Page 5 of 6
ACS Medicinal Chemistry Letters
5. Sangshetti, J. N.; Kalam Khan, F. A.; Kulkarni, A. A.; Aroteb,
R.; Patil, R. H. Antileishmanial drug discovery: comprehensive re-
view of the last 10 years. RSC Adv. 2015, 5, 32376-32415.
*For B.Š.: phone, +381-11-263-86-06; fax, +381-11-263-60-61;
*For N.B.: phone, +39-02 5031-5069; fax: +39-02-5031-5093;
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2
3
4
5
6
7
8
6. Gillespie, P. M.; Beaumier, C. M.; Strych, U.; Hayward, T.; Ho-
tez, P. J.; Bottazzi, M. E. Status of Vaccine Research and Develop-
ment of Vaccines for Leishmaniasis. Vaccine 2016, 34, 2992-2995.
7. Thompson, A. M.; O’Connor, P. D.; Marshall, A. J.; Yardley,
V.; Maes, L.; Gupta, S.; Launay, D.; Braillard, S.; Chatelain, E.;
Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Cooper, C. B.; Denny,
W. A. 7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines:
Novel Antitubercular Agents Lead to a New Preclinical Candidate for
Visceral Leishmaniasis. J. Med. Chem. 2017, 60, 4212-4233.
8. Carmo, A. M. L.; Silva, F. M. C.; Machado, P. A.; Fontes, A. P.
S.; Pavan, F. R.; Leite, C. Q. F.; Leite, S. R. de A.; Coimbra, E. S.; Da
Silva, A. D. Synthesis of 4-Aminoquinoline Analogues and Their
Platinum(II) Complexes as New Antileishmanial and Antitubercular
agents. Biomed. Pharmacother. 2011, 65, 204–209. and ref. therein.
9. Antinarelli, L. M. R.; Dias, R. M. P.; Souza, I. O.; Lima, W. P.;
Gameiro, J.; da Silva, A. D.; Coimbra, E. S. 4-Aminoquinoline Deriv-
atives as Potential Antileishmanial Agents. Chem. Biol. Drug Des.
2015, 86, 704-714.
Author Contributions
B.Š. and N.B. designed the research. The manuscript was written
by J.K. with contributions of all authors. All authors have given
approval to the final version of the manuscript.
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Funding Sources
This work was supported by the Ministry of Science and Techno-
logical Development of Serbia (Grant 172008), Serbian Academy
of Sciences and Arts, Executive Programme of Scientific and
Technological Cooperation between the Italian Republic and the
Republic of Serbia for the years 2016-2018 and by “Ministero
dell’Istruzione, dell’Università e della Ricerca (PRIN) Project:
20154JRJPP_004”.
10. Soares, R. R.; Antinarelli, L. M. R.; Souza, I. O.; Lopes, F. V.;
Scopel, K. K. G.; Coimbra, E. S.; da Silva, A. D.; Abramo, C. In Vivo
Antimalarial and In Vitro Antileishmanial Activity of 4- Aminoquino-
line Derivatives Hybridized to Isoniazid or Sulfa or Hydrazine
Groups. Lett. Drug Des. Discov. 2017, 14, 597 – 604.
11. Antinarelli, L. M. R.; Carmo, A. M. L.; Pavan, F. R.; Leite, C.
Q. F.; Da Silva, A. D.; Coimbra, E. S.; Salunke, D. B. Increase of
Leishmanicidal and Tubercular Activities Using Steroids Linked to
Aminoquinoline. Org. Med. Chem. Lett. 2012, 2, 16.
12. Terzić, N.; Konstantinović, J.; Tot, M.; Burojević, J.;
Djurković-Djaković, O.; Srbljanović, J.; Štajner, T.; Verbić, T.; Zla-
tović, M.; Machado, M.; Albuquerque, I. S.; Prudêncio, M.; Sciotti, R.
J.; Pecic, S.; D’Alessandro, S.; Taramelli, D.; Šolaja, B. A. Reinvesti-
gating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes
Potential Two-Stage Antimalarials? J. Med. Chem. 2016, 59, 264 –
281.
13. Konstantinović, J.; Videnović, M.; Srbljanović, J.; Djurković-
Djaković, O.; Bogojević, K.; Sciotti, R.; Šolaja, B. Antimalarials With
Benzothiophene Moieties as Aminoquinoline Partners. Molecules
2017, 22, 343.
