Design and synthesis of 4-Aminoquinoline-isoindoline-dione-isoniazid triads as potential anti-mycobacterials

Article abstract of DOI:10.1016/j.bmcl.2020.127576

A series of 4-aminoquinoline-isoindoline-dione-isoniazid triads were synthesized and assessed for their anti-mycobacterial activities and cytotoxicity. Most of the synthesized compounds exhibited promising activities against the mc²6230 strain of M. tuberculosis with MIC in the range of 5.1–11.9 μM and were non-cytotoxic against Vero cells. The conjugates lacking either isoniazid or quinoline core in their structural framework failed to inhibit the growth of M. tuberculosis; thus, further strengthening the proposed design of triads in the present study.

Full text of DOI:10.1016/j.bmcl.2020.127576

Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of 4-Aminoquinoline-isoindoline-dione-isoniazid triads
as potential anti-mycobacterials
a
b
b
b,c
d
Anu Rani , Matt D. Johansen , Françoise Roquet-Banères , Laurent Kremer , Paul Awolade ,
d
d
a
a,⁎
Oluwakemi Ebenezer , Parvesh Singh , Sumanjit , Vipan Kumar
a
b
c
d
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India
Institut de Recherche en Infectiologie (IRIM) de Montpellier, CNRS, UMR 9004 Université de Montpellier, France
INSERM, IRIM, 34293 Montpellier, France
School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa
A R T I C L E I N F O
Keywords:
A B S T R A C T
A series of 4-aminoquinoline-isoindoline-dione-isoniazid triads were synthesized and assessed for their anti-
mycobacterial activities and cytotoxicity. Most of the synthesized compounds exhibited promising activities
4
-aminoquinoline-isoindoline-dione-isoniazid
Anti-mycobacterial activity
Cytotoxicity
2
against the mc 6230 strain of M. tuberculosis with MIC in the range of 5.1–11.9 µM and were non-cytotoxic
against Vero cells. The conjugates lacking either isoniazid or quinoline core in their structural framework failed
Selectivity index
to inhibit the growth of M. tuberculosis; thus, further strengthening the proposed design of triads in the present
Molecular docking
study.
Tuberculosis (TB), an infectious disease caused by the bacterium,
Mycobacterium tuberculosis, has resulted in chronic granulomatous le-
sions in the lungs, which can be accompanied by extra-pulmonary in-
of mycolic acid, a vital component of the mycobacterial cell wall, by
targeting the enoyl-ACP reductase InhA of the type II fatty acid syn-
1
6–18
thase
. The decrease in catalase-peroxidase activity as a result of
1
fection foci in the skin, brain and lymph nodes . The disease is the
katG mutations is considered as the most common mechanism asso-
19
major cause of death after the Human Immune-deficiency Virus (HIV),
ciated with INH resistance . Among all the genes involved in INH re-
sistance, excluding katG, mutations of InhA confer clinically relevant
levels of resistance to INH. Multiple other genes such as nat coding for
N-acetyltransferase (NAT) contribute to resistance to INH in M. tu-
berculosis before KatG activation. Furthermore, both NAT and KatG
2
accounting for 1945 deaths every day . World Health Organization
(
WHO) estimated that at least 10 million people developed TB with 1.3
3
million deaths in 2017 . Despite the availability of an important variety
4
–5
of drugs, TB remains a significant global health threat . The foremost
obstacle in the total eradication of TB is the development of resistance
of M. tuberculosis to many existing drugs, which has led to the ap-
pearance of multidrug-resistance (MDR) and extensively drug-resistant
2
0
enzymes interact with the pro-drug directly . Following INH metabo-
lism in the liver, hydrazine metabolites (nitrogen-centered free radi-
cals) are produced which generate highly reactive oxygen species and
act as a stimulator of lipid peroxidation, resulting in cell death and
6
–11
(
XDR) strains
. Also, TB and HIV co-infection is a major concern with
2
1,22
nearly two-thirds of the patients diagnosed with TB also being HIV-1
hepatic necrosis
. As INH is the major therapeutic arsenal in the
1
2
seropositive . The re-designing and re-positioning of known anti-TB
scaffolds is an effective strategy for the development of new frame-
works with favorable pharmacological profiles such as high efficacy and
treatment of TB infection, continuous efforts are being made to develop
new INH derivatives with greater activity, low cytotoxicity, and fewer
2
3–24
side effects
. Several current reports show that the amalgamation of
1
3
low toxicity . Moreover, this strategy can enable the rapid synthesis of
highly effective compounds that are already clinically approved, ulti-
mately shortening the drug commercialization pipeline.
hydrophobic moieties into the basic structure of INH can enhance the
25
penetration of the drug into the lipophilic cell wall of the bacterium
.
Further, the N-acetyltrans-2 (NAT2) promoted inactivation of INH
2
6
Isoniazid (INH), a first-line anti-TB drug, is the most powerful agent
could also be avoided by functionalizing its hydrazine group .
1
4
used to treat M. tuberculosis infection since 1952 . It is a pro-drug re-
quiring activation via enzyme catalase-peroxidase encoded by katG to
its active form15. The activated metabolite of INH inhibits the synthesis
Quinoline moiety is present in a variety of natural products and has
diverse biological properties. Notably, quinoline appears as a central
core in the recently developed anti-TB drugs such as TMC 207 or
⁎
Corresponding author.
E-mail address: vipan_org@yahoo.com (V. Kumar).
https://doi.org/10.1016/j.bmcl.2020.127576
Received 28 July 2020; Received in revised form 19 September 2020; Accepted 21 September 2020
Available online 24 September 2020
0960-894X/ © 2020 Elsevier Ltd. All rights reserved.

