Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives

Article abstract of DOI:10.1016/j.bmcl.2016.11.030

In this study, using molecular hybridization approach, fourteen novel 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives (7a–n) were designed as inhibitor of HIV-1 RT. The binding affinity of the designed compounds with HIV-1 RT as wel

Full text of DOI:10.1016/j.bmcl.2016.11.030

Accepted Manuscript
Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophen-
yl)amino)-1-(piperazin-1-yl)ethanone derivatives
Subhash Chander, Ping Wang, Penta Ashok, Liu-Meng Yang, Yong-Tang
Zheng, Murugesan Sankaranarayanan
PII:
S0960-894X(16)31173-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.11.030
BMCL 24425
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 August 2016
13 October 2016
12 November 2016
Please cite this article as: Chander, S., Wang, P., Ashok, P., Yang, L-M., Zheng, Y-T., Sankaranarayanan, M.,
Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone
derivatives, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.11.030
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Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-
chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives
Subhash Chandera, Ping Wangb, Penta Ashoka, Liu-Meng Yangb, Yong-Tang Zhengb,* and
Murugesan Sankaranarayanana,*
a,*Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology
& Science, Pilani-333031. Rajasthan. India. E. mail: murugesan@pilani.bits-pilani.ac.in
b,*Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human
Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of
Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223. P.R. China. E. mail:
zhengyt@mail.kiz.ac.cn
ABSTRACT: In this study, using molecular hybridization approach, fourteen novel 2-
(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives (7a-n) were designed
as inhibitor of HIV-1 RT. The binding affinity of the designed compounds with HIV-1 RT as
well as their drug-likeness behaviour was predicted using in-silico studies. All the designed
compounds were synthesized, characterized and in-vitro evaluated for HIV-1 RT inhibitory
activity, in which tested compounds displayed significant to weak potency against the
selected target. Moreover, best active compounds of the series, 7k and 7m inhibited the
activity of RT with IC50 values 14.18 and 12.26 µM respectively. Structure Activity
Relationship (SAR) studies were also performed in order to predict the influence of
substitution pattern on the RT inhibitory potency. Anti-HIV-1 and cytotoxicity studies of best
five RT inhibitor (7a, 7d, 7k, 7l and 7m) revealed that, except compound 7d other
compounds retained significant anti-HIV-1 potency with good safety index. Best scoring pose
of compound 7m was analysed in order to predict its putative binding mode with wild HIV-1
RT.
Keywords: Enzymatic assay, Wild strain, Reverse transcriptase, Docking, Cytotoxicity
1

AIDS is a serious health threat, which if untreated eventually leads to death, mostly due to
opportunistic infections.1,2 UNAIDS 2015 report revealed that, around 36.7 million people
were living with HIV globally, in the same year around 2.1 million new infections were
reported and around 1.1 million people died from AIDS-related diseases.3 Highly Active Anti
Retroviral Therapy (HAART) is the most widely adopted therapy against HIV/AIDS across
the globe, which includes combination of three or more drugs having different mechanisms of
action.4 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) acting upon the reverse
transcriptase enzyme of HIV-1 is an important class of antiretroviral drugs and widely used in
HAART due to their less toxicity, high potency and high selectivity.5,6 Although, NNRTIs are
structurally diverse in nature, but mechanistically all interact with the allosteric site of HIV-1
RT, also known as non-nucleoside inhibitory binding pocket (NNIBP) in a non-competitive
manner, which results conformational changes in its catalytic domain, consequently leads to
inhibition of its DNA polymerase activity.7,8 Although, HAART is effective for the reduction
of viral load, but rapid development of drug resistance, in association with problems like
difficulty in adherence to therapy and long-term side effects hampered the effectiveness of
this therapy.9,10 To circumvent this problem, there is a continuous need of new anti-HIV
drugs effective against the multiple strains of HIV with suitable pharmacokinetic profile.
Molecular hybridization is a rational approach to design novel ligands, involves the
combination of two or more pharmacophoric subunits of known bioactive moieties and
similar approach has been successfully utilized for the search of potent HIV-1 RT
inhibitors.11-13 NNIBP is predominantly hydrophobic in nature and despite the structural
diversity of NNRTIs, they possessed several common features, for example most of these
constitute bulky aryl group connected to another hydrophobic or heteroaryl group via a
hydrophilic linker.14 In this direction, Cushman and group reported a series of diaryl
alkylidene based compounds as HIV-1 RT inhibitor, most potent compound of the series (A,
Fig. 1) displayed sub-micromolar (IC50 0.3 µM) potency.15 Another series of compounds
containing diarylmethane as bulky hydrophobic wings were also explored as HIV-1 RT
inhibitors by Silvestri and group, compound B (Fig. 1) of this group inhibited RT activity
with IC50 value 50 nM.16 In the last one decade, compounds containing diaryl ether has been
well explored as potent NNRTIs, moreover clinically used block buster drug Etravirine also
constitute the diaryl ether moiety.17-19 In similar study, Smith and group reported a series of
2

