Ultrasound-assisted synthesis of 4-alkoxy- 2-methylquinolines: An efficient method toward antitubercular drug candidates

Article abstract of DOI:10.3390/molecules26051215

Tuberculosis (TB) has been described as a global health crisis since the second half of the 1990s. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB in humans, is a very successful pathogen, being the main cause of death in the population among

Full text of DOI:10.3390/molecules26051215

molecules
Article
Ultrasound-Assisted Synthesis of 4-Alkoxy-
2-methylquinolines: An Efficient Method toward
Antitubercular Drug Candidates
Ana Flávia Borsoi 1,2,†, Josiane Delgado Paz 1,3,†, Kenia Pissinate 1, Raoní Scheibler Rambo 1
,
Víctor Zajaczkowski Pestana 1, Cristiano Valim Bizarro 1,3, Luiz Augusto Basso 1,2,3 and Pablo Machado 1,2,3,
*
1
Centro de Pesquisas em Biologia Molecular e Funcional, Instituto Nacional de Ciência e Tecnologia em
Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre,
Rio Grande do Sul, Brazil; afborsoi@gmail.com (A.F.B.); josiane.delgado@acad.pucrs.br (J.D.P.);
k.pissinate@gmail.com (K.P.); raoni.rambo@gmail.com (R.S.R.); victorzaj@hotmail.com (V.Z.P.);
cristiano.bizarro@pucrs.br (C.V.B.); luiz.basso@pucrs.br (L.A.B.)
Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio
Grande do Sul, 90616-900 Porto Alegre, Rio Grande do Sul, Brazil
Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio
Grande do Sul, 90616-900 Porto Alegre, Rio Grande do Sul, Brazil
2
3
*
Correspondence: pablo.machado@pucrs.br; Tel.: +55-51-3320-3629
†
These authors contributed equally to this work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Abstract: Tuberculosis (TB) has been described as a global health crisis since the second half of the
1990s. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB in humans, is a very successful
pathogen, being the main cause of death in the population among infectious agents. In 2019,
it was estimated that around 10 million individuals were contaminated by this bacillus and about
1.2 million succumbed to the disease. In recent years, our research group has reported the design
and synthesis of quinoline derivatives as drug candidates for the treatment of TB. These compounds
have demonstrated potent and selective growth inhibition of drug-susceptible and drug-resistant
Mtb strains. Herein, a new synthetic approach was established providing efficient and rapid access
(15 min) to a series of 4-alkoxy-6-methoxy-2-methylquinolines using ultrasound energy. The new
synthetic protocol provides a simple procedure utilizing an open vessel system that affords the
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Borsoi, A.F.; Paz, J.D.;
Pissinate, K.; Rambo, R.S.; Pestana,
V.Z.; Bizarro, C.V.; Basso, L.A.;
Machado, P. Ultrasound-Assisted
Synthesis of 4-Alkoxy-
2-methylquinolines: An Efficient
Method toward Antitubercular Drug
Candidates. Molecules 2021, 26, 1215.
https://doi.org/10.3390/
target products at satisfactory yields (45–84%) and elevated purities ( 95%). The methodology
allows the evaluation of a larger number of molecules in assays against the bacillus, facilitating the
determination of the structure–activity relationship with a reduced environmental cost.
≥
molecules26051215
Academic Editor: Graeme Barker
Received: 20 January 2021
Accepted: 10 February 2021
Published: 24 February 2021
Keywords: sonochemistry; heterocyclic synthesis; new methods; antituberculosis drug discovery
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
Despite the advances achieved in the last decade, tuberculosis (TB) remains a serious
public health problem. According to the World Health Organization, 10 million new
cases and 1.2 million deaths were reported worldwide in 2019 [
Mycobacterium tuberculosis (Mtb), the disease has been described as the main cause of death
by a single infectious agent [ ]. One of the main difficulties for the treatment of TB has
been the emergence of strains resistant to clinically available drugs [ ]. Infections caused
by Mtb strains resistant to rifampicin (RR-TB), resistant to rifampicin and isoniazid (MDR-
TB), or even resistant to rifampicin and isoniazid in addition to any fluoroquinolone and
injectable second-line drugs (XDR-TB) have created problems for health systems globally.
