Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

Article abstract of DOI:10.1016/j.cclet.2020.09.035

In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures, a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3H)-ones were designed, synthesized and evaluated for their antiviral activities in MT-4 cells. Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC₅₀ values ranging from 7.55 μmol/L to 0.018 μmol/L. Among them, compound 5c was identified as the most promising inhibitor against HIV-1 replication with an IC₅₀ = 0.018 μmol/L, CC₅₀ = 194 μmol/L, and SI = 12791, which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV. In addition, 5c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02. The preliminary structure-activity relationship (SAR) and molecular modeling studies were also discussed, which provides some useful indications for guiding the further rational design of new S-DACO analogues.

Full text of DOI:10.1016/j.cclet.2020.09.035

G Model
CCLET-5864; No. of Pages 5
Chinese Chemical Letters xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-
2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent
non-nucleoside HIV-1 reverse transcriptase inhibitors
Daxiong Lia,1, Chunsheng Zhanga,e,1, Wei Dinga, Siming Huanga, Le Yua, Nan Lua,
Wenkai Pana, Yiming Lia, Erik De Clercqb, Christophe Pannecouqueb, Hongbing Zhanga,
d,
Yueping Wangc, Yanping Hea, , Fener Chen
*
*
a
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of
Chemical Science and Technology, Yunnan University, Kunming, 650091, China
Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium
Department of Applied Chemistry, Faculty of Science, Kunming University of Science and Technology, Kunming, 650500, China
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China
b
c
d
e
Office of Academic Affairs, Yunnan University of Finance and Economics, Kunming, 650221, China
A R T I C L E I N F O
A B S T R A C T
Article history:
In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures, a
series of novel S-DACO analogues of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimi-
din-4(3H)-ones were designed, synthesized and evaluated for their antiviral activities in MT-4 cells. Most
of these new compounds showed moderate to good activities against wild type HIV-1 with IC50 values
Received 5 August 2020
Received in revised form 3 September 2020
Accepted 21 September 2020
Available online xxx
ranging from 7.55
m
mol/L to 0.018
mmol/L. Among them, compound 5c was identified as the most
promising inhibitor against HIV-1 replication with an IC50 = 0.018
m
mol/L, CC50 = 194 mol/L, and
m
Keywords:
NNRTIs
S-DABOs
S-DACOs
Anti HIV-1 activity
SAR
SI = 12791, which was much more potent than the reference drugs NVP and DLV and comparable to AZT
and EFV. In addition, 5c also exhibited improved activity against double mutant HIV-1 strain RES056
compared to that of the reference drugs NVP/DLV and DB02. The preliminary structure-activity
relationship (SAR) and molecular modeling studies were also discussed, which provides some useful
indications for guiding the further rational design of new S-DACO analogues.
© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
HIV-1 reverse transcriptase (HIV-1 RT), a key enzyme of the
human immunodeficiency virus (HIV) catalyzing the RNA-depen-
dent and DNA-dependent synthesis of double-strand vial DNA, is
still a major target for developing new anti-HIV/AIDS drugs [1–3].
Based on the inhibitory mechanism, there are two types of HIV-1
RT inhibitors: (1) nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs/NtRTIs) and (2) non-nucleoside reverse tran-
scriptase inhibitors (NNRTIs) [4]. NNRTIs as an indispensable
component of highly active antiretroviral therapy (HAART) are
widely used in the clinical treatment of HIV-1-infected patients
due to their unique antiviral potency and high selectivity [5,6].
Currently, six NNRTIs have been approved for clinical use:
nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine
(ETR), rilpivirine (RPV) and doravirine (DOR) [7,8]. Nevertheless,
therapeutic effectiveness of these available drugs has been limited
to a certain extent by the emergence of drug-resistant viruses and
potentially severe side effects in the long-term clinical use. As a
consequence, discovery of novel NNRTI candidates, especially with
better resistance profiles and improved safety and tolerability, is a
continuous pursuit of drug development [9–11].
