A novel approach for the synthesis of functionalized hydroxylamino derivative of dihydroquinazolinones

Article abstract of DOI:10.1080/00397911.2020.1768406

A new metal-free and modular approach for the synthesis of various functionalized dihydroquinazolinones has been developed from isatoic anhydride, amines, 4-chloro-N-hydroxybenzimidoylchloride to yield up to 71%. The reaction has been screened in various bases, solvents at different temperatures. The substrate scope of the reaction has been studied with various amines and the possible reaction mechanism for this reaction has also been proposed.

Full text of DOI:10.1080/00397911.2020.1768406

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
A novel approach for the synthesis of
functionalized hydroxylamino derivative of
dihydroquinazolinones
Chikkanti Jaganmohan, Vinay Kumar K. P., Venkateshwarlu R., Sandeep
Mohanty, Jaydeep Kumar, Venkateswara Rao B., Akula Raghunadh &
Krishnaji Tadiparthi
To cite this article: Chikkanti Jaganmohan, Vinay Kumar K. P., Venkateshwarlu R., Sandeep
Mohanty, Jaydeep Kumar, Venkateswara Rao B., Akula Raghunadh & Krishnaji Tadiparthi
(2020): A novel approach for the synthesis of functionalized hydroxylamino derivative of
dihydroquinazolinones, Synthetic Communications, DOI: 10.1080/00397911.2020.1768406
To link to this article: https://doi.org/10.1080/00397911.2020.1768406
View supplementary material
Published online: 23 May 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1768406
A novel approach for the synthesis of functionalized
hydroxylamino derivative of dihydroquinazolinones
Chikkanti Jaganmohana,b, Vinay Kumar K. P.a, Venkateshwarlu R.a,
Sandeep Mohantya, Jaydeep Kumara, Venkateswara Rao B.b, Akula Raghunadha,
and Krishnaji Tadiparthic
b
aDr. Reddy’s Laboratories Limited, Hyderabad, India; Department of Organic Chemistry and FDW,
c
Andhra University, Visakhapatnam, India; Department of Chemistry, CHRIST (Deemed to be
University), Bangalore, India
ABSTRACT
ARTICLE HISTORY
Received 19 March 2020
A new metal-free and modular approach for the synthesis of various
functionalized dihydroquinazolinones has been developed from isa-
toic anhydride, amines, 4-chloro-N-hydroxybenzimidoylchloride to
yield up to 71%. The reaction has been screened in various bases,
solvents at different temperatures. The substrate scope of the reac-
tion has been studied with various amines and the possible reaction
mechanism for this reaction has also been proposed.
KEYWORDS
4-Chloro-N-hydroxybenzimi-
doylchloride; dihydroquina-
zolinones; isatoic anhydride
GRAPHICAL ABSTRACT
R = Cyclopropyl, n-propyl, isobutyl, cycloheptyl,
cyclohexyl, isopropyl, napthyl, benzyl, n-hexyl, benzhydrile.
R’= H, Cl, Br
18 examples
Upto 71% yields
Introduction
Because of the structural diversification, heterocyclic chemistry has always been a chal-
lenging and emerging area of research for pharmaceutical industry.[1] Indeed, these
compounds are showing the intrinsic biological activity in the toxicological studies and
CONTACT Akula Raghunadh
Krishnaji Tadiparthi krishnaji.tadiparthi@christuniversity.in
University), Hosur Road, Bangalore 560029, India.
rgkraghu@gmail.com
Dr. Reddy’s Laboratories Limited, Hyderabad 500049, India;
Department of Chemistry, CHRIST (Deemed to be
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
C. JAGANMOHAN ET AL.
Figure 1. Some important biologically important dihydroquinazolinones compounds.
clinical studies. Notably, the innovative companies like AstraZeneca, Pfizer are affording
substantial effort to find the novel molecules like AZD1390, AZD2811, Capivasertib and
Adriatic.[2] Indeed, during the past decade, an aggressive research on heterocyclic chem-
istry has been developed especially after invention of Heck, Suzuki and Negishi coupling
reactions.[3] Notably, dihydroquinazolinones are one among them present in various
biologically active molecules like Quinethazone (1), Fenquizone (2), Benzouracil (3),
Evodiamine (4), Proquazone (5) and NC1 Substance T1D19143 (6) (Figure 1).