A. Rani, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
Fig. 1. Chemical structures of standard drug iso-
niazid (INH) and quinoline based anti-tubercular
agents.
Fig. 2. Promising anti-TB hits with cores highlighted used in the present design.
bedaquiline and some fluoroquinolones viz. gatifloxacin, and moxi-
Recently, we introduced a functionalized isoindoline-1,3-diones
into the alkyl chain of 4-aminoquinolines to access their anti-myco-
bacterial potency. The compounds were promising candidates with a
2
7
floxacin (Fig. 1)
.
Keeping in view the hybrid concept along with the anti-tubercular
2
8–39
2
potential of different moieties (Fig. 2) from the literature
, it was
MIC of 13.5–14.6 µM against the mc 6230 strain of M. tuberculosis
4
0,41
42
planned to synthesize hybrid compounds that comprise the isoniazid
nucleus with the aforementioned fragments and their evaluation of
anti-TB activity.
(Fig. 3)
. Motivated by these results and in continuation , the
present work is a logical extension and involves the synthesis and anti-
mycobacterial evaluation of 4-aminoquinoline-isoniazid hybrids linked
2

A. Rani, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
Fig. 3. Comparison of activity against mc 6230 and cytotoxicity against Vero cells of 6e, 8e and 11 with previously reported scaffolds I-IV40–41,43.
2
Scheme 1. Optimizing synthesis of the 4-aminoquinoline-isoindoline-dione-isoniazid triad 6a.
via isoindoline-1,3-diones. The length of the alkyl chain spacer between
the pharmacophores along with the position of INH and 4-aminoqui-
noline around the isoindoline-1,3-dione were meticulously altered to
study their influence on Structure-Activity Relationship.
aminoquinoline-isoindoline-diones 5a-e. EDC-HOBt promoted amide
coupling between 5a-e and isoniazid afforded the corresponding con-
jugates 6a-e. Different bases viz. N, N-Diisopropylethylamine, triethy-
lamine, 4-Dimethylaminopyridine were screened along with amide
coupling reagents in order to optimize the yield (Scheme 1). The best
result in terms of yield was obtained with DMAP at low temperature for
3 h.
For the synthesis of first series of desired 4-aminoquinoline-iso-
indoline-dione-isoniazid triads, 6a-e, the reaction of substituted
phthalic anhydride 1 with quinoline based diamines 2 was carried out
in DMSO at 150°C for 5 min, in a microwave synthesizer to result in 4-
Another set of 4-aminoquinoline-isoindoline-dione-isoniazid triads,
3

