Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1

Article abstract of DOI:10.1016/j.bmcl.2018.01.031

Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a–d, 5f–n, and 7a–b) exhibited Zmp1 inhibition with IC₅₀ values in the range 1.3–43.9 μM, whereas only aminothiazoles 12b and 12d proved active with IC₅₀ values of 41.3 and 35.7 μM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10 μg/ml. This work represents a step forward in targeting Zmp1 by small molecules.

Full text of DOI:10.1016/j.bmcl.2018.01.031

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)
rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis
Zmp1
Mattia Mori a,b, Davide Deodato a, Mohan Kasula a, Davide M. Ferraris c, Adriana Sanna d,
Alessandro De Logu e, Menico Rizzi c, Maurizio Botta a,f,
⇑
a Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019 Siena, Italy
b Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, viale Regina Elena 291, 00161 Roma, Italy
c DiSF-Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy
d Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy
e Department of Life and Enviromental Sciences, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy
f Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333,
1900 N 12th Street, Philadelphia, PA 19122, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed,
synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost
all rhodanines (5a–d, 5f–n, and 7a–b) exhibited Zmp1 inhibition with IC50 values in the range 1.3–43.9
mM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7 mM,
respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to
highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4
and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration
of 10 mg/ml. This work represents a step forward in targeting Zmp1 by small molecules.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 30 November 2017
Revised 16 January 2018
Accepted 17 January 2018
Available online xxxx
Keywords:
Rhodanines
Aminothiazoles
Zmp1
Tuberculosis
Metalloproteases
Tuberculosis (TB) is an infectious disease caused by Mycobac-
terium tuberculosis (Mtb) that has been one of the top ten causes
of death worldwide in 2015.1 To control TB spread, in the ’90s
the WHO has launched the DOTS (Directly Observed Treatment,
Short Course) strategy that proved successful in effectively achiev-
ing cure rates over 90% in countries where the health system works
well. On the contrary, DOTS proved notably less successful in cases
of HIV co-infections or in patients infected by multidrug-resistant
(MDR), extensively drug-resistant (XDR) and totally drug-resistant
(TDR) Mtb strains.2–4 Therefore, novel and effective strategies to
treat and control TB are still urgently needed, and may be achieved
by targeting Mtb validated targets or Mtb proteins that are rele-
vant for its replication and survival into the host.5–7 In this context,
Mtb-secreted extracellular proteins are attracting much interest
either as candidate drug targets or biomarkers of active and latent
TB, mostly because of their predominant role in virulence, in medi-
ating host-pathogen interaction, and in attenuating host immune
response.8–10 Among them, the extracellular zinc metalloprotease
1 (Zmp1)11–13 has been reported to play a key role in phagosome
maturation and to elicit TB-specific humoral immune response,14
thus enhancing the overall survival of Mtb in the host. In a guinea
pig model of TB infection, Zmp1 deletion has led to increase the
protective efficacy of the live vaccine Mycobacterium bovis BCG,12
in agreement with Master et al.,15 showing that Zmp1 deletion is
associated to virulence attenuation. In contrast, Muttucumaru
et al. have showed that deletion of the Zmp1 gene leads to bacterial
hypervirulence in a murine model.16 Nevertheless, it is clear from
multiple reports that Zmp1 plays a relevant role in host–pathogen
interaction, and that the design of specific small molecule inhibi-
tors could be a valuable strategy towards anti-TB therapeutics.
Zmp1 inhibitors may also serve as tools to further understanding
the pathogenic role of Zmp1.