However, these compounds having immense potential therapeutic properties against
anti-cancer, antidiabatic, antihypertension, anticonvelsant, and antianxieticactivities.[4–12]
Inspite of their biological activity and various applications in organic chemistry, a
good number of publications and patents have been reported.[13] Moreover, this has
stimulated us for the development of various functionalized dihydroquinazolinones by
different strategies. However, the invention of novel molecules with reliability, effi-
ciency, and elegant approach is always
organic chemistry
a challenging and encouraging in
Results and discussion
In continuation of our earlier efforts for the preparation of various biologically
active heterocyclic compounds (Scheme 1),[14] herein, we report a novel functional-
ized synthesis of dihydroquinazolinones starting from commercially available isa-
toic anhydride.
The syntheses of various dihydroquinazolinones have been prepared by taking isatoic
anhydride, 4-chloro-N-hydroxybenzimidoylchloride with various amines. Initially, the
reaction conditions were optimized by taking isatoic anhydride, 4-chloro-N-hydroxyben-
zimidoylchloride with cyclopropyl amine as model substrates.
The reaction has been screened in various solvents like DCM, CHCl3, IPA, DMF,
and THF with a combination of different bases like Et3N, NaHCO3 at different

R
SYNTHETIC COMMUNICATIONSV
3
Scheme 1. Different approaches for the synthesis of dihydroquinazolinone derivatives.
Table 1. Optimization of reaction conditions.
Solvent
Temperature (ꢀC)
Base (eq.)
Time (hr)
Yield (%)
DCM
DCM
DCM
Chloroform
Chloroform
IPA
IPA
IPA
IPA
IPA
IPA
DMF
THF
IPA
IPA
No solvent
35
40
45
35
60
35
35
35
35
85
35
35
35
35
35
35
TEA (1)
TEA (1)
TEA (2)
TEA (2)
NaHCO3 (2)
TEA (1)
TEA (2)
TEA (2.5)
TEA (2.5)
TEA (2.5)
NaHCO3 (2.5)
TEA (2.5)
TEA (2.5)
TEA.HCl (3)
No base
TEA (1)
3
2
3
3
3
2
2
2
4
2
3
3
3
2
3
2
40
40
45
46
48
55
65
70
60
50
55
65
65
50
30
45
Bold values represents final optimum conditions.

4
C. JAGANMOHAN ET AL.
Table 2. Substrate scope for the synthesis of various 2-aryl-2-(hydroxyl amino)-3-alkyl or aryl 2,3-
dihydroquinazolin-4(1H)-ones.
temperatures (Table 1). After screening the reaction in different stoichiometric ratios,
the reaction was proceeded well in the presence of isopropylalcohol as a solvent and
Et3N as a base at 35 ꢀC to get moderate yields.
Bold values represents final optimum conditions.
In continuation, after finding the optimum conditions in our hand, the substrate
scope of the reaction has been studied with various amines and N-hydroxybenzimidoyl-
chloride. To our delight, the reaction proceeded well with all types of amines like

R
SYNTHETIC COMMUNICATIONSV
5
Scheme 2. Synthesis of quinolines.
Scheme 3. The plausible reaction mechanism.
cyclopropyl, n-propyl, isobutyl, isopropyl, cycloheptyl, aryl, napthyl, benzyl, n-hexyl
amines to get moderate yields (Table 2).
Nevertheless, to understand the feasibility of reaction on higher scale, we have dem-
onstrated the reaction on a 10 g scale and gratifyingly we could amenable to reproduce
the same results (Table 2, 10[a]). Moreover, the synthetic application of these com-
pounds were demonstrated by heating the compound (10a) in isopropylalcohol at
80–85 ꢀC to get a biologically important quinolone by dehydroxylamination (Scheme 2).
Furthermore, the possible reaction mechanism for this reaction has been proposed
based on the reaction conditions and the experimental data (Scheme 3).