Up to now, more than 50 structurally diverse classes of
compounds have been identified as NNRTIs with dihydro-
alkyloxy-benzyl-oxopyrimidines (DABOs, Fig. 1) being one of
them. Since DABOs were firstly disclosed in 1992 [12], a number
of more potent and selective derivatives have been designed and
synthesized [13,14], especially the S-DABOs with subnanomolar
activity against both the HIV-1 wild type (WT) and clinically
relevant HIV-1 mutants, where the C-2 alkyloxy is replaced by an
alkylthio moiety [15–18]. Studies on S-DABOs suggested that an
alkylthio (cycloalkylthio) substituent at the C-2 position and an
aromatic ring linked through a methylene bridge to the C-6
* Corresponding authors.
E-mail addresses: yphe@ynu.edu.cn (Y. He), rfchen@fudan.edu.cn (F. Chen).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.cclet.2020.09.035
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: D. Li, C. Zhang, W. Ding et al., Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-
phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors, Chin. Chem. Lett., https://doi.org/
10.1016/j.cclet.2020.09.035

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D. Li, C. Zhang, W. Ding et al.
Chinese Chemical Letters xxx (xxxx) xxx–xxx
Fig. 1. Structures of DABOs and newly designed compounds 5a-x.
position, as well as the unmodified NHCO fragment representing
the N-3 and C-4 positions of the pyrimidine ring, are structural
determinants for the antiviral activity of these compounds [19].
Moreover, a series of conformationally restricted S-DABOs
(1, Fig. 1) featuring a methyl or ethyl at the benzylic carbon of C-6
position was reported by A. Mai et al. [20,21]. Among these
compounds, the 2,6-difluorobenzyl-α-methylthymidine deriva-
tives (2, Fig. 1) were identified as the most active compounds to
exert inhibitory activity against RT in the nanomolar range. The
SAR analysis indicated that significant improvement of potency
associated with two methyl groups, one at the benzylic carbon and
the other at the pyrimidine 5-position, was related to an
intramolecular steric effect.
In arduous efforts to discover more potent S-DABOs, a novel
series of oxophenethyl-S-DABOs (3, Fig. 1) compounds was
reported by He et al. as unique NNRTIs [22–25]. To follow up on
this work, a further series of oxophenethyl-S-DACOs (4, Fig. 1) was
designed and synthesized subsequently by our group, the most
significant characteristic of which being the replacement of the C-6
arylring with a C-6 cyclohexylmethyl moiety [26,27]. In compari-
son with a planar aromatic ring, this replacement would result in
better conformational flexibility to the mutated drug-binding site,
connected to the thiopyrimidinone scaffold via spacers of different
alkyl lengths. We postulated that the newly constructed S-DACOs,
retaining C-2 preferential active groups and introducing novel C-6
side chain linker, might permit the terminal cyclohexyl to extend
farther into the depth of the hydrophobic sub-pocket and make
tighter interactions with surrounding residues, especially the
conserved residue Trp229. Herein we describe the synthesis, anti-
HIV activity evaluation in vitro, and preliminary SAR studies of
these new compounds.
The general synthetic route utilized to obtain desired com-
pounds 5a-x is outlined in Scheme 1. Detailed procedures and
compound characterizations can be found in supporting informa-
tion. The commercially available bromides 6 were converted to
cyclohexyl substituted acids 8 by the reaction with proper malonic
esters 7 in the presence of sodium ethoxide followed by alkaline
hydrolysis and decarboxylation. The latter key intermediate β-
ketoesters
9 were synthesized by exposure of cyclohexyl
substituted acids 8 to N,N’-carbonyl-diimidazole (CDI) followed
by treatment with different ethyl potassium malonates in the
magnesium chloride/triethylamine system [29]. Condensation of
where
a better binding efficiency could be achieved from
optimized van der Waals contacts. It should highlight that
compound DB02 (Fig. 1) possessed outstanding anti-HIV-1 activity
in cell culture and displayed an improved activity against K103 N or
Y181C compared to most S-DABOs [28].