Based on the available X-ray structure of Zmp1/ligand com-
plex,17 we recently identified the 3-(carboxymethyl)rhodanine as
privileged scaffold of Zmp1 inhibitors by disclosing ZTB23(R),
ZTB28(R) and ZTB29(R) (Fig. 1) as confirmed hits.18 Subsequent
⇑
Corresponding author at: Department of Biotechnology, Chemistry and Phar-
macy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
E-mail address: botta@unisi.it (M. Botta).
https://doi.org/10.1016/j.bmcl.2018.01.031
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mori M., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.031

2
M. Mori et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
to our work, two reports on rhodanine and quinolidene-rhodanine
Zmp1 inhibitors have been published.19,20
condensation with the opportune benzaldehydes 4a–i, using b-ala-
nine as base (Scheme 1), furnished the final Z-rhodanines 5a–n
listed in Table 1. 1H NMR analysis of compounds 5a–n confirmed
the presence of a single peak for the olefin proton (CH@) in the
range of 7.70–7.50 ppm, at lower field values than expected for
the E-isomer. This observation suggests the Z configuration of the
double bond due to the higher termodynamic stability of this iso-
mer.21,22 Heteroaromatic derivatives 7a–b bearing a pyridine and a
thiophene substituent were similarly obtained by using the corre-
sponding heteroaromatic aldehydes 6a–b (Scheme 2).
Aminothiazole derivatives were obtained as outlined in
Scheme 3. Starting material was D-phenylalanine 1a, which was
converted to the corresponding methyl ester 8 by treatment with
thionyl chloride in methanol. Compound 8 was then reacted with
methoxycarbonyl isothiocyanate, using DIPEA as the base, to give
Here, to further understanding the structure–activity relation-
ships (SAR) of the 3-(carboxymethyl)rhodanine scaffold and to
investigate its effect on Mtb growth, we designed, synthesized
and tested in silico and in vitro sixteen rhodanines and twelve
aminothiazoles as possible rhodanine-mimetics (Fig. 1).
Particularly, we modified i) the amino acid moiety of rhodani-
nes responsible for zinc coordination,18 ii) the nature of the aro-
matic ring linked to the rhodanine core, and iii) the position and
type of substituents to the phenyl ring (Fig. 1). Moreover, to under-
stand the relevance of the rhodanine core, it was replaced by the
aminothiazole moiety (Fig. 1). The preparation of the rhodanine
derivatives followed the synthetic route already described previ-
ously (see also Supporting Information for chemistry directions
and compounds characterization).18 Briefly,
D
-amino acids 1a–c
the N-methoxycarbonylthiourea 9 that was hydrolyzed with
were reacted with carbon disulfide in water to give compounds
2a–c, which were treated in situ with sodium chloroacetate and
lastly with HCl, affording cyclized compounds 3a–c. Knoevenagel
sodium hydroxide to furnish the thiourea 10, bearing a free car-
boxylic acid function. The aminothiazole products were synthe-
sized according to the Hantzch thiazole synthesis,23 in which
S
COOR1
S
N
HOOC
O
ZTB23(R): R1 = H
ZTB28(R): R1 = CH3
ZTB29(R): R1 = CH2Ph
S
S
R1
R2
R1
S
S
N
N
S
HOOC
R1
HOOC
HOOC
HN
N
O
O
n
12a-l
5a-n
7a-b
Fig. 1. Chemical structure of Zmp1 inhibitors ZTB23(R), ZTB28(R) and ZTB29(R) identified previously (top),18 and rational design of novel rhodanine and aminothiazole
derivatives investigated in this work as Zmp1 inhibitors (bottom).
R1
a: R2 = 3-COOH
b: R2 = 3-COOCH3
c: R2 = 3-COOBn
d: R2 = 4-COOiBu
e: R2 = 4-COOCH2CH2Ph
f: R2 = 4-OCH3
S
R1
S
CHO
R1
a
b
HOOC
N
+
S
HOOC
N
H
S
HOOC
NH2
O
R2
4a-i
2a-c
3a-c
64-72%
(2 steps)
1a-c
a: R1 = CH2Ph
b: R1 = CH3
c: R1 = H
g: R2 = 3-OCH3
h: R2 = 4-CN
i: R2 = 4-COOH
c
R1
S
HOOC
N
S
R2
O
5a-n
50-94%
Scheme 1. aReagents and conditions: (a) carbon disulfide, NaOH, H2O, r.t. 12 h; (b) i. sodium chloroacetate solution, r.t. 2 h; ii. 6 N HCl, cat. POCl3, 75 °C, 4 h; (c) b-alanine,
AcOH, ref, 6 h.