Experimental Section
General procedure for the synthesis of dihydroquinazolinone
To a stirred solution of isatoic anhydride (0.5 g, 3.1 mmol) in 1,4-Dioxane (15mL), benzyl-
amine (0.33g, 3.1 mmol) was added at room temperature and the reaction temperature was
slowly increased to 80–90ꢀC. The reaction mass was stirred for 3 h and water was added to
the reaction mass at room temperature. The reaction mass was extracted with dichlorome-
thane (2 ꢁ 20mL) and separated both the layers. The combined organic layers were dried
over anhydrous sodium sulfate and concentrated under reduced pressure to get 2-
amino-benzamide.

6
C. JAGANMOHAN ET AL.
To a solution of 2-amino-benzamide (250.0 mg, 1.41 mmoles, 1.0 eq.) in isopropylal-
cohol (10 mL), N-hydroxybenzimidoylchloride (540.0 mg 2.83 mmoles 2.0 eq.), triethyl-
amine (360.0 mg 3.54 mmoles 2.5 eq.) were added and the reaction mass was stirred for
2 h. After completion of the reaction, the reaction mass was cooled to 0–5 ꢀC, and the
inorganic material was filtered. The solvent in the filtrate was evaporated under reduced
pressure and the crude residue was purified by column chromatography (EtOAc/Pet-
Ether (3:7) to get the pure product as a solid.
Analytical data for selected compounds
2-(4-Chlorophenyl)-3-cyclopropyl-2-(hydroxyamino)-2,3-dihydroquinazolin-4(1H)-
one (10a)
1
Solid; Yield: 70%; H NMR (400 MHz, DMSO-d6):d 10.92 (s, 1H), 10.00 (s, 1H), 8.60 (t,
J ¼ 5.6 Hz, 1H),7.52 (dd, J ¼ 7.8 Hz, 1.4 Hz, 1H),7.44–7.35 (m, 4H),7.07–7.02 (m, 1H),
6.85–6.79 (m, 1H), 6.15 (d, J ¼ 7.6 Hz, 1H), 2.91–2.87 (m, 1H), 0.74–0.70 (m, 2H),
0.62–0.58 (m, 2H); 13C NMR (400 MHz, DMSO-d6): d 170.0, 147.3, 140.4 134.0, 131.4,
131.0, 129.1(2 C), 129.0(3 C), 121.1, 119.4, 119.2, 23.0, 6.0(2 C); HRMS (ESI): m/z calcd
for C17H16ClN3O2: 330.1004; found: 330.1003.
2-(4-Chlorophenyl)-2-(hydroxyamino)-3-propyl-2,3-dihydroquinazolin-4(1H)-one (10b)
1
Solid; Yield: 68%; H NMR (400 MHz, DMSO-d6): d 10.90 (s, 1H), 9.99 (s, 1H), 8.60
(t, J ¼ 5.5 Hz, 1H), 7.55 (dd, J ¼ 7.8, 1.4 Hz, 1H), 7.44–7.42 (m, 2H), 7.39–7.36 (m, 2H),
7.10–7.05 (m, 1H), 6.84 (t, J ¼ 7.2 Hz, 1H), 6.17 (d, J ¼ 7.9 Hz, 1H), 3.26–3.22 (m, 2H),
1.61–1.52 (m, 2H), 0.92 (t, J ¼ 7.4 Hz, 3H); 13C NMR (400 MHz, DMSO-d6): d 168.8,
147.8, 140.9, 134.2, 131.9, 131.0, 129.6(2 C), 129.1(2 C), 128.8, 122.0, 120.0, 119.7, 41.3,
22.8, 12.0; HRMS (ESI): m/z calcd. for C17H18ClN3O2: 332.1160; found: 332.1192.
