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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

General Research Article

Preliminary Anti-Coxsackie Activity of Novel 1-[4-(5,6-dimethyl(H)- 1H(2H)-benzotriazol-1(2)-yl)phenyl]-3-alkyl(aryl)ureas

Author(s): Sandra Piras, Paola Corona, Roberta Ibba, Federico Riu, Gabriele Murineddu, Giuseppina Sanna, Silvia Madeddu, Ilenia Delogu, Roberta Loddo* and Antonio Carta*

Volume 16, Issue 5, 2020

Page: [677 - 688] Pages: 12

DOI: 10.2174/1573406416666191226142744

Price: $65


Background: Coxsackievirus infections are associated with cases of aseptic meningitis, encephalitis, myocarditis, and some chronic disease.

Methods: A series of benzo[d][1,2,3]triazol-1(2)-yl derivatives (here named benzotriazol-1(2)-yl) (4a-i, 5a-h, 6a-e, g, i, j and 7a-f, h-j) were designed, synthesized and in vitro evaluated for cytotoxicity and antiviral activity against two important human enteroviruses (HEVs) members of the Picornaviridae family [Coxsackievirus B 5 (CVB-5) and Poliovirus 1 (Sb-1)].

Results: Compounds 4c (CC50 >100 μM; EC50 = 9 μM), 5g (CC50 >100 μM; EC50 = 8 μM), and 6a (CC50 >100 μM; EC50 = 10 μM) were found active against CVB-5. With the aim of evaluating the selectivity of action of this class of compounds, a wide spectrum of RNA (positive- and negativesense), double-stranded (dsRNA) or DNA viruses were also assayed. For none of them, significant antiviral activity was determined.

Conclusion: These results point towards a selective activity against CVB-5, an important human pathogen that causes both acute and chronic diseases in infants, young children, and immunocompromised patients.

Keywords: Benzotriazole derivatives, antiviral activity, enterovirus, coxsackievirus, cytotoxicity, rna virus, picornaviridae.