The molecular modeling indicated that the cyclohexyl group of
compound DB02 is positioned in the top hydrophobic pocket
formed by the residues of Tyr181, Tyr188, Phe227, and Trp229, and
forms hydrophobic contact with these hydrophobic residues [28].
Furthermore, it seems that there still is extra space to accommo-
date a larger group to make interactions with surrounding residues
(Fig. 1). Based on these findings, together with the above
conformationally restricted strategy, we have recently investigated
novel S-DACOs of general formula 5a-x designed to further obtain
the chemically diverse space and preliminary SAR information of
these oxophenethyl-S-DACOs. Most of these investigations mainly
focused on the C-6 position where a cyclohexyl moiety was
Scheme 1. Synthesis of compounds 5a–x. Reagents and conditions: (a) (i) Na, EtOH,
reflux, 2-4 h; (ii) NaOH, EtOH, H2O, reflux, 2 h; (iii) heat at 160-170 ꢀC, 4 h. (b) (i) CDI,
CH3CN, r.t., 30 min; (ii) R2CH(CO2Et)(COOK), MgCl2, Et3N, CH3CN, r.t., overnight,
reflux, 2 h; (iii) 13 % HCl, r.t. (c) thiourea, EtONa, reflux, 6-8 h. (d) R3PhCOCH2Br,
K2CO3, DMF, r.t., 8-24 h.
2

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Chinese Chemical Letters xxx (xxxx) xxx–xxx
β-ketoesters 9 with thiourea in alkaline medium afforded the
substituted thiouracils 10, which were subsequently treated in
anhydrous N,N-dimethylformamide (DMF) with the appropriate
halide (R3PhCOCH2Br) in the presence of potassium carbonate to
yield the corresponding target compounds 5a–x. Both analytical
and spectral data of all the newly synthesized compounds are in
full agreement with the proposed structures.
selectivity inhibitor against HIV-1
IC50 = 0.018 mol/L, CC50 = 194 mol/L, and SI = 12791. Taking into
account the results of the cytotoxicity assessment, 5c was much
replication with an
IIIB
m
m
more potent than the reference drug NVP (IC50 = 0.06
m
mol/L,
SI > 63),
DLV
(IC50 = 0.021
mmol/L,
SI > 942)
and EFV
(IC50 = 0.001
(IC50 = 0.002
m
m
mol/L, SI > 1982), and comparable to AZT
mol/L, SI = 13293) and DB02 (IC50 = 0.02 mol/L,
m
According the MTT method [30,31], the newly synthesized
oxophenethyl-S-DACO derivatives (compounds 5a–x) were evalu-
ated for their biological activity in MT-4 cells infected with WT
HIV-1IIIB strain, HIV-1 mutant strain RES056 (K103N + Y181C
double RT mutant) and HIV-2 ROD strain in comparison with
nevirapine (NVP), dideoxycytidine (DDC), efavirenz (EFV) and
azidothymidine (AZT) used as reference drugs. The results,
expressed as inhibitory concentration (IC50), cytotoxic concentra-
tion (CC50) and selective index (SI, given by the CC50/IC50 ratio), are
depicted in Table 1. In addition, DB02 was also included in our
assays for comparison.
SI = 14050). In addition, some other compounds 5e, 5 j, 5k and 5 L,
also displayed higher anti-HIV-1 activities (IC50 = 0.08, 0.10, 0.14
and 0.05
mmol/L, respectively) and better selectivity indices
(SI = 3354, 2334, 1168 and 2843, respectively) than those of NVP,
DDC and DLV.
In view of the hydrophobic nature of NNRTI binding site, the
common characteristic of NNRTIs is poor water solubility, which
often leads to low bioavailability and difficulties in formulation. As
can be seen from Table 1, the cLogP values of most compounds
range from 4.40 to 5.90, indicating that water solubility of these
compounds is still not ideal enough. Experimentally, the water
solubility of 5c, 5e and DB02 at pH 6.0 was 216 ng/mL, 213 ng/mL
and 407 ng/mL respectively, which was higher than RPV
(20 ng/mL) [32].
