2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains

Article abstract of DOI:10.1021/acsmedchemlett.5b00324

2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC₅₀s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.

Full text of DOI:10.1021/acsmedchemlett.5b00324

Letter
pubs.acs.org/acsmedchemlett
2‑(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible
and Drug-Resistant Mycobacterium tuberculosis Strains
Kenia Pissinate,† Anne Drumond Villela,†,‡ Valnes Rodrigues-Junior,†,§ Bruno Couto Giacobbo,†,§
̂
Estevao Silveira Grams,† Bruno Lopes Abbadi,†,§ Rogerio Valim Trindade,†,§ Laura Roesler Nery,∥
̂
́
̃
Carla Denise Bonan,§,∥ Davi Fernando Back,⊥ Maria Martha Campos,†,‡,§ Luiz Augusto Basso,†,‡,§
Diogenes Santiago Santos,*,†,§ and Pablo Machado*,†,§
́
†Instituto Nacional de Cien
̂
cia e Tecnologia em Tuberculose (INCT-TB), Centro de Pesquisas em Biologia Molecular e Funcional,
Pontifícia Universidade Catolica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil
‡Programa de Pos
-Graduacao em Medicina e Ciencias da Saude, Pontifícia Universidade Catol
Porto Alegre, RS, Brazil
§Programa de Pos
-Graduaca
Porto Alegre, RS, Brazil
∥Laborator
io de Neuroquímica e Psicofarmacologia, Pontifícia Universidade Catol
RS, Brazil
⊥Departamento de Química, Laborator
̂
io de Materiais Inorganicos, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS,
́
́
̧
̂
́
́
ica do Rio Grande do Sul, 90619-900
́
̧ o em Biologia Celular e Molecular, Pontifícia Universidade Catolica do Rio Grande do Sul, 90619-900
̃
̃
́
́
́
ica do Rio Grande do Sul, 90619-900 Porto Alegre,
́
Brazil
S
* Supporting Information
ABSTRACT: 2-(Quinolin-4-yloxy)acetamides have been de-
scribed as potent in vitro inhibitors of Mycobacterium
tuberculosis growth. Herein, additional chemical modifications
of lead compounds were carried out, yielding highly potent
antitubercular agents with minimum inhibitory concentration
(MIC) values as low as 0.05 μM. Further, the synthesized
compounds were active against drug-resistant strains and were
devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥
20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides
showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug−drug
interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class
of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.
KEYWORDS: Tuberculosis, quinoline-based compounds, drug-resistant research, SAR
uberculosis (TB) is an infectious contagious disease
Tcaused mainly by Mycobacterium tuberculosis (Mtb) and is
one of the most devastating public health problems worldwide.
Approximately 9.6 million new cases claiming 1.5 million lives
were reported in 2014.1 The emergence of multidrug-resistant
TB (MDR-TB) and extensively drug-resistant TB (XDR-TB),2
HIV coinfection,3 and the lack of effective vaccines have
currently placed TB as the second leading cause of global
mortality due to an infectious agent. Further complicating the
Figure 1. Quinoline-containing compounds.
situation, one-third of the world population have been
estimated to carry a latent or dormant phenotype of Mtb.4
This diarylquinoline-based drug was the first antitubercular
compound approved for clinical use after rifampin, which was
introduced in the early 1960s. However, some possible cardiac
MDR-TB and XDR-TB treatments are limited and recom-
mended medicines are often not available, reducing the
treatment success rate and revealing an urgent need for new
anti-TB alternatives.5 Within this context, in 2012, the United
States Food and Drug Administration (FDA) approved
bedaquiline (1) for the treatment of MDR-TB in adults when
no other therapeutic alternatives were available (Figure 1).6
Received: August 10, 2015
Accepted: January 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00324
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ACS Medicinal Chemistry Letters
Letter
side effects attributed to bedaquiline7 and the elevated adaptive
capacity of Mtb, which culminate with rapid cases of drug-
resistance, reinforce the need for continuing research efforts to
the development of new anti-TB drugs.
catalyzed hydrogenation reaction of 5o yielded the 4-amino
derivative 5p with 32% yield. According to a previous report,14
when the 2-methyl group was substituted with hydrogen, the
N-alkylation was obtained with high chemoselectivity, leading
to compound 7 with 72% yield (Scheme 2).