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M. Mori et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Table 1
Table 2
Substitution patterns of final compounds 5a–n.
Substitution patterns of final compounds 12a–l.
Cmpd
R1
R2
Cmpd
R1
R2
Cmpd
12a
12b
12c
12d
12e
12f
n
R
Cmpd
n
R
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3-COOH
5h
5i
5j
5k
5l
5m
5n
Ph
CH3
CH3
CH3
H
4-CN
0
3-OCH3
4-CN
4-OCH3
4-NO2
4-COOH
3-COOH
12g
12h
12i
12j
12k
12l
1
1
1
1
1
1
H
3-COOCH3
3-COOBn
4-COOiBu
4-COOCH2CH2Ph
4-OCH3
4-COOH
3-COOH
3-OCH3
4-COOH
3-COOH
3-OCH3
0
0
0
0
0
3-OCH3
4-COOCH3
3-COOCH3
4-COOH
3-COOH
H
H
5g
3-OCH3
14g–j. The methylene group was inserted with a two-step protocol
of chlorination and reaction with (trimethylsilyl)diazomethane,
furnishing intermediates 15g–j. In situ cleavage of the trimethylsi-
lyl groups with hydrobromic acid in anhydrous acetonitrile,
CHO
S
Ph
S
N
O
N
HOOC
afforded the desired
a-bromoacetophenones 11g–j. Unavailable
N
6a
a
Ph
HOOC
carboxymethyl-phenylacetic acids 14i–j were prepared by palla-
dium-catalyzed arylation of acetic acid, using the appropriate aryl
iodide 13i–j as starting material (Scheme 4).
S
7a
N
56%
S
Zmp1 inhibitory activity of synthesized compounds was first
evaluated at a fixed dose of 50 mM (Table 3). IC50 was then calcu-
lated only for molecules showing less than 40% of Zmp1 residual
activity, as well as for the reference Zmp1 inhibitor ZTB23(R) that
was included for comparison (experimental data in Supporting
Information). Results are reported in Table 3, and clearly show that
rhodanine derivatives are potent inhibitor of Zmp1, whereas
aminothiazoles showed only a modest inhibition.
a
O
S
N
Ph
S
3a
S
CHO
S
HOOC
6b
O
7b
79%
The following SAR can be drawn from data of Table 3. In rhoda-
nines bearing D-phenylalanine as Zn-binding group (5a–h and 7a–
Scheme 2. aReagents and conditions: (a) b-alanine, AcOH, ref, 6 h.
b), the introduction of small and lipophilic substituents to the dis-
tal phenyl ring in meta or in para position does not affect signifi-
cantly Zmp1 inhibition (5f and 5g share a similar potency),
whereas the introduction of a carboxylic function in meta (compare
5a and ZTB23(R)) or the esterification of a carboxylic acid in any
positions is detrimental for activity (compare 5b–c with 5a, and
5d–e with ZTB23(R)). In contrast, bulky esters are allowed only
in meta to the distal phenyl ring (compare 5c with 5d–e). A nitrile
group in para position is well tolerated (5h) and leads to the stron-
thiourea 10 was condensed with the opportune
a-bromo ace-
tophenone 11a–j in dimethylformamide. The desired products
12a–j were obtained after a single purification step in good overall
yields (40–78%). Dicarboxylic derivatives 12k–l were obtained
after saponification of the corresponding methyl esters 12i–j.
Commercially unavailable
a-bromoacetophenones 11g–j were
synthesized starting from the corresponding phenylacetic acids
Ph
Ph
H3COOC
Ph
H3COOC
Ph
HOOC
1a
S
S
O
c
a
b
HOOC
N
H
NH2
NH2
N
H
N
H
O
NH2
8
9
10
99%
94%
74%
O
R
Br
d
n=0-1
11a-j
Ph
HOOC
R
Ph
HOOC
COOH
e
S
S
N
H
N
n=0-1
N
n=0-1
N
H
12a-j
12k-l
83-87%
72-91%
Scheme 3. aReagents and conditions: (a) thionyl chloride, dry MeOH, 0 °C to r.t., 1 h; (b) methoxycarbonyl isothiocyanate, DIPEA, DCM, 0 °C to r.t., 1 h; (c) NaOH 3 N, MeOH,
ref., 1 h; (d) DMF, r.t., 1–3 h; (e) NaOH/MeOH/THF, ref. 3 h. The substitution pattern of 11a–j can be found in Table 2 within the description of the corresponding final products
12a–j.