As shown in Table 1, the majority of tested compounds, with the
exception of five compounds 5 h, 5i, 5n, 5p and 5q, exhibited
moderate to good activities against HIV-1IIIB with IC50 values in the
range of 7.55–0.018
22–12791. Compound 5c was found to be the most active and
m
mol/L and SI values in the variable range of
These analogues were also assayed against the frequently
encountered HIV-1 double mutant strain K103 N/Y181C (RES056).
Table 1
Anti-HIV activities, cytotoxicities and selectivity indices of newly designed oxophenethyl-S-DACO derivatives (5a-x) and reference drugs.
a
b
c
d
Compd.
R1
R2
R3
n
IC50
(m
mol/L)
CC50
(
mmol/L)
SI
cLogP
HIV-1 IIIB
HIV-2
5a
5b
5c
5d
5e
5f
5g
5 h
5i
5 j
5k
5 L
5 m
5n
5o
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
Et
Et
CH3
CH3
CH3
H
H
Et
Et
Et
CH3
CH3
CH3
H
H
H
Et
Et
H
F
H
OCH3
H
OH
OCH3
F
OCH3
H
F
OH
H
F
OH
H
F
OH
H
OCH3
H
F
OH
OCH3
H
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
2.17 Æ 0.15
7.55 Æ 0.21
0.018 Æ 0.001
0.03 Æ 0.004
0.08 Æ 0.004
0.05 Æ 0.03
0.06 Æ 0.02
79.9 Æ 3.20
35.7 Æ 5.40
0.10 Æ 0.01
0.14 Æ 0.02
0.05 Æ 0.00
1.72 Æ 0.06
7.32 Æ 0.08
0.24 Æ 0.01
9.58 Æ 0.18
10.9 Æ 0.53
1.44 Æ 0.07
0.09 Æ 0.002
0.07 Æ 0.01
0.35 Æ 0.00
1.01 Æ 0.004
0.13 Æ 0.01
0.93 Æ 0.36
0.02 Æ 0.002
0.06 Æ 0.15
0.001 Æ 0.15
0.021 Æ 0.15
0.0019 Æ 0.15
266
165
194
30
259
13
267 Æ 20.05
165 Æ 9.72
194 Æ 13.64
30 Æ 0.58
259 Æ 4.93
13 Æ 0.58
28 Æ 0.40
80 Æ 6.64
156 Æ 6.93
241 Æ 12.45
164 Æ 7.99
132 Æ 8.05
124 Æ 20.78
7.3 Æ 0.30
8.2 Æ 0.67
151 Æ 7.97
108 Æ 5.18
31 Æ 0.59
32 Æ 0.66
31 Æ 0.34
179 Æ 28.83
115 Æ 26.80
24 Æ 0.97
43 Æ 18.40
263 Æ 8.70
>4
123
22
4.40
4.61
5.37
5.59
4.84
4.71
5.06
4.74
4.74
5.50
5.72
5.37
4.97
5.19
4.84
4.92
5.14
4.79
5.90
6.12
5.37
5.59
5.24
5.59
4.97
–
12791
925
3354
260
439
1
28
80
156
241
164
132
124
7.3
8.2
151
108
31
32
31
179
115
24
4
2334
1168
2843
72
1
34
16
10
22
359
469
509
114
179
46
14050
>63
>1982
>942
>13293
H
H
H
5p
5q
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
5 r
5 s
5 t
5 u
5v
CH3
CH3
CH3
CH3
Et
5 w
5x
43
263
–
DB02
NVP
EFV
DLV
AZT
–
>2
>20
>25
–
–
–
–
a
IC50: concentration of compound required to achieve 50 % protection of MT-4 cells against HIV-induced cytopathicity, as determined by the MTT method.
CC50: concentration required to reduce the viability of mock-infected cells by 50 %, as determined by the MTT method.
SI: selectivity index (CC50/IC50).
b
c
d
cLogP: predicted by using software ChemBioDraw Ultra 12.0.