Present in the molecular structure of clinically important
drugs such as bedaquiline6 and some fluoroquinolones,8 the
quinoline ring has emerged as a privileged scaffold in medicinal
chemistry campaigns that are designing novel antitubercular
structures.9 Incidentally, 2-(quinolin-4-yloxy)acetamides have
been described as noncytotoxic compounds endowed with
potent inhibitory activity against M. tuberculosis H37Rv in
vitro.10 These molecules were obtained from phenotypic
screening leading to a set of 177 lead-compounds. The lead
structure 2 (Figure 1) from the quinoline series exhibited
minimum inhibitory concentration (MIC) of 0.70 μM.10 As
part of our ongoing program, we are interested in obtaining
novel antimycobacterial compounds that are active against
drug-resistant Mtb strains.
In this study, we synthesized a series of 2-(quinolin-4-
yloxy)acetamides for further evaluation of MICs using drug-
susceptible Mtb strains. In addition, the structural requirements
for activity of the compounds were investigated in a preliminary
structure−activity relationship (SAR) study. The most active
molecules against M. tuberculosis H37Rv were tested against a
panel of clinically isolated drug-resistant strains and in a
macrophage-infected model. Finally, thermodynamic solubility,
metabolic stability in human liver S9 fraction, cytochrome P450
inhibition, and cardiotoxicity risk were also evaluated.
a
Scheme 2
a
Reaction conditions: (i) DMF, K2CO3, 25 °C, 16 h.
All synthesized compounds showed the proposed structures
based on spectroscopic and spectrometric data (Supporting
Information). In addition, a crystal structure of 2-(quinolin-4-
yloxy)acetamide 5s was determined by X-ray diffraction.15
According to NMR data, N-arylacetamide was attached to the
quinoline ring via a 4-hydroxyl group (Figure 2). The crystal
data and parameters for structure refinement are summarized in
Table S1 (Supporting Information).
The syntheses of 2-(quinolin-4-yloxy)acetamides 2, 5a−o,
and 5q−t were conducted in two synthetic steps. Our structural
modifications were aimed primarily at the creation of a small-
molecule library containing structures with different electronic
and lipophilic properties. Accordingly, substituents directly
attached to the N-arylacetamide group were chosen in an
attempt to find chemical groups from maximal quadrants of the
Craig plot correlating sigma constants of the Hammett
equation (σ) and lipophilic substituent constants (Π).11 First,
the 2-bromo-N-arylacetamides 4a−o and 4q−t were prepared
by the acylation reaction of substituted anilines or 1(2)-
naphthylamine using bromoacetyl chloride in the presence of 4-
dimethyl aminopyridine (DMAP) as a catalyst, according to a
previously described protocol.12,13 Subsequently, 2-(quinolin-4-
yloxy)acetamides 2, 5a−o, and 5q−t were synthesized by the
O-alkylation reaction of 4-hydroxyquinolines 3a−b with 2-
bromo-N-arylacetamides 4a−o and 4q−t in the presence of
potassium carbonate using N,N-dimethylformamide (DMF) as
the solvent (Scheme 1). The reaction mixtures were stirred for
16 h at 25 °C to afford the products with 32−98% yields.
Notably, 4-hydroxyquinolines 3a−b could be easily obtained
from the cyclocondensation reaction between anilines and β-
ketoesters; however, these compounds were purchased from
suppliers and used without further purification. The Pd/C-
Figure 2. Structure of compound 5s with atomic labeling. Hydrogen
atoms are represented by circles of arbitrary radii.