After a long period without new alternatives on the market, the last decade has witnessed
1]. Caused mainly by
1
2
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© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
the approval of three drugs. “Bedaquiline (2012) [
(2019) [ ]” are new approved drugs for the treatment of TB caused by resistant strains.
However, the adaptive capacity of mycobacteria with the possibility of rapid resistant
3], delamanid (2014) [4], and pretomanid
5
Molecules 2021, 26, 1215. https://doi.org/10.3390/molecules26051215
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 1215
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strain emergence [
6
] demonstrates that new drug candidates for the treatment of TB should
still be a high priority on the global health agenda.
In this context, our research group has reported the design and synthesis of 2-(quinolin-
4-yloxy)acetamides as drug candidates for the treatment of TB with some encouraging
results [
7–
9]. Recently, using a molecular simplification strategy, a series of 2-(quinolin-
4-yloxy)acetamide-based compounds was synthesized [9]. These molecules exhibited
potent and selective growth inhibition of drug-susceptible and drug-resistant Mtb strains
with minimal inhibitory concentrations (MICs) in the submicromolar range. In addition,
the synthesized structures that carry out their antitubercular activity by targeting the
cytochrome bc1 complex showed improved metabolic properties compared with their
counterparts and were able to inhibit the intracellular growth of Mtb [9].
As part of our research program, we are interested in the development of alternative
and environmentally benign methodologies to obtain pharmacologically active compounds.
The possibility of aligning green chemistry concepts with obtaining drug candidates has
been of great interest in both the pharmaceutical sector and scientific community [10,11].
The pharmaceutical industry has the highest unit cost of production and generates the
largest amount of waste among the chemical processing industries [12]. These costs of
production have been related, among other factors, to the efficiency of the processes used to
obtain products with high purity, which allows their pharmaceutical use; the numbers and
time spent on the unit operations; the amount of solvent with a subsequent need for treat-
ment; and the energy spent on the process. Within this context, developing more efficient
methodologies with lower environmental costs in the early drug discovery stages has been
highly recommendable [10,11]. As an alternative to classical methods, sonochemical-based
protocols have been used to increase the rates of a wide variety of reactions, resulting
in products generated under milder conditions with a significant reduction in reaction
times [13,14]. These methods have been described as more environmentally friendly and
sustainable and are associated with greater selectivity and lower energy consumption
for the desired transformations [15]. The mechanism of such methods is based on the
phenomenon of acoustic cavitation, which induces unique conditions of pressure and
temperature through the formation, growth, and adiabatic collapse of bubbles in the liquid
medium [13,14]. This effect improves mass transfer and increases turbulent flow in the
liquid, facilitating the chemical transformations. In our studies, the use of ultrasound
has led to the production of compounds in reduced reaction times with high yields and
purity [16,17]. Such characteristics have increased the number of compounds evaluated in
pharmacological models, contributing to accelerating the hit to lead optimization process.
Therefore, because of the interesting antitubercular activity of 2-(quinolin-4-yloxy)
acetamide-based compounds [9], in an attempt to improve the synthetic protocol, a new
ultrasound-assisted method for obtaining these compounds is described.
2. Results
Regarding ultrasound-based methods for O-alkylation of heterocyclic compounds, ex-
isting protocols have described the treatment of 3-hydroxychromones [18] or
5-hydroxychromone [19] with alkyl(allyl) halides in the presence of potassium carbon-
ate (K2CO3) as the base for the synthesis of the desired products. In these procedures,
dimethylformamide (DMF) and N-methylpyrrolidinone were used as solvents to furnish
the compounds with satisfactory yields.
Thus, ultrasound-assisted O-alkylation reactions of 6-methoxy-2-methylquinolin-4-ol
(1) were performed in the presence of K2CO3 as the base and DMF as the solvent. Nucle-
ophilic substitution reaction was achieved by using appropriate reagents and reactants
in an open vessel system after sonication for 15 min (Table 1). When reduced reaction
times were tested, the product 3a was isolated with lower yields or with incomplete con-
version based on high-performance liquid chromatography (HPLC) analysis. In addition,
the 1:1.2:3 molar ratio between quinoline 1a, benzyl bromide (2a), and K2CO3, respectively,
provided higher yields when compared with other concentrations (Table 1, Entries 5 and

Molecules 2021, 26, 1215
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6). It is noteworthy that the absence of K2CO3 significantly reduced the conversion to
compound 2a (Table 1, Entry 7). Finally, the modification of solvents did not produce
better results when compared with the reactions performed in DMF. In order to verify
the existence of a catalytic effect produced by ultrasonic waves on the synthetic process
under study, the synthesis of compound 3a was performed under conventional thermal
heating using the same experimental conditions described in the ultrasound-assisted pro-
cedure. After 15 min at 120 ◦C, the reaction provided a mixture of 1a
:3a at a ratio of 17:83,
respectively, based on HPLC determination.