2-(4-Chlorophenyl)-3-cycloheptyl-2-(hydroxyamino)-2,3-dihydroquinazolin-4(1H)-
one (10e):
1
Solid; Yield: 69%; H NMR (400 MHz, DMSO-d6): d 10.88 (s, 1H), 9.91 (s, 1H), 8.40 (t,
J ¼ 7.8 Hz, 1H), 7.53 (dd, J ¼ 7.7, 1.3 Hz, 1H), 7.44–7.41 (m, 2H), 7.39–7.35 (m, 2H),
7.09–7.04 (m, 1H), 6.83 (dd, J ¼ 11.0, 4.1 Hz, 1H), 6.16 (d, J ¼ 8.0 Hz, 1H), 4.01–3.93
(m, 1H), 1.92–1.84 (m, 2H), 1.68–1.40 (m, 10H); 13C NMR (100 MHz, DMSO-d6): d
167.7, 147.8, 140.8, 134.3, 131.9, 130.9, 129.6(2 C), 129.1(2 C), 122.5, 120.1, 119.9, 119.7,
50.8, 34.7(2 C), 28.2(2 C), 24.5(2 C); HRMS (ESI): m/z calcd for C21H24ClN3O2:
386.1630; found: 386.1636.
2-(4-Chlorophenyl)-3-(3,4-dimethoxyphenethyl)-2-(hydroxyamino)-2,3-dihydroquina-
zolin-4(1H)-one (10 l):
Solid; Yield: 58%;1H NMR (400 MHz, DMSO-d6): d 10.93 (s, 1H), 9.96 (s, 1H), 8.65 (t,
J ¼ 5.4 Hz, 1H), 7.51 (d, J ¼ 6.7 Hz, 1H), 7.43 (d, J ¼ 8.6 Hz, 2H), 7.35 (d, J ¼ 8.6 Hz,
2H), 7.07 (t, J ¼ 7.3 Hz, 1H), 6.88–6.81 (m, 4H), 6.16 (d, J ¼ 8.1 Hz, 1H), 4.37 (t,
J ¼ 7.0 Hz, 2H). 3.74 (s, 3H), 3.70 (s, 3H), 2.82 (t, J ¼ 7.2 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6): d 168.0, 141.0, 140.8, 134.3, 133.9, 131.8, 131.2, 130.8, 129.6, 129.2, 129.1,

R
SYNTHETIC COMMUNICATIONSV
7
127.8, 126.7, 126.1, 126.0, 123.6, 123.0, 122.0, 120.0, 119.8, 45.2, 41.0(2 C), 22.0; HRMS
(ESI): m/z calcd for C24H24ClN3O2: 454.1528; found: 454.1550.
Conclusions
In summary, we have developed a simple, metal-free reaction for the synthesis of novel
functionalized dihydroquinazolinones. The reaction conditions are optimized and sub-
strate scope of the reaction has been carried out to get moderate yields. Finally, the syn-
thetic application of these compounds has also been demonstrated by synthesizing a
quinolone pharmacore unit and similar kind of dihyroquinazolinone derivatives are
under progress in our laboratory.
Acknowledgements
The authors would like to thank Dr. Reddy’s Laboratory, Hyderabad for providing facilities to
carry out this work. One of the authors Dr. Krishnaji acknowledges CHRIST (Deemed to be
University) for funding Major Research Project (MRP # MRPDSC-1723).
ORCID
Krishnaji Tadiparthi
http://orcid.org/0000-0003-1727-6305
References
[1] (a) Kunied, T.; Mutsanga, H. The Chemistry of Heterocyclic Compounds; Palmer, B, 2002,
175. (b) Foye, W. O.; Thomas, L. Foye’s Principles of Medicinal Chemistry, 6th ed.;
Lippincott Williams & Wilkins: Philadelphia, 2007, p 36. (c) Czarnik, A. Acc. Chem. Res.
1996, 29, 112–113. DOI: 10.1021/ar950256n.
[2] (a) Adriana, E. T.; Belmonte1, M. A.; Adam1, A.; Aquila1, B. M.; Boise, L. H.; Chiarparin,
E.; Cidado1, J.; Embrey, K. J.; Gangl, E.; Gibbons, F. D.; et al. Nature Comm. 2018, 9,
5341. (b) The Pharmaceutical Century: Ten Decades of Drug Discovery; ACS Publications:
Washington, DC, 2000.