14. Konstantinović, J.; Kiris, E.; Kota, K.; Kugelman-Tonos, J.;
Videnović, M.; Cazares, L. H.; Terzić, N.; Verbić, T. Ž.; Andjelković,
B.; Duplantier, A. J.; Bavari, S.; Šolaja, B. A. New Steroidal 4-
Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in
Mouse Embryonic Stem Cell Derived Motor Neurons in Post-
intoxication Model. J. Med. Chem. 2018, 61, 1595-1608.
15. Marković, O. S.; Cvijetić, I. N.; Zlatović, M. V.; Opsenica, I.
M.; Konstantinović, J. M.; Terzić Jovanović, N. V.; Šolaja, B. A.;
Verbić, T. Ž. Human Serum Albumin Binding of Certain Antimalari-
als. Spectrochim. Acta Mol. Biomol. Spectrosc. 2018, 192, 128-139.
16. Šolaja, B. A.; Opsenica, D.; Smith, K. S.; Milhous, W. K.; Ter-
zic, N.; Opsenica, I.; Burnett, J. C.; Nuss, J.; Gussio, R.; Bavari, S.
Novel 4-Aminoquinolines Active against Chloroquine-Resistant and
Sensitive P. falciparum Strains that also Inhibit Botulinum Serotype
A. J. Med. Chem. 2008, 51, 4388−4391.
17. Gerster, J. F.; Lindstrom, K. J.; Miller, R. L.; Tomai, M. A.;
Birmachu, W.; Bomersine, S. N.; Gibson, S. J.; Imbertson, L. M.; Ja-
cobson, J. R.; Knafla, R. T.; Maye, P. V.; Nikolaides, N.; Oneyemi, F.
Y.; Parkhurst, G. J.; Pecore, S. E.; Reiter, M. J.; Scribner, L. S.;
Testerman, T. L.; Thompson, N. J.; Wagner, T. L.; Weeks, C. E.; An-
dre, J.-D.; Lagain, D.; Bastard, Y.; Lupu, M. Synthesis and Struc-
ture−Activity-Relationships of 1H-Imidazo[4,5-c]quinolines That In-
duce Interferon Production. J. Med. Chem. 2005, 48, 3481–3491.
18. Korotchenko,V.; Sathunuru,R.; Gerena, L.; Caridha, D.; Li, Q.;
Kreishman-Deitrick, M.; Smith, P. L.; Lin, A. J. Antimalarial Activity
of 4-Amidinoquinoline and 10- Amidinobenzonaphthyridine Deriva-
tives. J. Med. Chem. 2015, 58, 3411-3431.
Notes
The authors declare no competing financial interest.
Ethical approval: The study followed the International Guiding
Principles for biomedical research involving animals (European
Directive 2010/63/UE), and it was reviewed by a local Ethics
Committees. The study was approved by the Veterinary Direc-
torate at the Ministry of Agriculture and Environmental Protection
of Serbia (decision no. 323-07-02444/2014-05/1) and by the Di-
rectorate of Animal Health and Veterinary Drugs at the Ministry
of Health of Italy (authorization no. 120/2015-PR).
ACKNOWLEDGMENT
We thank Dr. Olgica Djurković-Djaković and MSc Jelena Srblja-
nović (Institute for Medical Research, University of Belgrade) for
performing in vivo toxicity studies and Loredana Cavicchini for
assistance in culturing leishmania in vitro. We also thank Prof.
Donatella Taramelli (Dipartimento di Scienze Farmacologiche e
Biomolecolari, University of Milan) for helpful discussion, and
COST Action CM1307 for support.
ABBREVIATIONS
BMDM, murine bone marrow-derived macrophages; MTT, 3-
(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium
Tween 80, Polysorbate 80; HEC, hydroxyethyl cellulose; ROS,
reactive oxygen species; MOA, mechanism of action; AQ3, N-(7-
chloroquinolin-4-yl)propane-1,3-diamine.
Bromide;
REFERENCES
1. Leishmaniasis, Fact Sheet N°375, February 2015.
ber 16, 2017).
2. Centers for Disease Control and Prevention, Parasites - Leish-
(accessed October 16, 2017).
3. WHO Technical Report Series no. 949, Report of a Meeting of
the WHO Expert Committee on the Control of Leishmaniases, Gene-
va,
22–26
March
2010.
(accessed October 16, 2017).
March 22, 2018).
19. Dea-Ayuela, M. A.; Castillo, E.; Gonzalez-Alvarez, M.; Vega,
C.; Rolón, M.; Bolás-Fernández, F.; Borrás, J.; González-Rosende, M.
E. In Vivo and in Vitro Anti-leishmanial Activities of 4-Nitro-N-
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