a
Table 1. Reagents and conditions: i = K2CO3, solvent, ultrasound or conven◦tional, 5–20 min. Iso-
b
lated yields. Reaction performed under conventional thermal heating (120 C).
Molar Ratio
(1a:2a:K2CO3)
Yield (%) a or
(Ratio 1a:3a)
Entry
Time (min)
Solvent
1
2
3
4
5
6
7
8
9
5
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:2
1:1.2:1.2
1:1.2:0
1:1.2:3
1:1.2:3
1:1.2:3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
EtOH
DMF
(21:79)
65
84
81
59
48
(99:1)
73
10
15
20
15
15
15
15
15
15
44
(17:82) b
10
Afterwards, the protocol was extended to other benzyl bromides (
pounds 3a
obtained to agree with the proposed structures already described [
sibility of obtaining N-alkylated products, using this method followed by aqueous work-up,
has been excluded based on data already described in the literature [ ]. Interestingly, com-
2), leading to com-
–
n
with 45–76% yields (Table 2). Spectroscopic and spectrometric data were
]. Additionally, the pos-
9
7
pounds purities were >95% based on HPLC determinations. This finding allows the use of
such compounds in pharmacological assays without the need for any further purification
procedure. Additionally, electronic variations of the substituents did not significantly alter
the observed results. In addition, the methods described in the literature have reported the
synthesis of compounds from quinoline and benzyl bromide derivatives in the presence
of K2CO3 in DMF under conventional conditions with reaction times ranging from 5 to
8 h [20
,21]. These procedures have led to products with 17–76% yields, one of which
described the use of chromatography in the purification of compounds. In particular,
compounds 3a
of K2CO3 in DMF [
–
n
have been synthesized under conventional conditions in the presence
◦
9]. The products were obtained after stirring for 18 h at 25 C with
49–95% yields (Table 2). Comparing the conventional method with sonochemical condi-
tions, the ultrasound protocol highly reduced the reaction time for the O-alkylation of
quinoline derivative compounds. In addition, the method provided the compounds at high
purity without the need for any additional purification procedures. Synthesized structures
were endowed with potent antimycobacterial activity, with MICs in the range of 0.3 to
30.8 µM [9].
In summary, the preparation of quinoline derivative compounds has been success-
fully accomplished via sonochemical conditions. The simplicity of execution, significantly
shorter reaction times (15 min), satisfactory yields (45–84%), and the purity of the iso-
lated products make this protocol attractive. The use of the ultrasound-assisted method
described has been applied in the generation of a wide variety of compounds with po-

Molecules 2021, 26, 1215
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tent antimycobacterial activity (MIC = 0.3–30.8
µM [9]) through a method that has lower
environmental and operational costs compared with existing ones.
a
b
Table 2. Conditions: i = K2CO3, DMF, 15 min. Isolated yields. Ultrasound-assisted method.
Conventional stirring method [9].