[3] (a) Galardon, E.; Ramdeehul, S.; Brown, J. M.; Cowley, A.; Hii, K. K.; Jutand, A. Angew.
Chem. Int. Ed. 2002, 41, 1760–1763. DOI: 10.1002/1521-3773(20020517)41:10<1760::AID-
ANIE1760>3.0.CO;2-3. (b) Tolman, C. A. Chem. Rev. 1977, 77, 313–348. DOI: 10.1021/
cr60307a002.
[4] (a) Jiang, J. B.; Hesson, D.; Dusak, B.; Dexter, D.; Kang, G.; Hamel, E. J. Med. Chem.
1990, 33, 1721–1728. DOI: 10.1021/jm00168a029. (b) Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.;
Liu, S. Y.; Ding, G. Y.; Li, R. T. Bioorg. Med. Chem. Lett. 2005, 15, 1915–1917. DOI: 10.
1016/j.bmcl.2005.01.083.
[5] Chern, J. W.; Tao, P. L.; Wang, K. C.; Gutcait, A.; Liu, S. W.; Yen, M. H.; Chien, S. L.;
Rong, J. K. J. Med. Chem. 1998, 41, 3128–3141. DOI: 10.1021/jm970159v.
[6] Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.; Greenwood, T. D. J. Med.
Chem. 1990, 33, 161–166. DOI: 10.1021/jm00163a027.
[7] (a) Pendergast, W.; Johnson, J. V.; Dickerson, S. H.; Dev, I. K.; Duch, D. S.; Ferone, R.;
Hall, W. R.; Humphreys, J.; Kelly, J. M.; Wilson, D. C. J. Med. Chem. 1993, 36,
2279–2291. DOI: 10.1021/jm00068a004. (b) Kung, P. P.; Casper, M. D.; Cook, K. L.;
Wilson-Lingardo, L.; Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt, J. R.;
Cook, P. D.; Ecker, D. J. J. Med. Chem. 1999, 42, 4705–4713. DOI: 10.1021/jm9903500.

8
C. JAGANMOHAN ET AL.
[8] (a) Rorsch, F.; Buscato, E.; Deckmann, K.; Schneider, G.; Zsilavecz, M. S.; Geisslinger, G.;
Proschak, E.; Grosch, S. J. Med. Chem. 2012, 55, 3792–3803. DOI: 10.1021/jm201687d. (b)
de Laszlo, S. E.; Quagliato, C. S.; Greenlee, W. J.; Patchett, A. A.; Chang, R. S.; Lotti, V. J.;
Chen, T. B.; Scheck, S. A.; Faust, K. A.; Kivlighn, S. S. J. Med. Chem. 1993, 36, 3207–3210.
DOI: 10.1021/jm00073a024.
[9] Mustazza, C.; Borioni, A.; Sestili, I.; Sbraccia, M.; Rodomonte, A.; Ferretti, R.; Giudice,
M. R. D. Chem. Pharm. Bull. 2006, 54, 611–622. DOI: 10.1248/cpb.54.611.
[10] Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492–1503. DOI: 10.1021/
jm00108a038.
[11] (a) Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds.;
Comprehensive Heterocyclic Chemistry III Elsevier: Oxford, UK, 2008. (b) Horton, D. A.;
Bourne, G. T.; Smyth, M. L. Chem. Rev. 2003, 103, 893–930. DOI: 10.1021/cr020033s.
[12] (a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787–9826. DOI: 10.1016/j.tet.
2006.07.098. (b) Lee, S. H.; Son, J.-K.; Jeong, B. S.; Jeong, T.-C.; Chang, H. W.; Lee, E.-S.;
Jahng, Y. Molecules 2008, 13, 272–300. DOI: 10.3390/molecules13020272.
[13] (a) Shaabani, A.; Maleki, A.; Mofakham, H. Synth. Commun. 2008, 38, 3751–3759. DOI:
10.1080/00397910802213802. (b) Vns Murthy, P.; Rambabu, D.; Rama Krishna, G.; Malla
Reddy, C.; Prasad, K. R. S.; Basaveswara Rao, M. V.; Pal, M. Tetrahedron Lett. 2012, 53,
863–867. DOI: 10.1016/j.tetlet.2011.12.023. (c) Kiaee, S.; Masoumnia, A.; Maghsoodlou, M.
