodeficiency virus type 1 non-nucleoside reverse
transcriptase inhibitor, in healthy subjects. Antimicrob. Agents Che-
mother., 2009, 53, 1739-1746.
Klibanov O.M.; Kaczor R.L. IDX-899, an aryl phosphinate-indole
non-nucleoside reverse transcriptase inhibitor for the potential
treatment of HIV infection. Curr. Opin. Investig. Drugs, 2010, 11,
Park, H.; Lee, S. Free energy perturbation approach to the critical
assessment of selective cyclooxygenase-2 inhibitors. J. Comput.
Aided Mol. Des., 2005, 19, 17-31.
Reddy, M.R.; Erion, M.D. Relative binding affinities of fructose-
1,6-bisphosphatase inhibitors calculated using a quantum mechan-
ics-based free energy perturbation method. J. Am. Chem. Soc.,
2007, 129, 9296-9297.
Barreiro, G.; Kim, J.T.; Guimarães, C.R.; Bailey, C.M.; Domaoal,
R.A.; Wang, L.; Anderson, K.S.; Jorgensen, W.L. From docking
false-positive to active anti-HIV agent. J. Med. Chem., 2007, 50,
Barreiro, G.; Guimarães, C.R.; Tubert-Brohman, I.; Lyons, T.M.;
Tirado-Rives, J.; Jorgensen, W.L. Search for non-nucleoside inhibi-
tors of HIV-1 reverse transcriptase using chemical similarity, mo-
lecular docking, and MM-GB/SA scoring. J. Chem. Inf. Model,
2007, 47, 2416-2428.
Jorgensen, W.L. Efficient Drug Lead Discovery and Optimization.
Acc. Chem. Re., 2009, 42, 724-733.
Zeevaart, J.G.; Wang, L.; Thakur, V.V.; Leung, C.S.; Tirado-Rives,
J.; Bailey, C.M.; Domaoal, R.A.; Anderson, K.S.; Jorgensen, W.L.
Optimization of azoles as anti-human immunodeficiency virus
agents guided by free-energy calculations. J. Am. Chem. Soc.,
2008, 130, 9492-9499.
Leung, C.S., Zeevaart, J.G., Domaoal, R.A., Bollini, M., Thakur,
V.V., Spasov, K.A., Anderson, K.S., Jorgensen, W.L. Eastern ex-
tension of azoles as non-nucleoside inhibitors of HIV-1 reverse
transcriptase; cyano group alternatives. Bioorg. Med. Chem. Lett.,
2010, 20, 2485-2488.
Received: September 28, 2010
Revised: November 27, 2010 Accepted: November 29, 2010