A. Rani, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
Scheme 2. Synthesis of 4-aminoquinoline-isoindoline-dione-isoniazid conjugates.
8
a-g were prepared via an initial microwave heating of substituted
to imide- and amide carbonyls, along with methylene carbons at 36.5
and 40.7 further validated the assigned structure.
phthalic anhydride 1 with isoniazid 3 to result in isoniazid-isoindoline-
dione 7. Amide/Ester coupling between 7 and quinoline based diamine
The synthesized 4-aminoquinoline-isoniazid conjugates were as-
sessed for their anti-mycobacterial activities against avirulent M. tu-
2
/quinoline based alcohol 2′ afforded 8a-g in good yields. A cycloalkyl
2
viz. piperazinyl analogue 11 was also synthesized to determine the in-
fluence of alkyl chain on anti-mycobacterial activities. Further, in order
to rationalize the anti-mycobacterial effect of quinoline core in the
present series of triads, amide-tethered isoniazid-isoindoline-dione
conjugates 13a-b were synthesized via an initial treatment of 1 with
amino acids 4 to afford 12 with subsequent treatment with isoniazid
using standard coupling procedure (Scheme 2). The structures of the
synthesized 4-aminoquinoline-isoindoline-isoniazid conjugates were
assigned based on the spectral and analytical evidence. For example,
the compound 6a showed a molecular ion peak at 515.1177 in its high-
berculosis mc 6230 strain and the results are enlisted in Table 1. The
cytotoxicity of all derivatives to mammalian Vero cells was also eval-
uated to establish whether the observed activities were due to their
inherent anti-mycobacterial ability or due to cytotoxicity (Table 1). As
evident, the compounds showed promising anti-mycobacterial activ-
ities, although they were not as active as INH. A closer examination of
the results showed the activity dependence on both the length of the
alkyl chain between the pharmacophores as well as the position of INH
and 4-aminoquinoline around isoindoline core. Among the 4-amino-
quinoline-isoindoline-1,3-diones 5a-e (without INH-core), the com-
pounds lack any anti-mycobacterial activity except 5c and 5d with
weak activity but cytotoxicity. Inclusion of INH among these conjugates
not only improved their anti-mycobacterial activity substantially but
also decreased their cytotoxicity as seen in triads, 6a-e. The improve-
ment in anti-mycobacterial and cytotoxicity profile is apparent at
longer chain lengths, as displayed by 6d and 6e with MIC99 of 21.9 and
1
resolution mass spectrum (HRMS). The significant features of its H
NMR spectrum involved the presence of a triplet at δ 3.82 because of
methylene (N-CH -); two doublets at 6.62 (J = 5.3 Hz) and 7.76
2
(
J = 2.2 Hz) corresponding to quinoline protons along with a multiplet
of isoindoline ring protons at 8.27–8.31. The presence of signals in its
1
3
C NMR spectrum at δ 164.6, 164.7, 167.7, and 167.8 corresponding
4

A. Rani, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
Table 1
2
In vitro anti-mycobacterial activity (MIC99) of synthesized compounds against mc 6230 strain of M. tuberculosis and cytotoxicity (IC50) evaluation on mammalian
Vero cells and their selectivity index (SI).
Code
Structure
% Yield
MIC99 (µM)
IC50 (µM)
SI value
5
a
81
> 506.2
> 253.1
> 0.5
5
b
86
87
86
488.8
236.3
221.6
242.0
40.1
24.3
0.5
5
5
c
0.16
0.11
d
5
6
e
a
89
91
417.3
389.0
> 208.6
> 194.5
> 0.5
> 0.5
6
6
b
c
86
82
47.3
23.0
119.2
16.6
2.5
0.7
6
6
8
d
e
a
88
81
85
21.9
5.1
128.0
128.7
64.1
5.8
25
6.0
10.6
8
8
b
c
87
74
5.8
160.9
14.7
27
23.0
0.6
8
d
76
11.0
33.3
3
8
8
e
f
72
85
5.1
> 167.1
> 194.1
> 32.7
> 0.5
> 388.2
8
1
g
1
84
89
11.9
6.0
> 194.1
> 195.2
> 16
> 32.5
(
continued on next page)
5