Res. Pharm. Sci. 2012, 7, 5.(d) Darvatkar, N. B.; Bhilare, S. V.; Deorukhkar, A. R.; Raut,
D. G.; Salunkhe, M. M. Green Chem. Lett. Rev. 2010, 3, 301–306. DOI: 10.1080/17518253.
2010.485581. (e) Chen, J.; Wu, D.; He, F.; Liu, M.; Wu, H.; Ding, J.; Su, W. Tetrahedron
Lett. 2008, 49, 3814–3818. DOI: 10.1016/j.tetlet.2008.03.127. (f) Ghorbani-Choghamarani,
A.; Taghipour, T. Loc. 2011, 8, 470–476. DOI: 10.2174/157017811796505025. (g) Chen, J.
X.; Su, W. K.; Wu, H. Y.; Liu, M. C.; Jin, C. Green Chem. 2007, 9, 972. DOI: 10.1039/
b700957g. (h) Rueping, M.; Antonchick, A. P.; Sugiono, E.; Grenader, K. Angew. Chem.
Int. Ed. Engl. 2009, 48, 908–910. DOI: 10.1002/anie.200804770. (i) Abdel-Jalil, R. J.;
Voelter, W.; Saeed, M. Tetrahedron Lett. 2004, 45, 3475–3476. DOI: 10.1016/j.tetlet.2004.
03.003. (j) Davoodnia, A.; Allameh, S.; Fakhari, A. R.; Tavakoli-Hoseini, N. Chin. Chem.
Lett. 2010, 21, 550–553. DOI: 10.1016/j.cclet.2010.01.032. (k) Jianguang, Z.; Jie, F. J. Org.
Chem. 2011, 142, 631. (l) Cheng, X.; Vellalath, S. K.; Goddard, R.; List, B. J. Am. Chem.
Soc. 2008, 130, 15786–15787. DOI: 10.1021/ja8071034. (m) Bharate, S. B.; Mupparapu, N.;
Manda, S.; Bharate, J. B.; Mudududdla, R.; Yadav, R. R.; Vishwakarma, R. A. ARKIVOC
2012, 8, 308. (n) Zeng, L.-Y.; Cai, C. J. Heterocyclic Chem. 2010, 47, 1035–1039. DOI: 10.
1002/jhet.414.
[14] (a) Kumar, S. P.; Murthy, V. N.; Ganesh, K. R.; Rao, G. S.; Krishnaji, T.; Raghunadh, A.
Chem. Select 2018, 3, 6836. (b) Jaganmohan, C.; Kumar, K. P. V.; Reddy, G. S.; Mohanty,
S.; Kumar, J.; Rao, B. V.; Krishnaji, T.; Raghunadh, A. Synth. Commun. 2018, 48,
168–174. DOI: 10.1080/00397911.2017.1391291. (c) Murthy, V. N.; Nikumbh, S. P.;
Tadiparthi, K.; Madhubabu, M. V.; Jammula, S. R.; Rao, L. V.; Raghunadh, A. RSC Adv.
2018, 8, 22331–22334. DOI: 10.1039/C8RA03308K. (d) Madhubabu, M. V.; Shankar, R.;
More, S. S.; Basaveswara Rao, M. V.; Kumar, U. K. S.; Raghunadh, A. RSC Adv. 2016, 6,
36599–36601. DOI: 10.1039/C5RA28097D. (e) Raghavendra, R.; Ramamohan, K.;
Raghunadh, M.; Suresh, A.; Praveen, B. M.; Kalita, K. S.; Laxminarayana, D.; Prasad, E.;
Pal, B. RSC Adv. 2015, 5, 61575–61579. DOI: 10.1039/C5RA10928K. (f) R.
Venkateshwarlu, V. N. Murthy, T. Krishnaji, S. P. Nikumbh, R. Jinkala, V. Siddaiah, M.
V. M. babu, H. Rama Mohan and A. Raghunadh RSC Adv., 2020, 10, 9486–9491.