The synthesized compounds were evaluated in a whole-cell
assay against M. tuberculosis strain H37Rv using isoniazid
(INH) as the standard drug.10,16 The antibacterial screening
revealed that most of the 2-(quinolin-4-yloxy)acetamides tested
showed MICs at submicromolar concentrations (except
compounds 5a, 5g−h, and 5n−q) and were more potent
than the first-line anti-TB drug INH (Table 1). In general,
electron withdrawing groups yielded compounds with
decreased activity, while bulky lipophilic substituents improved
the antimycobacterial action of the synthesized compounds.
The lead compound 2 presented an MIC value of 0.44 μM. In
an attempt to determine the necessity of the methyl group
attached at the 2-position on the quinoline ring of 2, we tried to
obtain the O-alkylated derivative of 6-methoxyquinolin-4-ol
(6). Unfortunately, the N-alkylated compound 7 was the only
structure isolated. This compound showed MIC > 31 μM,
denoting the importance of N-arylamide at the 4-position of the
quinoline ring and/or the presence of the 2-methyl group for
activity. As the 6-methoxy-2-methylquinolin-4-ol (3b) was
devoid of any activity under the tested conditions (data not
shown), the former proposal appears more plausible. Addition-
ally, the 6-methoxy group was found to be pivotal for activity
because compound 5a exhibited an MIC > 29 μM. However,
a
Scheme 1
a
Reaction conditions: (i) DMF, K2CO3, 25 °C, 16 h.
B
DOI: 10.1021/acsmedchemlett.5b00324
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Table 1. ClogP Values, in Vitro Activity against M. tuberculosis H37Rv, Drug-Resistant Clinical Isolates, and Intracellular
Activity of 2-(Quinolin-4-yloxy)acetamides against the M. tuberculosis H37Rv Strain in Infected Macrophages
a
b
ClogP calculated by ChemBioDraw Ultra version 13.0.0.3015. Data are expressed as the means SEM of triplicates for each compound tested at 5
μM. INH, isoniazid. RIF, Rifampin. UNT, Untreated. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the untreated group (Dunnett post-test).
when the N-phenylacetamide portion was considered, the
methoxy group did not appear to be imperative to
antimycobacterial activity because compound 5b exhibited an
MIC value of 0.48 μM, which differed only slightly from 2 (0.44
μM).
Additionally, the change from the 2- to 4-position did not
alter the activity because the 4-methoxy derivative 5d exhibited
an identical MIC value of 0.44 μM. However, the MIC of 2-
(quinolin-4-yloxy)acetamide 5c was 0.88 μM, denoting that
positioning the methoxy group at the 3-position of the benzyl
ring decreased the potency of the compound 2-fold. These data
encouraged us to synthesize the 2,4-dimethoxy derivative 5e,
which showed a MIC value of 0.15 μM. Compared with 2-
(quinolin-4-yloxy)acetamide 2, the disubstituted compound
(5e) showed an improvement in the antimycobacterial activity
of nearly 3-fold. Changing the electron-donating group with 2-
methyl, the potency was maintained because compound 5f
showed a MIC of 0.46 μM. By contrast, the presence of an
additional ethyl group at the ortho-position of the aryl ring (5g)
greatly decreased the activity of this compound (MIC > 27
μM). Trifluoromethyl substituents at the 3- (5h) and 4-
positions (5i) yielded MICs of 6.39 and 0.80 μM, respectively.