c
Yield (%) a,b
Entry
R1
Yield (%) a,c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Ph
F-4-C6H4
F-2-C6H4
84
62
45
83
72
79
74
73
76
81
82
50
68
57
49
67
52
90
73
90
86
63
95
81
90
64
80
64
(F)2-3,4-C6H3
Cl-4-C6H4
Cl-3-C6H4
Cl-2-C6H4
(Cl)2-3,4-C6H3
Br-3-C6H4
F3C-4-C6H4
F3C-3-C6H4
O2N-4-C6H4
iPr-4-C6H4
2-Naphthyl
3. Experimental
3.1. Chemistry
Commercially available reactants and solvents were obtained from commercial sup-
pliers, and were used without additional purification. The reactions were carried out with
a standard probe (25 mm) connected to a 1500 Watt Sonics Vibra-Cell ultrasonic processor
(Newtown, CT, USA) equipped with integrated temperature control. The device operates at
20 kHz, and the amplitude was set to 20% of the maximum power output. In all reactions,
the temperature was raised to 115–120 ◦C after sonication for 7–8 min. The progress of the
reaction was monitored using thin-layer chromatography (TLC, Kenilworth, NJ, USA) with
Merck TLC Silica gel 60 F254. The melting points were measured using a Microquímica
MQAPF-302 apparatus. 1H and 13C NMR spectra were acquired on an Avance III HD
Bruker spectrometer (Bruker Corporation, Fällanden, Switzerland). Chemical shifts (δ)
were expressed in parts per million (ppm) relative to DMSO-d6, which was used as the
solvent, and to TMS, which was used as an internal standard. High-resolution mass spectra
(HRMS) were obtained for all compounds on an LTQ Orbitrap Discovery mass spectrome-
ter (Thermo Fisher Scientific, Bremen, Germany). The analyses were performed through
the direct infusion of the sample in MeOH/MeCN (1:1) with 0.1% formic acid (flow rate
10 mL/min), in a positive-ion or negative-ion mode using electrospray ionization (ESI).
For elemental composition, calculations were performed using the specific tool included in
the Qual Browser module of Xcalibur software. The compound purity was determined
using an Äkta HPLC system (GE Healthcare® Life Sciences) equipped with a binary pump,
manual injector, and UV detector. Unicorn 5.31 software (Build 743) was used for data
acquisition and processing. The HPLC conditions were as follows: RP column, 5
µm
Nucleodur C-18 (250 4.6 mm); flow rate, 1.5 mL/min; UV detection, 254 nm; 100% water
×
(0.1% acetic acid) was maintained from 0 to 7 min, followed by a linear gradient from 100%
water (0.1% acetic acid) to 90% acetonitrile/methanol (1:1, v/v) from 7 to 15 min (15–30
min) and subsequently returned to 100% water (0.1% acetic acid) in 5 min (30–35 min) and
maintained for an additional 10 min (35–45 min).

Molecules 2021, 26, 1215
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3.2. General Procedure for the Synthesis of 6-Methoxy-2-Methylquinolines
6-Methoxy-2-methylquinolin-4-ol ( ) (1 mmol), benzyl bromides ( ) (1.2 mmol), and K2CO3
1
2
(0.415 g, 3 mmol) were mixed in DMF (20 mL) in a 100 mL beaker. The reaction mixture
was sonicated for 15 min using an ultrasonic probe. Afterwards, the amount of solvent
was decreased under reduced pressure, and the resultant mixture was diluted in water.
Subsequently, the solid formed was filtered off and washed under agitation with water
(
3 × 20 mL); after each wash, the product was separated from the liquid phase by centrifu-
◦
gation (10 min, 18,000 rpm at 4 C). Finally, the product was dried under reduced pressure
for at least 24 h. Analytical data were found to be in agreement with the already reported
data [9]. Compounds 3a and 3b were selected for exemplification.
4-(Benzyloxy)-6-methoxy-2-methylquinoline (3a): yield 84%; white to slightly yellow
solid; m.p.: 140–141 ◦C; HPLC 95% (tR = 14.57 min); 1H NMR (400 MHz, DMSO-d6)
δ 2.55
(s, 3H, CH3), 3.84 (s, 3H, CH3), 5.38 (s, 2H, CH2), 7.00 (s, 1H, Qu-H*), 7.40–7.30 (m, 3H,
Qu-H*, Ph-H), 7.49–7.41 (m, 2H, Ph-H), 7.58 (dt, J = 6.3, 1.4 Hz, 2H, Qu-H*, Ph-H), 7.79 (d,
J = 9.1 Hz, 1H, Qu-H*); HRMS (FTMS + pESI) m/z calcd. for C18H17NO2 (M)+: 280.1332;
found: 280.1325; Qu-H*: quinolines hydrogens.