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4
M. Mori et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
HO
b
a
Si
Br
O
O
O
R
R
I
R
14g-j
15g-j
11g R = H
11h R = 3-OCH3
11i R = 4-COOCH3
11j R = 3-COOCH3
c
HO
O
COOCH3
COOCH3
13i-j
14i-j
Scheme 4. aReagents and conditions: (a) i. thionyl chloride, DMF, dry DCM, 0 °C to r.t., 30 min; ii. TMSCH2N2, dryCH3CN, 0 °C to r.t., 1 h; (b) HBr 33%, dry CH3CN, 0 °C to r.t., 2 h;
(c) PdCl2, AgOAc, NaOAc, AcOH, ref, 24 h.
Table 3
Inhibition of Mtb Zmp1 with rhodanines 5a–n and 7a–b, and aminothiazoles 12a–l.
Cmpd
% Zmp1 residual activity at 50 mM
IC50 (mM)
Cmpd
% Zmp1 residual activity at 50 mM
IC50 (mM)
ZTB23(R)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
0.87
9.3
7a
7b
19.1
10.4
91.9
35.0
100
36.3
100
100
100
100
61.0
100
100
100
26.9
11.4
n.d.
41.3
n.d.
35.7
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
13.4
13.2
13.5
28.1
58.7
12.3
10.0
7.1
12.5
24.0
43.9
n.d.
20.4
18.4
6.6
2.9
1.3
23.4
3.9
15.7
28.2
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
7.2
12.7
12.6
10.3
11.2
18.9
n.d. = not determined – Zmp1 residual activity above the threshold.
gest Zmp1 inhibitor among rhodanines bearing
Finally, the replacement of the distal phenyl ring with the bioisos-
teres thiophene or pyridine does not provide significant benefits
D
-phenylalanine.
function of 5j is H-bonded to Arg628 and Thr606, while the phenyl
ring is stacked to Phe48 (Fig. 2A). The para-nitrile substituent
of 5h establishes an H-bond with Thr606 (Fig. 2B) although its
steric hindrance does not allow the phenyl ring to stack with
Phe48, which may explain the slightly weaker potency of 5h com-
pared to 5j. Finally, the nitro group of the aminothiazole 12d is H-
p-p
(see 7a–b). In the Zn-binding portion of the inhibitors,
nine provided generally stronger Zmp1 inhibition than
and glycine, even though an exception to this trend was observed
for the -alanine derivative 5j that showed stronger inhibition of
Zmp1 compared to the corresponding -phenylalanine 5a. Besides,
-amino acids inhibit Zmp1 more
D
-phenylala-
p-p
D-alanine
D
bonded to Thr606 (Fig. 2C) but also in this case no p-p stacking
D
with Phe48 is observed. Docking poses correlate with SAR, thus
providing hints for further structure-guided design and optimiza-
tion studies.
rhodanines bearing bulky
D
potently than glycine, S-amino acids18 and
D-amino acids endowed
with a small side chains.
Compounds 5a, 5b and 5c showed a very low activity in vitro
against isolated Mtb H37Ra ATCC 25177 (experimental procedures
in Supporting Information), with MIC values of 64 mg/L or higher
(Table 4). This is consistent with the fact that Zmp1 is secreted
by Mtb, and its targeting should not impair directly Mtb replication
outside the host cell. With the exception of 5a, which showed CC50
values higher than 100 mg/ml both in Vero and THP-1 cell lines, 5b
and 5c showed CC50 at concentrations much lower than the MICs.