compounds containing pyridone diaryl ether, in which one of the promising active compound
(C, Fig. 1) exhibited IC50 12 nM against selected RT strain and EC50 50 nM against HIV-1.20
Although, compounds A-C are structurally diverse in nature, despite that these share
some ubiquitous features, for example all three possess electron rich biaryl moiety
(highlighted by the green color), which helps them to stabilize inside the hydrophobic NNIBP
via hydrophobic or pi-pi stacking interactions and subsequently may be responsible for their
potent RT inhibitory activity. So, inspired by these findings, model E was designed as
prototype (Fig. 1) HIV-1 RT inhibitor, which constituted N-benzyl-p-chlorophenyl amine as
electron rich hydrophobic entity (green color, E) attached with N-substituted ethanone
piperazine, a bioisosters component (coral color highlight, Fig. 1) of compound D, which is
already reported for RT inhibition.21,22 In the designed prototype E, rationality for adding the
N-benzyl ring was to provide extra flexibility, while p-chloro phenyl moiety was kept in
order to increase the hydrophobic area of contact with receptor. Further, based upon the
designed prototype E, series of compounds (7a-n) was generated by making different
substitution with phenyl or aryl group.
Figure 1. Literature reported HIV-1 RT inhibitors (A-D) and designed prototype model (E)
Pharmacokinetic properties play indispensible role in early stages of drug discovery and
development, clinically approved drugs possess a favourable balance between
3

pharmacokinetic properties and intrinsic potency. But, experimental determination of such
properties for all novel molecules using in-vivo models is very costly, challenging and time
consuming task.23,24 So, considering these factors, the drug-likeness behavior and
pharmacokinetic parameters of the designed series was in-silico predicted using three
different tools; Qik-prop module of Schrödinger,25 admetSAR 26 and FAF-Drugs3.27
The optimum range of these parameters (followed by 95% known drug molecules) is
given in Table S1 (Supplementary information). The results of the predicted parameters
(Table 1) for compounds (7a-n) revealed that, predicted values of Mol. Wt, HBD, HBA and
logP lied within the optimum range as described in Table S1. Although, logS value of
compound 7n found to be lower than the prescribed optimum range (–6.5 to 0.5), but it
deviate by a small margin, which may not change its pharmacokinetic profile much
significantly. So, considering this, compound 7n was retained for further studies. All
compounds displayed good value of caco-2 cell permeability (PCaco), except compound 7k
which exhibited moderate permeability. Values of other parameters like SASA, logBB, Rot
were also found within the optimum range. Further, none of the compounds exhibited
predicted mutagenicity (predicted in qualitative terms). So, considering the predicted
parameters, overall majority of the compounds possessed the drug-likeness behavior.
Table 1 In-silico predicted drug likeness and pharmacokinetic parameters of the titled
compounds
Comp
M Wt
SASAa
HBDb
HBAc
logP
logS
PCacod
logBBe
Rotf
Mutg
.Code
7a
7b
7c
419.18 726.04
433.19 748.46
433.19 758.24
449.19 764.68
449.19 763.21
449.19 763.04
437.17 732.21
437.17 735.05
453.14 750.13
453.14 750.10
464.16 781.60
433.19 778.21
0
0
0
0
0
0
0
0
0
0
0
0
4
4
4
5
5
5
4
4
4
4
7
4
5.57
5.88
5.90
5.68
5.63
5.63
5.74
5.81
6.07
6.08
4.87
6.34
-6.23
-6.36
-6.44
-6.21
-6.18
-6.18
-6.24
-6.40
-6.27
-6.27
-6.19
-6.37
5164.05
5606.61
5161.92
5417.31
5165.21
5197.91
5344.61
5165.42
5161.12
5165.16
429.54
0.24
0.28
0.24
0.20
0.18
0.18
0.32
0.36
0.45
0.42
-0.99
0.55
6
6
6
7
7
7
6
6
6
6
7
7
None
None
None
None
None
None
None
None
None
None
None
None
7d
7e
7f
7g
7h
7i
7j
7k
7l
5521.95
4