Notably, independent of the position of the chloro group
attached to the aryl group in compounds 5j−l, the MIC values
were 0.44 μM. Increasing lipophilicity with bioisosteric
replacement of 4-chloro by 4-bromo improved the inhibitory
capacity toward M. tuberculosis H37Rv, resulting in a MIC of
0.10 μM for compound 5m. Compared with the lead
compound 2, the 2-(quinolin-4-yloxy)acetamide 5m was 4.4-
fold more potent against the bacilli. By contrast, nitro-
substituted compounds 5n and 5o exhibited an identical MIC
of 6.79 μM, which was approximately 16-fold less effective than
C
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ACS Medicinal Chemistry Letters
Letter
the 2-methoxy derivative 2. This potency decrease may be
related to electronic and/or molecular charge effects. The 4-
amino-substituted compound 5p also did not show improved
activity and presented a MIC of 7.39 μM. Additionally,
displacing the position of the aryl ring by inserting a benzyl
group resulted in decreased activity of structure 5q when
compared with the phenyl counterpart 5b. To improve the
molecular volume and hydrophobicity (Table 1) at the N-
arylamide portion, the 1- and 2-naphthyl substituted com-
pounds (5r and 5s) were synthesized. Compound 5s was the
most active structure tested from the 2-(quinolin-4-yloxy)-
acetamide series here described with an MIC of 0.05 μM,
leading to a potency 8.8-fold higher than compound 2.
Compared with INH, the 2-(quinolin-4-yloxy)acetamide 5s
was about 30-fold more potent. By contrast, 1-naphthyl
derivative 5r exhibited a MIC value 0.42 μM denoting that
hydrophobicity can explain only part of antimycobacterial
elicited by compounds. Finally, benzo[d][1,3]dioxole derivative
5t yielded a similar potency compared with lead molecule 2
with an MIC of 0.42 μM.
Using a threshold of 2 μM for the MIC values, 14 2-
(quinolin-4-yloxy)acetamides (2, 5b−f, 5i−m, 5q, and 5s−t)
were selected for both inhibitory activity of three clinical
isolates (RS-036, RS-032, and PE-003) and viability studies
using Vero and HaCat cells (Table S2, Supporting
Information). Due to antimycobacterial activity of compounds
5r and 5s and their structural similarity, only the 2-naphthyl-
derivative (5s) was selected. The RS-036 and RS-032 are
isoniazid monoresistant strains that contain mutations in the
inhA regulatory regions C(−15)T and katG S315T, respec-
tively.17 The PE-003 strain is a multidrug-resistant clinical
isolate that is resistant to isoniazid, rifampin, etambutol, and
streptomycin and contains a mutation in the inhA regulatory
region C(−15)T.18 In general, potency in the submicromolar
range was maintained for the evaluated compounds (Table 1).
The three most active structures were the 2,4-dimethoxy (5e),
4-bromo (5m), and 2-naphthyl (5s) substituted compounds
(Figure S3, Supporting Information). From the data shown in
Table 1, it can be concluded that the mutation in the katG gene
observed in the RS-032 strain decreased the activity of the
compounds from 2- to 16-fold based on the MIC values.
However, participation of the katG gene product in the
mechanism of action of 2-(quinolin-4-yloxy)acetamides should
be carefully considered because targeted sequencing was
employed to evaluate the genome mutations involved in drug
resistance, contrary to whole genome sequencing. Accordingly,
it cannot be discarded that mutations in other regions of the
bacilli genome may be involved in the mechanism of drug
resistance. Cellular viability was evaluated after exposing the
Vero and HaCat cell lineages to the compounds for 72 h.19
Except for 5s, in vitro incubation of the compounds at the
concentration of 20 μM did not significantly affect the cell
viability of either cell line tested (Table S2, Supporting
Information). Additionally, the compounds were screened in
vitro against Escherichia coli (ATCC 25922), Pseudomonas
aeruginosa (ATCC 27853), Staphylococcus aureus (ATCC
25923), and Acinetobacter baumannii (ATCC BAA 747). At
the 20 μM concentration, the 2-(quinolin-4-yloxy)acetamides
2, 5b−f, 5i−m, 5q, and 5s−t did not show antimicrobial
activity, exhibiting selective action against Mtb (data not
shown).