4-((4-Fluorobenzyl)oxy)-6-methoxy-2-methylquinoline (3b): yield 62%; white solid;
mp.: 114–115 ◦C; HPLC 95% (tR = 15.12 min); 1H NMR (400 MHz, DMSO-d6)
δ 2.59 (s, 3H,
CH3), 3.84 (s, 3H, CH3), 5.35 (s, 2H, CH2), 6.98 (s, 1H, Qu-H*), 7.40–7.25 (m, 4H, Ph-H, Qu-
H*), 7.69–7.58 (m, 2H, Ph-H, Qu-H*), 7.81 (d, J = 9.0 Hz, 1H, Qu-H*); HRMS (FTMS + pESI)
m/z calcd. for C18H16FNO2 (M)+: 298.1238; found: 298.1245; Qu-H*: quinolines hydrogens.
Author Contributions: A.F.B. and J.D.P. are equal-contributing first authors. Writing—Original Draft
Preparation: A.F.B., J.D.P., K.P., R.S.R., V.Z.P., C.V.B., L.A.B. and P.M. Writing—Review and Editing:
P.M. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by CNPq/FAPERGS/CAPES/BNDES, Brazil (grant numbers:
421703-2017-2/17-1265-8/14.2.0914.1) to C.V.B., L.A.B. and P.M. In addition, this study was financed
in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES),
Finance Code 001. C.V.B., L.A.B. and P.M. are Research Career Awardees of the National Research
Council of Brazil (CNPq). Fellowships from CNPq (R.S.R. and V.Z.P.) and CAPES (J.D.P. and A.F.B.)
are also acknowledged.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the synthesized compounds are available from the authors.
References
1.
2.
3.
WHO. Global Tuberculosis Report. 2020. Available online: https://www.who.int/publications/i/item/9789240013131 (accessed
on 19 January 2021).
Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. The challenge of new drug discovery for tuberculosis. Nature 2011,
469, 483–490. [CrossRef] [PubMed]
Diacon, A.H.; Pym, A.; Grobusch, M.; Patientia, R.; Rustomjee, R.; Page-Shipp, L.; Pistorius, C.; Krause, R.; Bogoshi, M.;
Churchyard, G.; et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N. Engl. J. Med. 2009, 360, 2397–2405.
[CrossRef] [PubMed]
4.
5.
6.
Gler, M.T.; Skripconoka, V.; Sanchez-Garavito, E.; Xiao, H.; Cabrera-Rivero, J.L.; Vargas-Vasquez, D.E.; Gao, M.; Awad, M.;
Park, S.K.; Shim, T.S.; et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N. Engl. J. Med. 2012, 366, 2151–2160.
[CrossRef] [PubMed]
Stover, C.K.; Warrener, P.; VanDevanter, D.R.; Sherman, D.R.; Arain, T.M.; Langhorne, M.H.; Anderson, S.W.; Towell, J.A.; Yuan, Y.
McMurray, D.N.; et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 2000
405, 962–966. [CrossRef] [PubMed]
;
,
Bloemberg, G.V.; Keller, P.M.; Stucki, D.; Trauner, A.; Borrell, S.; Latshang, T.; Coscolla, M.; Rothe, T.; Hömke, R.C.;
Feldmann, J.; et al. Acquired resistance to bedaquiline and delamanid in therapy for tuberculosis. N. Engl. J. Med. 2015
373, 1986–1988. [CrossRef] [PubMed]
,

Molecules 2021, 26, 1215
6 of 6
7.
8.
9.
Pissinate, K.; Villela, A.D.; Rodrigues-Junior, V.; Giacobbo, B.C.; Grams, E.S.; Abbadi, B.L.; Trindade, R.V.; Nery, L.R.; Bonan, C.D.;
Back, D.F.; et al. 2-(Quinolin-4-yloxy)acetamides are active against drug-susceptible and drug-resistant Mycobacterium tuberculosis
strains. ACS Med. Chem. Lett. 2016, 7, 235–239. [CrossRef]
Giacobbo, B.C.; Pissinate, K.; Rodrigues-Junior, V.; Villela, A.D.; Grams, E.S.; Abbadi, B.L.; Subtil, F.T.; Sperotto, N.; Trindade, R.V.
;
Back, D.F.; et al. New insights into the SAR and drug combination synergy of 2-(quinolin-4-yloxy)acetamides against Mycobac-
terium tuberculosis. Eur. J. Med. Chem. 2017, 126, 491–501. [CrossRef] [PubMed]
Borsoi, A.F.; Paz, J.D.; Abbadi, B.L.; Macchi, F.S.; Sperotto, N.; Pissinate, K.; Rambo, R.S.; Ramos, A.S.; Machado, D.;
Viveiros, M.; et al. Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy)acetamide-based antituberculosis agentes. Eur.