3

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Both the absolute activity against the HIV-1 mutant (IC50 value)
and the relative activity (fold-resistance) were used to define the
resistance profile of the tested compounds. The results indicated
that most derivatives, including the lead compound DB02, lost
activity against the double mutant strain RES056, while four
compounds (5c, 5d, 5 s, 5 t) were more potent than the reference
drug DLV against the resistant mutant strain with the IC50 value of
11.68, 7.89, 9.84 and 4.39 mmol/L respectively (versus > 20 mmol/L,
DLV) and a fold-resistance ratio of 770, 243,108 and 66 respectively
(versus > 942, DLV). In this work, all compounds were also screened
for their inhibition against the replication of the HIV-2 strain (ROD)
in MT-4 cells, but none of them exhibited inhibitory activity at sub-
toxic concentrations, indicating that the novel series of S-DACO
derivatives were specific to HIV-1. Preliminary structure-activity
relationship (SAR) derived from these results was analyzed as
follows.
First, we focused our attention on the linker optimization at the
C-6 position of the pyrimidine ring. As we can see, methylation of
C-6 secondary carbon of the lead compound DB02 led to
compound 5c with similar potency (IC50 = 0.018
mmol/L) to
DB02 (IC50 = 0.020 mol/L), while the insertion of a carbon into
C-6 CH2-cyclohexyl substituted moiety of DB02 yielded compound
5 j, the increased length of the carbochain linker reduced the
m
Fig. 2. Predicted binding modes of selected compounds with RT (PDB: 1RT2). (A)
DB02 (carbons in yellow) with RT; (B) 5 j (carbons in magenta) with DB02; (C) (R)-
5c (carbons in orange) with DB02; (D) (S)-5c (carbons in slate) with DB02. Residues
involved in interactions are shown as green sticks. Dotted lines show the
interactions between HIV-1 RT and inhibitors.
activity about 5-fold (IC50 = 0.10
tion of the secondary carbon of the CH2CH2-cyclohexyl of the 5 j
gave the 0.09 mol/L inhibitor 5 s, which is as potent as 5 j but the
mmol/L). Subsequently, methyla-
m
cytotoxicity was increased about 8-fold. The above results of the
C6-linker optimization provided some support for our hypothesis
that introduction of a methyl group to the C6-CH2 linker would be
feasible and effective.
information). Binding modes of compounds 5c and 5 j in the
allosteric site of HIV-1 WT RT in comparison with DB02 were
present at Fig. 2. The location of compound 5c was different due to
the presence of C-6 chiral carbon (Fig. 2. C and D). Results showed
that compound 5c and 5 j had similar binding pattern with DB02 in
the NNIBP that the pyrimidine ring was stabilized by the hydrogen
bond between the 3-NH of the pyrimidine ring with the carbonyl
oxygen of Lys101. While the C-2 side chain extend in the same
direction, forming hydrogen bonds between the carbonyl oxygen
of the C-2 side chain and the NH group of the Lys103 backbone. The
interactions between 5c and RT were almost identical to that of
DB02 with RT, explains the fact that 5c and DB02 have the same
anti-HIV activity. On the other hand, the hydrogen bond between
compound 5 j and RT is weaker than that of DB02, so the activity of
compound 5 j is decreased by 5 times compared with DB02. The
C6-cyclohexyl group of the inhibitors is positioned in a hydropho-
bic sub-pocket formed by Try181, Try188, Phe227 and Trp229 and
develops additional interactions with the hydrophobic pocket.
Moreover, the C6-cyclohexyl group of 5c and 5 j is closer to Trp229
than that of DB02, because Trp229 is highly conserved, this
interaction is expected to be retained despite mutations in the
binding pocket, and this may be the reason why 5c retains potency
against the mutant strain compared to DB02. In particular, it can be
seen from Fig. 2. C and D, that the hydrogen bond between
compound (R)-5c and RT is stronger than that between compound
(S)-5c and RT (distances 1.66 Å and 2.10 Å vs 1.76 Å and 2.18 Å), and
the cyclohexyl group of compound (R)-5c is closer to Trp229 than
compound (S)-5c (distance 3.33 Å vs 3.86 Å). Therefore, we inferred
that compound (R)-5c had better anti-HIV activity than compound
(S)-5c.