RAW 264.7 cells.20 The compounds 2, 5e−f, 5i−m, 5q, and
5s−t did not interfere with cell viability at the tested
concentration (Table S3, Supporting Information) and were
then evaluated for their intracellular activities (Table 1). The
rifampin (5 μM)-treated group showed a decrease of 0.92 log10
(P < 0.001) in CFU counts compared with the untreated
control (Table 1). Unfortunately, compounds 5f and 5k did not
show intracellular activity. However, treatment with com-
pounds 2, 5e, 5i−j, 5l-m, 5q, and 5s−t resulted in statistically
significant decreases in CFU units compared with the untreated
control (Table 1). Notably, compounds 2, 5e, 5j, 5l, and 5q
exhibited intracellular activity closely related to rifampin. These
findings revealed that the 2-(quinolin-4-yloxy)acetamides
possess physicochemical features that permit crossing cellular
and mycobacterial barriers to inhibit the Mtb growth inside
macrophages.
Beyond their early activities, basic in vitro and in vivo profiling
of the compounds 2, 5e, 5m, and 5s were determined (Table
S4, Supporting Information). Thermodynamic solubility was
evaluated in aqueous solutions with pH of 1.5, 4, and 7.4. As
expected, the solubility of compounds was markedly higher at
pH 1.5 than at a physiological pH. 2-(Quinolin-4-yloxy)-
acetamides 5e, 5m, and 5s exhibited solubilities ranging from
0.03 to 2.1 mM at pH 1.5 and values of less than 4.4 μM at pH
7.4. Although chemical modifications have reduced aqueous
solubility of compounds throughout the course of our lead
optimization efforts, at pH 1.5, the compounds 5e and 5s
showed solubility higher than 100 μM, which has been
described as a cutoff in early drug discovery.21 Furthermore,
the in vitro intrinsic clearance analysis revealed that 2-(quinolin-
4-yloxy)acetamides 5e and 5m exhibit moderate metabolic
stability, whereas compound 5s displays high rates of
metabolism. In addition, compared with lead molecule 2, the
compounds 5e and 5m showed an improvement of in vitro half-
life. Nevertheless, potential drug−drug interactions were
evaluated using human CYP450 inhibition studies. Compounds
5e, 5m, and 5s did not show any significant inhibition (IC50
value < 10 μM)21 to the evaluated liver enzymes, denoting a
minimal risk of metabolic drug−drug interactions. Finally, the
most active compounds 5e, 5m, and 5s were subjected to
potential cardiac toxicity evaluation in a zebrafish (Danio rerio)
model.22 Compounds were analyzed with heart rate variations
and were found to be safe to the embryos at 1 and 5 μM. By
contrast, when tested at 20 μM, 2-(quinolin-4-yloxy)acetamides
5e, 5m, and 5s significantly reduced heart rate compared with
control. Moreover, embryo survival was also reduced after 72 h
of exposition to 20 μM of compound 5s (data not shown). It is
important to mention that selectivity index of compound 5s
was at least >100 considering a MIC value of 0.05 μM and both
eukaryotic cell viability and cardiac toxicity profiles.
In summary, in this work we demonstrated the synthesis of a
series of 2-(quinolin-4-yloxy)acetamides and their anti-TB
activity in vitro. The simplicity, easily accessible reactants and
reagents, reasonably good yields (32−98%), and high purity
make this synthetic method attractive. In addition, the
synthesized compounds showed potent and selective activity
against drug-sensitive and drug-resistant Mtb strains as well as
activity in a macrophage-infected model. The data described in
this study reveal that this class of compounds may furnish
promising candidates for future development of novel drugs for
TB treatment. To achieve this objective, new structural
modification and/or pharmaceutical formulation studies should
be performed as low aqueous solubility coupled with rapid
To evaluate intracellular activity, compounds were chosen
based on their cytotoxic effects (concentration of 5 μM) on
D
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00324.