A. Rani, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
Table 1 (continued)
Code
Structure
% Yield
MIC99 (µM)
IC50 (µM)
SI value
1
3a
3b
92
308.5
> 308.5
> 1
1
90
–
129.4
0.07
> 258.9
> 2
INH
Fig. 4. Structure-Activity Relationship (SAR) of both series of synthesized 4-aminoquinoline-isoindoline-dione-INH triads.
5
.1 µM and IC50s of 128 and 128.7 µM, respectively.
Molecular docking studies and ADME properties prediction
Furthermore, interchanging the position of INH with quinoline
diamines around isoindoline core in compound 8a-e improved the anti-
mycobacterial activities without much dependence on the alkyl chain
length. The triad 8e with an octyl spacer not only retained the anti-
mycobacterial efficacy (MIC99 = 5.1 µM), it is also non-cytotoxic
Molecular docking studies were conducted using AutoDock to ex-
plore the potential binding interactions of selected compounds with M.
tuberculosis enoyl-acyl carrier protein reductase (InhA; PDB ID: 4TZK).
InhA is a prominent enzyme involved in the biosynthesis of mycolic
acid for mycobacterial cell wall and the molecular target of isoniazid.
Six inhibitors were docked into the active site of InhA, as shown in
Figs. 5 and 6, while the docking results are summarized in Table 2.
In consonant with the experimental results, the binding energies and
receptor interactions of compounds 6e, 8e and 11 were superior to
compounds I, II and III (Table 2). For instance, in compound I (Fig. 5a),
the chlorine atom was sandwiched between residues Phe149 and Met199
via hydrophobic interactions while the amino group of quinoline core
formed a hydrogen bond interaction with the hydroxyl oxygen of
Gly192. The isoindoline core also afforded alkyl, π-π stacking, π-alkyl,
and π-σ interactions with Ile95, Phe41, Val65, Ile122, Phe149, and
Met199. A similar binding profile was observed for the isoindoline core
of compound II (Fig. 5b), i.e. π-π stacking with residue Phe41 as well as
(
IC50 ≥ 167 µM). The inclusion of a cyclic amine viz. piperazine instead
of alkyl amine as in triad 11 also resulted in the good anti-myco-
bacterial activity.
The conjugates, 13a and 13b without a quinoline core, did not show
any substantial anti-mycobacterial activity; thus, justifying the importance
of the proposed design of 4-aminoquinoline-isoindoline-dione-isoniazid
triads to elicit anti-mycobacterial activity and reduce cytotoxicity.
Relating the activity and cytotoxicity data of currently synthesized
4
0–41,43
compounds (6e, 8e, 11) with our earlier report (I-IV)
, the in-
troduction of INH at C-5 of isoindoline ring not only improved anti-
mycobacterial activity but also resulted in the reduction of cytotoxicity
(
Fig. 3). The general anti-TB SAR/cytotoxicity of the synthesized series
of 4-aminoquinoline-isoindoline-isoniazid triads is elucidated in Fig. 4.
6

A. Rani, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
Fig. 5. Binding interactions of compounds (a) I (b) II (c) III.
7