487.10 765.82
509.22 852.75
0
0
4
4
5.02
6.38
-5.10
1274.70
1355.44
0.51
0.47
6
8
None
None
7m
7n
-
6.61
a Solvent accessible surface area, b No. of hydrogen bond donors, c No. of hydrogen bond acceptors, d Predicted
e
f
apparent Caco-2 cell permeability in nm/sec, Predicted brain/blood partition coefficient, No. of rotatable
bonds, g Mutagenicity
In order to predict the in-silico binding affinities of the designed compounds with HIV-1 RT,
docking studies were performed using Glide28 module of Schrödinger in extra precision
mode29, taking efavirenz as reference ligand for comparison. HIV-1 RT enzyme used for the
docking studies was wild type (no mutation at NNRTIs binding site), retrieved from Protein
Data Bank (PDB ID: 3MEE) in complex with co-crystallized ligand rilpivirine (detailed
protocol is given in the supplementary part). The value of RMSD obtained between
superimposed (Fig. S1, supplementary information) re-docked pose of co-crystallized ligand
and its experimental binding pose (as in X-ray) was found to be 0.64, which suggested the
reliability of docking protocol. In-silico binding affinities of the compounds are expressed in
terms of Glide dock score (G score), which signify that more is the value of G score (in
negative term), greater will be the binding affinity of test compound with enzyme 3MEE.
Dock score of test compounds (Table 2), revealed their moderate to excellent in-silico
binding affinity (G score -8.97 to -12.41) with HIV-1 RT as compared to the reference drug
efavirenz (-13.07).
Designed compounds (7a-n) were synthesized via four step synthetic route, details of the
reaction conditions are summarized in scheme 1. First step involved reaction of p-
chloroaniline (1) with benzaldehyde 2 using ethanol as solvent afforded imine 3 as
intermediate, which on subsequent reduction with sodium borohydride using methanol as
solvent gave N-benzyl-4-chloroaniline (4). In next step, intermediate 4 was treated with
bromo acetic acid using acetonitrile as solvent and triethylamine as base under reflux
conditions afforded compound 5. Further, coupling reaction of intermediate acid 5 with
different substituted aryl piperazines (6a-n) in the presence of 1-hydroxybenzotriazole
(HOBt) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) using
triethylamine as base and dichloro methane (DCM) as solvent afforded final compounds (7a-
n) in good to excellent yields. Details of synthetic procedure followed for the synthesis of
titled compounds is provided in the supplementary information.
5

Scheme 1. Reagents and conditions: (a) EtOH, Caltalytic AcOH, 3 h, reflux (b) MeOH, NaBH4, 0˚C-
rt, 2 h (c) ACN, BrCH2COOH, Et3N, reflux, 5 h (d) HOBT, EDC.HCl, Et3N, DCM, rt, 6-8 h
All the synthesized compounds were characterized by spectral techniques like FT IR,
1H NMR, ESI-MS and elemental analysis (spectral data is given in supplementary
information). FTIR spectra of the titled compounds exhibited the expected absorption bands,
for example, all compounds possessed amide linkage, a corresponding C=O stretching peak
(with strong intensity) appeared in IR spectra at 1645–1661 cm-1. The 1H NMR spectra of the
compounds showed characteristic singlet at δ~4.65 corresponding to two benzylic protons.
Further, the two hydrogen of methylene group (at carbon connecting carbonyl group and
nitrogen) appeared as singlet around δ~4.19. Position of eight piperazine protons in the
proton spectra of series varied depending upon the nature of substitution, for example except
compounds 7l and 7m, these appeared at around δ~3.85 to 3.05 while in compounds 7l and
7m, these appeared at around δ~3.66 to 3.43. Proton counting and peak pattern of NMR
signals corresponding to the other protons of compounds was observed in compliance with
the proposed structure. The calculated and observed elemental values of C H N were found
within the acceptable range. ESI-MS spectra of the synthesized compounds exhibited
corresponding M+1 peak.
HIV-1 RT inhibitory activity of the synthesized compounds (7a-n) was in-vitro
evaluated using colorimetric ELISA kit in accordance with the kit protocol using efavirenz as
reference positive control.30,31 The results of in-vitro assay revealed that, compounds 7a, 7b,
7d, 7k, 7l and 7m exhibited significant inhibition of HIV-1 RT with IC50 ≤25 µM. Further,
compounds 7c, 7e, 7g and 7j displayed moderate potency (IC50 25 > to ≤ 40 µM), while rest
of the compounds displayed weak to least RT inhibitory activity. Compound 7a having un-
6