Just as SAR studies on S-DABOs, the para substituents
(-F, ÀOCH3, ÀOH) of the terminal phenyl ring at the C-2 side
chain also had significant effects on the antiviral activity of these
novel S-DACOs. As shown in Table 1, introduction of a 4’-hydroxyl
group at the phenyl ring led to compounds 5f, 5 L, 5o, 5 r and 5 w
with slightly better anti-HIV-1 activities than their unsubstituted
counterparts 5e, 5 j, 5 m, 5p and 5 u. On the other hand, all of the
4'-fluoro-substituted compounds displayed decreased activities
comparing to their 4'ÀOCH3/OH/H-substituted counterparts.
Generally, the sequence of beneficial effects of the para sub-
stituents at the C-2 terminal phenyl ring on activity is as follows
decreasing order: OH > H ꢁ OCH3 > F. At the same time, it is worth
noting that the introduction of 4'ÀOH, 4'ÀOCH3 or 4'-F at the C-2
v-
phenyl ring led to increased cytotoxicity.
When tested against wt HIV-1, the compounds 5b, 5p, 5q and
5 r displayed low inhibitory activity andparticularly compounds
5 h and 5i almost lost their activity. With the insertion of a methyl
or ethyl group at the C-5 position of the pyrimidine, a marked
increase of anti-HIV-1 activity and selectivity index was observed
for all of the substituted compounds. Moreover, the influence on
activity of an ethyl substituent was obviously better than its methyl
counterpart. For instance, compounds 5c, 5 L, 5 j, 5k, 5 t and 5 s
(IC50 = 0.018, 0.05, 0.10, 0.14, 0.07 and 0.09
were more potent than their methyl counterparts 5e, 5o, 5 m, 5n,
5x and 5 u (IC50 = 0.08, 0.24, 1.72, 7.32, 0.93 and 0.35 mol/L,
mmol/L, respectively)
m
respectively). So, the order of activity of the C-5 substituents can be
summarized as follows: Et > Me > H, which is in agreement with
our previously reported results on the S-DACO series [26,27].
In conclusion, to extend the range of NNRTIs chemical
structures and overcome the issue of resistance, we designed a
series of oxophenethyl-S-DACO derivatives as potent new HIV-1
NNRTIs based on the molecular modeling of lead compound DB02
and using conformationally restricted strategy. The experimental
data indicated that most of the compounds showed moderate to
good anti-HIV activity with IC50 values in the range of 7.55–
Since the lead compound DB02 showed an IC50 of 0.28 mmol/L
against the RT enzyme and a similar dose-dependent pattern in
inhibiting HIV-1 RT activity with NVP [33], we inferred that these
newly synthesized compounds also acted as classical NNRTIs. To
better understand the activity and the interaction mechanism
between these compounds and RT, the selected compounds 5c and
5 j were docked into the NNRTIs binding pocket (NNIBP) compared
with DB02 using the AutoDock4.2 program (Supporting
0.018
mmol/L. Among them, the most potent HIV-1 inhibitor was
5c (SI = 12791), which was much more potent than the reference
4

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D. Li, C. Zhang, W. Ding et al.
Chinese Chemical Letters xxx (xxxx) xxx–xxx
drugs NVP, DLV and EFV and comparable to AZT and DB02. In
addition, 5c also exhibited improved activity against double
mutant HIV-1 strain RES056 compared to that of the reference
drugs NVP/DLV and DB02. The preliminary SARs were discussed
and the molecular simulation was performed, providing insights
for discovery of more active and selective S-DACOs with diverse
structures. At last, since some active derivatives contain one
stereogenic center, therefore, exist as racemic or stereoisomeric
mixtures. Further systematic investigation on their potential
enantio-/diastereoselective anti-HIV-1 activity is still ongoing in
our lab.
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Declaration of Competing Interest
The authors report no declarations of interest.
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Appendix A. Supplementary data
Supplementarymaterialrelatedto thisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2020.09.035.
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