A. Rani, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
π-σ, π-alkyl, and alkyl interactions with Ile21, Val65, Ile122, Phe149,
Ala198, Met147 and Ile95. The unit also featured a hydrogen bond in-
teraction between the isoindoline and Ile95, while the fluorine sub-
stituent formed a halogen bond with Asp64. The docked complex of III
(
Fig. 5c) was established in the hydrophobic pocket created by hydro-
phobic interaction with the side chains of ten amino acid residues. Sur-
prisingly, the oxygen atom of the isoindoline core formed a strong hy-
drogen bond with Tyr168. The interaction was absent in compounds I
and II; hence, a potential platform for further structural modifications to
enhance the anti-mycobacterial activity.
Furthermore, compound 6e, 8e and 11 binds in essentially the same
manner within the active site of InhA. The compound 6e-InhA complex
is characterized by six hydrogen bond interactions between the amino
acid residues of side chain and both the oxygen atom of isoniazid
moiety and the amine linker. Besides, the quinoline core was anchored
in the hydrophobic pocket containing Val65, Ile95, Phe41, and Ile122,
which suggested that the two-fold increase in potency might stem from
additional interactions between the isoniazid moiety and the side
chains of the active site residues (Fig. 6a). Furthermore, the isoniazid
moiety in compound 8e interacts with Gly192, Ala191 and Lys165 via
hydrophobic and H-bonding interactions while the aminoquinoline
group formed hydrophobic interactions with residue Val65, Leu63,
Gly14 and Gly40, respectively. Other residues that made H-bond in-
teractions include, Gly96, Ile95, Ile165, which also serve as motivators
for the stabilization of the inhibitor within the catalytic pocket of the
receptor (Fig. 6b). Moreover, the docked complex of compound 11
showed additional hydrogen bond interactions between the piperazine
ring and the carbonyl oxygen of Gly96, which was accompanied by
hydrophobic interaction with Ile16 (Fig. 6c).
On the other hand, the molecular descriptors ADME properties were
calculated for potent compounds using web-based software pkCSM
(
(
http://biosig.unimelb.edu.au/pkcsm/prediction) and SwissADME
http://www.swissadme.ch/). The results are presented in Table 2. The
drug candidates with TPSA values of 140 Å or lower are expected to
have good absorption. Accordingly, all the compounds were within this
limit, i.e., < 140 Å, which implies that these compounds fulfilled the
optimal requirement for drug absorption.
In conclusion, a series of 4-aminoquinoline-isoindoline-dione-iso-
niazid triads have been synthesized with the target of reviewing their
SAR against M. tuberculosis. Nearly all of the synthesized conjugates
presented promising anti-TB activity and useful selectivity index. The
conjugates without the quinoline core 13a/13b and the INH nucleus
5
a-e failed to inhibit the growth of M. tuberculosis as was observed in
43
our previous report on 1,8-naphthalimide-isoniazid hybrids , further
validating the design of triads in the present case.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Fig. 6. Binding interactions of compounds (a) 6e (b) 8e (c) 11.
Table 2
Molecular descriptors and the binding energy of the potent compounds.
Compound
B.E(kcal/mol)
TPSA
logP
HBD
HBA
logS
Caco2
log Kp
logBB
I
−9.7
62.30
91.40
5.05
2.77
4.35
4.42
4.40
2.27
1
2
3
3
3
1
3
5
3
6
6
5
−5.5
0.465
0.645
0.76
−2.773
−2.816
−2.877
−2.735
−2.735
−2.767
0.133
II
III
−9.9
−3.716
−4.945
−4.094
−4.324
−4.044
−1.407
0.231
−10.2
−10.4
−10.3
−11.7
65.54
6
8
1
e
e
1
133.39
133.39
98.74
0.768
1.65
−1.745
−1.544
−1.129
0.692
TPSA – Topological Polar Surface Area (60–140); log BB – logarithm of predicted blood/brain barrier partition coefficient (−3.0–1.2); Caco-2 – cell membrane
permeability (> 0.9 is high); HBA – number of hydrogen bond acceptors; HBD number of hydrogen bond donors; log K – predicted skin permeability(SP) > −2.5
p
is low.
8

A. Rani, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127576
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