However, 5a and 5c exhibited a significant inhibition of the growth
of Mtb in THP-1 infected cells also at a concentration as low as 10
mg/ml (23.4 and 53.8%, respectively, Table 4). Zmp1 inhibitors iden-
tified previously ZTB23(S) and ZTB23(R) showed inhibition of Mtb
growth in THP-1 infected cells comparable to 5a at 100 mg/ml
(Table 4). Furthermore, 10 lg/ml of 5c induced a 53.8% inhibition
of Mtb growth, comparable with ZTB23(S) and much higher than
ZTB23(R) at the same concentration.
Novel therapeutic agents able to eradicate latent Mtb from the
host are highly desirable to complement the current anti-TB war-
heads. Here, with the aim to address SAR of the rhodanine scaffold
Only aminothiazoles 12b and 12d inhibited Zmp1 with a
potency above the threshold thus providing insufficient data for
SAR analysis. However, the aminothiazole scaffold emerged as
new possible chemotype of Zmp1 inhibitors that is worth of fur-
ther investigation.
The possible binding mode of compounds to Zmp1 catalytic
site17 was investigated by molecular docking simulations (compu-
tational details in Supporting Information).18 We describe here the
binding mode of 5j that was the most potent Zmp1 inhibitor stud-
ied in this work, 5h that was the most potent among D-phenylala-
nine bearing rhodanines, and 12d that was the most potent among
aminothiazols (Fig. 2). Overall, the amino acid carboxylic group of
5j, 5h and 12d coordinates the catalytic Zn(II) ion by a canonical
geometry,17,18,24 while H-bonding to key residues Glu494 and
His622 (Fig. 2); the side chain is projected towards the solvent
area. Different from the aminothiazole, the rhodanine core estab-
lishes an H-bond with Asn452 that may explain its stronger inhibi-
tory potency. Moving to the distal groups, the meta-carboxylic
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M. Mori et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
5
Table 4
MIC, cytotoxicity and macrophage assay of tested compounds.
Cmpd
CC50 Vero
g/ml]
CC50 THP-1
g/ml]
MIC
[lg/ml]
% inhibition of Mtb
growth in THP-1
[
l
[
l
10
lg/ml
100 lg/ml
ZTB23(S)
ZTB23(R)
5a
5b
5c
>125
>125
>125
32.5
23.2
115.0
>125
101.9
21.9
>64
>64
>64
64
57.4 2.5
0.1 2.2
23.4 2.9
0.5 3.0
53.8 3.4
58.3 2.9
60.0 2.6
54.5 2.6
ND
11.2
64
ND
ND = Not Determined (tested concentration is above the CC50 value).
Zmp1 inhibition compared to the aminothiazole (this latter
becoming – however – worth of investigation). In fact, almost all
rhodanines (5a–d, 5f–n, and 7a–b) showed inhibition of recombi-
nant Zmp1 with IC50 values in the range 1.3–43.9 mM, whereas only
two aminothiazoles (namely, 12b and 12d) proved active with IC50
values of 41.3 and 35.7 mM, respectively. The druggability of the
Zmp1 was further substantiated in vitro against THP-1 infected
cells, where rhodanines 5a and 5c exhibited 23.4 and 53.8% of
Mtb growth inhibition, respectively, at the non-toxic concentration
of 10 mg/ml. For the first time we showed that rhodanine-derived
Zmp1 inhibitors impair the growth of Mtb in infected macrophages
at low concentrations, which opens new venues to further devel-
oping these molecules up to anti-TB lead candidates.
Declaration of interest
None.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.01.031.
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Fig. 2. Predicted binding mode of 5j (A), 5h (B), and 12d (C) within the catalytic
active site of Zmp1. The protein secondary structure is shown as colored cartoon
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ligands are shown as lines, while those interacting with the inhibitors are shown as
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identified in a prior work,18 a number of rhodanines and aminoth-
iazoles were designed, synthesized and tested against the recombi-
nant Zmp1 enzyme from Mtb as well as in a cellular model system
of TB infection. Rhodanine emerged as a privileged scaffold for
Please cite this article in press as: Mori M., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.031