J. Med. Chem. 2020, 192, 112179. [CrossRef]
10. Bryan, M.C.; Dillon, B.; Hamann, L.G.; Hughes, G.J.; Kopach, M.E.; Peterson, E.A.; Pourashraf, M.; Raheem, I.; Richardson, P.
Richter, D.; et al. Sustainable practices in medicinal chemistry: Current state and future directions. J. Med. Chem. 2013
56, 6007–6021. [CrossRef] [PubMed]
;
,
11. Aliagas, I.; Berger, R.; Goldberg, K.; Nishimura, R.T.; Reilly, J.; Richardson, P.; Richter, D.; Sherer, E.C.; Sparling, B.A.; Bryan, M.C.
Sustainable practices in medicinal chemistry. Part 2: Green by design. J. Med. Chem. 2017, 60, 5955–5968. [CrossRef] [PubMed]
12. Martins, M.A.P.; Frizzo, C.P.; Moreira, D.N.; Buriol, L.; Machado, P. Solvent-free heterocyclic synthesis. Chem. Rev. 2009
109, 4140–4182. [CrossRef] [PubMed]
,
13. Cravotto, G.; Cintas, P. Power ultrasound in organic synthesis: Moving cavitational chemistry from academia to innovative and
large-scale applications. Chem. Soc. Rev. 2006, 35, 180–196. [CrossRef] [PubMed]
14. Puri, S.; Kaur, B.; Parmar, A.; Kumar, H. Applications of ultrasound in organic synthesis—A green approach. Curr. Org. Chem.
2013, 17, 1790–1828. [CrossRef]
15. Banerjee, B. Recent developments on ultrasound assisted catalyst-free organic synthesis. Ultrason. Sonochem. 2017, 35, 1–14.
[CrossRef]
16. Gazzi, T.P.; Basso, L.A.; Santos, D.S.; Machado, P. A greener approach toward gadolinium-based contrast agents. RSC Adv. 2014
4, 9880–9884. [CrossRef]
,
17. Borsoi, A.F.; Coldeira, M.E.; Pissinate, K.; Macchi, F.S.; Basso, L.A.; Santos, D.S.; Machado, P. Ultrasound-assisted synthesis of
2-amino-1,3,4-oxadiazoles through NBS-mediated oxidative cyclization of semicarbazones. Synth. Commun. 2017, 47, 1319–1325.
[CrossRef]
18. Dofe, V.F.; Sarkate, A.P.; Lokwani, D.K.; Shinde, D.B.; Kathwate, S.H.; Gill, C.H. Novel O-alkylated chromones as antimicrobial
agents: Ultrasound mediated synthesis, molecular docking and ADME prediction. J. Heterocyclic Chem. 2017, 54, 2678–2685.
[CrossRef]
19. Mason, T.J.; Lorimer, J.P.; Paniwnyk, L.; Harris, A.R.; Wright, P.W.; Bram, G.; Loupy, A.; Ferradou, G.; Sansoulet, J. The O-alkylation
of 5-hydroxy chromones. A comparison of two non-classical techniques, PTC in the absence of solvent and sonochemical activation
in polar aprotic solvents. Synth. Commun. 1990, 20, 3411–3420. [CrossRef]
20. Escribano, J.; Rivero-Hernández, C.; Rivera, H.; Barros, D.; Castro-Pichel, J.; Pérez-Herrán, E.; Mendoza-Losana, A.;
Angulo-Barturen, I.; Ferrer-Bazaga, S.; Jiménez-Navarro, E.; et al. 4-Substituted thioquinolines and thiazoloquinolines: Potent,
selective, and Tween-80 in vitro dependent families of antitubercular agents with moderate in vivo activity. ChemMedChem. 2011
6, 2252–2263. [CrossRef] [PubMed]
,
21. Du, Z.; Li, P.; Zhao, M.; Gu, Y.; Zhou, W.; Zhang, K. Preparation of Quinoline-Based Derivative, and Applications of Quino-line-
Based Derivative in Anti-Inflammation. CN Patent 106,588,909A, 6 January 2017.