Synthetic procedures, analytical data, crystal data and
details of the data collection, and bioassay protocols
(PDF)
(13) Pissinate, K.; Rostirolla, D. C.; Pinheiro, L. M.; Suryadevara, P.;
Yogeeswari, P.; Sriram, D.; Basso, L. A.; Machado, P.; Santos, D. S.
Synthesis and evaluation of thiazolyl-1H-benzo[d]imidazole inhibitors
of Mycobacterium tuberculosis inosine monophosphate dehydrogenase.
J. Braz. Chem. Soc. 2015, 26, 1357−1366.
(14) Lilienkampf, A.; Mao, J.; Wan, B.; Wang, Y.; Franzblau, S. G.;
Kozikowski, A. P. Structure-activity relathionships for a series of
quinoline-based compounds active against replicanting and non-
replicating Mycobacterium tuberculosis. J. Med. Chem. 2009, 52, 2109−
2118.
(15) CCDC number 1416527 contains the supplementary crystallo-
graphic data for compound reported in this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033).
(16) Palomino, J. C.; Martin, A.; Camacho, M.; Guerra, H.; Swings,
J.; Portaels, F. Resazurin microtiter assay plate: Simple and inexpensive
method for detection of drug resistance in Mycobacterium tuberculosis.
Antimicrob. Agents Chemother. 2002, 46, 2720−2722.
(17) Maschmann, R. A.; Spies, F. S.; Nunes, L. S.; Ribeiro, A. W.;
Machado, T. R. M.; Zaha, A.; Rossetti, M. L. R. Performance of the
GenoType MTBDRplus assay directly on sputum specimens from
Brazilian patients with tuberculosis treatment failure or relapse. J. Clin.
Microbiol. 2013, 51, 1606−1608.
AUTHOR INFORMATION
Corresponding Authors
*Phone/Fax: +55 51 3320 3629. E-mail: diogenes@pucrs.br.
*Phone/Fax: +55 51 3320 3629. E-mail: pablo.machado@
pucrs.br.
Author Contributions
The manuscript was written through contributions of all
authors.
■
Funding
This work was supported by funds from the National Institute
of Science and Technology on Tuberculosis (INCT-TB),
Decit/SCTIE/MS-MCT-CNPq-FNDCT-CAPES (Brazil) to
D.S.S. and L.A.B. C.D.B., D.F.B., M.M.C., L.A.B., and D.S.S.
are Research Career Awardees of the National Research
Council of Brazil (CNPq). The fellowships from CNPq
(K.P., V.R.-J., and E.S.G.), CAPES (A.D.V. and B.L.A.), and
FAPERGS (R.V.T.) are also acknowledged.
Notes
The authors declare no competing financial interest.
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Rostirolla, D. C.; Cafrune, P. I.; Espinoza, R. C.; Palaci, M.; Telles, M.
A.; Ritacco, V.; Suffys, P. N.; Lopes, M. L.; Campelo, C. L.; Miranda, S.
S.; Kremer, K.; Silva, P. E. A.; Fonseca, L. S.; Ho, J. L.; Kritski, A. L.;
Rossetti, M. L. R. Correlations of mutations in katG, oxyR-ahpC and
inhA genes and in vitro susceptibility in Mycobacterium tuberculosis
clinical strains segregated by spoligotype families from tuberculosis
prevalent countries in South America. BMC Microbiol. 2009, 9, 39.
(19) Tuberculosis Antimicrobial Acquisition & Coordinating Facility
(TAACF): Description of TAACF Assays.
(20) Rodrigues-Junior, V. S.; dos Santos, A. A. J.; Villela, A. D.;
Belardinelli, J. M.; Morbidoni, H. R.; Basso, L. A.; Campos, M. M.;
Santos, D. S. IQG-607 abrogates the synthesis of mycolic acids and
displays intracellular activity against Mycobacterium tuberculosis in
infected macrophages. Int. J. Antimicrob. Agents 2014, 43, 82−85.
(21) Hughes, J. P.; Rees, S.; Kalindjian, S. B.; Philpott, K. L.
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