substituted phenyl ring showed significant potency against HIV-1 RT (IC50 20.56 µM).
Substitution of phenyl ring with methyl group at ortho and para position (7b and 7c) slightly
decreased their potency (IC50 23.47 and 28.14 µM respectively). Further, substitution with
methoxy group slightly increased the potency at ortho position, while it decreased at meta
and para position, so for methoxy substituted compounds (7d, 7e and 7f), potency against RT
varied in the order ortho > meta > para. Compounds having fluoro substitution at ortho
position (7g) exhibited moderate while at para position (7h) it showed weak potency.
Furthermore, meta chloro substituted compound (7i) exhibited weak potency against RT,
while chloro at para position (7j) showed moderate potency. Interestingly, para nitro
substitution at phenyl ring (7k) found to be favourable for the HIV-1 RT inhibition (IC50
14.18 µM) and replacement of phenyl ring with benzyl (7l) slightly reduced the inhibitory
potency (21.51µM). Further, upon di-substitution of phenyl ring with chloro (7m) resulted in
enhancement of RT inhibitory activity, moreover compound 7m exhibited highest potency
(IC50 12.26 µM) against RT among the tested series. Replacement of phenyl ring with
benzhydryl, a more bulky entity (7n) markedly decreases the potency against RT. So, overall
SAR study revealed that, the RT inhibitory potency of the designed compounds changed
significantly with change in nature as well as position of substitution. In general, compounds
having un-substituted phenyl ring (7a), electron donating group like methoxy at ortho
position (7d) and strong electron withdrawing nitro group at para position (7k) exhibited
significant RT inhibitory potency. Moreover, replacement of phenyl with benzyl (7l) as well
as chloro di-substitution at phenyl ring (7m) were also found to be favourable for RT
inhibitory activity.
Table 2 Results of in-vitro HIV-1 RT inhibition studies of the titled compounds
aRT inhibitory activity IC50
(µM)a
Glide Score
(G score)
Comp. Code
R
-11.67
Ph
20.56±1.86
23.47±1.34
28.14±2.74
16.27±1.71
34.32±3.4
7a
7b
7c
7d
7e
7f
2-Me-Ph
4-Me-Ph
2-MeO-Ph
3-MeO-Ph
4-MeO-Ph
2-F-Ph
-10.81
-10.24
-11.08
-10.16
-11.15
-9.58
77.53±7.22
38.41±0.82
56.24±4.56
61.83±2.02
7g
7h
7i
4-F-Ph
-8.97
3-Cl-Ph
-11.76
7

4-Cl-Ph
31.48±1.85
14.18±1.21
21.51±0.84
12.26±1.21
>100
-11.48
-12.41
-10.26
-12.07
-10.28
-13.07
7j
4-NO2-Ph
Benzyl
7k
7l
2,3-DCl-Ph
Benzhydryl
7m
7n
0.037±0.0056
Efavirenz
aAverage of at least duplicate independent experiments, ±SD
Top five active HIV-1 RT inhibitors 7a, 7d, 7k, 7l and 7m were evaluated for anti-HIV-1
activity (HIV-1IIIB strain) by cytopathic effect method, which measured the viability of HIV-1
infected cells.32 In this study, marketed drug zidovudine (AZT) was used as reference
positive control. All five compounds were also evaluated for cytotoxicity against CD4+
bearing T cells by MTT colorimetric assay.33 Details of experimental procedures followed for
anti-HIV-1 assay and cytotoxicity are given in the supplementary part of this manuscript. The
results of anti-HIV-1 activity and cytotoxicity studies (Table 3) revealed that, except
compound 7d, compounds 7a, 7k, 7l and 7m retained potency against HIV-1 with good
safety index. Moreover, compound 7a exhibited most significant activity against HIV-1
among the tested compounds with EC50 value around 10.11 µM and therapeutic index >94.4.
Table 3 Results of anti-HIV-1 activity and cytotoxicity of selected compounds
Comp. Code
Inhibition of syncytia
formation EC50 (µM)a
Cytotoxicity concentration Therapeutic index
CC50 (µM)a
(TI)
7a
10.11±0.72
102.49±4.21
21.22±1.08
13.64±0.78
11.52±0.68
0.013±0.004
>954.24
>94.4
2.2
228.32±19.45
>430.89
7d
>20.3
44.7
7k
7l
610.36±25.20
>410.59
>35
7m
5858.85±440.12
460505.88
Zidovudine
aAverage of at least triplicate independent experiments, ±SD
Comparative studies between the RT inhibition and anti-HIV-1 activity of top five
compounds revealed that, compound like 7m displayed no significant difference in the RT
inhibitory and anti-HIV-1 potency (IC50 12.26 and EC50 11.52, respectively), so excellent co-
relation was observed between the both activity. Further compounds like 7k and 7l showed
good/moderate co-relation between both activity with RSD (Relative Standard Deviation)
around 28.12 and 31.66, respectively. Further, 7a possessed around two times more potent
activity against HIV-1 as compared to RT and demonstrated comparatively weak co-relation.
8

Compound 7d displayed significant potency against HIV-1 RT, but un-expectedly it showed
around six times less potency against HIV-1 and thereby no co-relation between the both
activities was observed.
Best docked pose of one significantly active compound (7m) was analysed in order to predict
its putative binding mode inside the NNIBP of HIV-1 RT. Further, docked pose view of 7m
(Fig. 2 and Fig. 3) revealed that, its chloro phenyl moiety exhibited prominent pi-pi stacking
interaction with residues Tyr-188; it also interacted with Phe-227 and Trp-229 via
hydrophobic interaction, while second aromatic wing (benzyl) exhibited similar interactions
with Val-106 and Trp-318. Further, central axis of compound 7m consisting of aceto phenyl
piperazine moiety showed hydrophobic interactions with Tyr-181 and Val-179. So, presence
of prominent pi-pi stacking and hydrophobic interactions may be responsible for strong
binding of 7m inside the NNIBP and subsequently for significant HIV-1 RT inhibitory
activity.
Figure 2. Three dimensional docked view of compound 7m inside the NNIBP of 3MEE showing
hydrophobic interaction represented by green dotted lines
9

Figure 3. Docked pose of compound 7m inside the NNIBP of 3MEE showing two-dimensional
interactive diagram
In summary, fourteen novel 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-
yl)ethanone derivatives were designed, synthesized and evaluated for HIV-1 RT inhibitory
activity, in which compounds 7a, 7b, 7d, 7k, 7l and 7m exhibited significant inhibition of
HIV-1 RT (IC50 ≤25 µM). Further, among the top five RT inhibitors evaluated for anti-HIV-1
activity and cytotoxicity studies, except compound 7d, others compounds (7a, 7k, 7l and 7m)
retained significant anti-HIV-1 potency with good safety index. Docking studies of
compound 7m against wild HIV-1 RT revealed its prominent pi-pi stacking and hydrophobic
interactions within NNIBP of selected RT strain, which may be responsible for its strong
binding affinity with receptor and subsequently for significant HIV-1 RT inhibitory activity.
So, overall studies can be helpful in the direction of further lead optimization or designing of
novel potent anti-HIV agents.
Acknowledgments
Authors gratefully acknowledge BITS-Pilani for providing the necessary facilities to do this work.
This work was carried out under a grant from Science and Engineering Research Board of Department
of Science and Technology, New Delhi. (Ref. No: SR/FT/LS-58/2011), the National Science
Foundation of China (81102483) and the STS Program of CAS (KFJ-EW-STS-026).
10

Supplementary data
Supplementary data associated with this article can be found, in the online version, at
xxxxxxxxxxxx
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 Fourteen novel compounds were designed, synthesized, and evaluated for HIV-1 RT
inhibition.
 Tested compounds displayed significant to weak potency against the selected target.
 Among top five RT inhibitors, four retained significant potency against HIV-1 with
good safety index.
 Docked view of compound 7m with RT revealed prominent pi-pi stacking and
hydrophobic interaction.
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