Graphical Abstract
Briguglio, I.; Piras, S.; Corona, P.; Gavini, E.; Nieddu, M.; Boatto, G.; Carta, A. Benzotriazole: An overview on its versatile biological behavior. Eur. J. Med. Chem., 2015, 97, 612-648.
[] [PMID: 25293580]
Paglietti, G.; Sanna, P.; Carta, A.; Sparatore, F.; Vazzana, I.; Peana, A.; Satta, M. Choleretic activity of 3-[ring substituted benzotriazol-1(2)-yl]alkanoic and alkenoic acids. Farmaco, 1994, 40(11), 693-702.
[PMID: 7832971]
Fromtling, R.A. Overview of medically important antifungal azole derivatives. Clin. Microbiol. Rev., 1988, 1(2), 187-217.
[] [PMID: 3069196]
Jamkhandi, C.M.; Disouza, J.I. Benzotriazole derivatives as antimicrobial Agents. Asian J. Biochem. Pharm. Res., 2012, 2(3), 123-130.
López-Vallejo, F.; Castillo, R.; Yépez-Mulia, L.; Medina-Franco, J.L. Benzotriazoles and indazoles are scaffolds with biological activity against Entamoeba histolytica. J. Biomol. Screen., 2011, 16(8), 862-868.
[] [PMID: 21821786]
Borowski, P.; Deinert, J.; Schalinski, S.; Bretner, M.; Ginalski, K.; Kulikowski, T.; Shugar, D. Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses. Eur. J. Biochem., 2003, 270(8), 1645-1653.
[] [PMID: 12694177]
Carta, A.; Briguglio, I.; Piras, S.; Boatto, G.; La Colla, P.; Loddo, R.; Tolomeo, M.; Grimaudo, S.; Di Cristina, A.; Pipitone, R.M.; Laurini, E.; Paneni, M.S.; Posocco, P.; Fermeglia, M.; Pricl, S. 3-Aryl-2-[1H-benzotriazol-1-yl]acrylonitriles: a novel class of potent tubulin inhibitors. Eur. J. Med. Chem., 2011, 46(9), 4151-4167.
[] [PMID: 21741130]
Christian, K.A.; Ijaz, K.; Dowell, S.F.; Chow, C.C.; Chitale, R.A.; Bresee, J.S.; Mintz, E.; Pallansch, M.A.; Wassilak, S.; McCray, E.; Arthur, R.R. What we are watching--five top global infectious disease threats, 2012: a perspective from CDC’s Global Disease Detection Operations Center. Emerg. Health Threats J., 2013, 6(1), 20632.
[] [PMID: 23827387]
Zell, R.; Delwart, E.; Gorbalenya, A.E.; Hovi, T.; King, A.M.Q.; Knowles, N.J.; Lindberg, A.M.; Pallansch, M.A.; Palmenberg, A.C.; Reuter, G.; Simmonds, P.; Skern, T.; Stanway, G.; Yamashita, T. Ictv Report Consortium. ICTV Virus Taxonomy Profile: Picornaviridae. J. Gen. Virol., 2017, 98(10), 2421-2422.
[] [PMID: 28884666]
Pallansch, M.A.; Oberste, M.S.; Enteroviruses, J.L.W. Enteroviruses: Polioviruses, Coxsackieviruses, Echoviruses, and Newer Enteroviruses Fields Virology; Pa. Wolters Kluwer; Lippincott Williams Wilkins: Philadelphia, USA, 2013, pp. 491-530.
Racaniello, V.R. Picornaviridae: The Viruses and Their Replication Fields Virology; Wolters Kluwer Health/Lippincott Williams Wilkins: Philadelphia, USA, 2007, pp. 795-838.
Tapparel, C.; Siegrist, F.; Petty, T.J.; Kaiser, L. Picornavirus and enterovirus diversity with associated human diseases. Infect. Genet. Evol., 2013, 14, 282-293.
[] [PMID: 23201849]
Khetsuriani, N.; Lamonte-Fowlkes, A.; Oberst, S.; Pallansch, M.A. Centers for Disease Control and Prevention. Enterovirus surveillance--United States, 1970-2005. MMWR Surveill. Summ., 2006, 55(8), 1-20.
[PMID: 16971890]
Lugo, D.; Krogstad, P. Enteroviruses in the early 21st century: new manifestations and challenges. Curr. Opin. Pediatr., 2016, 28(1), 107-113.
[] [PMID: 26709690]
Yu, W.; Tellier, R.; Wright, J.R., Jr Coxsackie virus A16 infection of placenta with massive perivillous fibrin deposition leading to intrauterine fetal demise at 36 weeks gestation. Pediatr. Dev. Pathol., 2015, 18(4), 331-334.
[] [PMID: 25826430]
Lagae, D.; Rigo, V.; Senterre, J-M.; Kalenga, M.; Piérart, J. Early Enterovirus neonatal infection: when should we think about it? Rev. Med. Liege, 2016, 71(2), 78-82.
[PMID: 27141650]
Betancourt, W.; Shulman, L. Polioviruses and Other Enteroviruses.Global Water Pathogen Project; Meschke, J.S; Girones, R., Ed.; Michigan State University, 2018.
Zhong, Q.; Yang, Z.; Liu, Y.; Deng, H.; Xiao, H.; Shi, L.; He, J. Antiviral activity of Arbidol against Coxsackie virus B5 in vitro and in vivo. Arch. Virol., 2009, 154(4), 601-607.
[] [PMID: 19291363]
Wang, Y.X.; Li, Y.H.; Li, Y.H.; Gao, R.M.; Wang, H.Q.; Liu, Y.X.; Gao, L.M.; Lu, Q.N.; Jiang, J.D.; Song, D.Q. Synthesis, structure-activity relationship and in vitro biological evaluation of N-arylethyl isoquinoline derivatives as Coxsackievirus B3 inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(19), 5787-5790.
[] [PMID: 21880491]
Aguado, L.; Thibaut, H.J.; Priego, E.M.; Jimeno, M.L.; Camarasa, M.J.; Neyts, J.; Pérez-Pérez, M.J. 9-Arylpurines as a novel class of enterovirus inhibitors. J. Med. Chem., 2010, 53(1), 316-324.
[] [PMID: 19924996]
Ji, X.Y.; Zhong, Z.J.; Xue, S.T.; Meng, S.; He, W.Y.; Gao, R.M.; Li, Y.H.; Li, Z.R. Synthesis and antiviral activities of synthetic glutarimide derivatives. Chem. Pharm. Bull. (Tokyo), 2010, 58(11), 1436-1441.
[] [PMID: 21048333]
Zanetti, S.; Sechi, L.A.; Molicotti, P.; Cannas, S.; Bua, A.; Deriu, A.; Carta, A.; Paglietti, G. In vitro activity of new quinoxalin 1,4-dioxide derivatives against strains of Mycobacterium tuberculosis and other mycobacteria. Int. J. Antimicrob. Agents, 2005, 25(2), 179-181.
[] [PMID: 15664491]
Sanna, P.; Carta, A.; Paglietti, G.; Zanetti, S.; Fadda, G. 1,2,3-triazolo[4,5-h]quinolines. III. Preparation and antimicrobial evaluation of 4-ethyl-4,7-dihydro-1(2)-R-1(2)H triazolo[4,5-h]quinolin-7-one-6-carboxylic acids as anti-infectives of the urinary tract. Farmaco, 1992, 47(7-8), 1001-1019.
[PMID: 1332728]
Briguglio, I.; Loddo, R.; Laurini, E.; Fermeglia, M.; Piras, S.; Corona, P.; Giunchedi, P.; Gavini, E.; Sanna, G.; Giliberti, G.; Ibba, C.; Farci, P.; La Colla, P.; Pricl, S.; Carta, A. Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. Eur. J. Med. Chem., 2015, 105, 63-79.
[] [PMID: 26479028]
Carta, A.; Sanna, G.; Briguglio, I.; Madeddu, S.; Vitale, G.; Piras, S.; Corona, P.; Peana, A.T.; Laurini, E.; Fermeglia, M.; Pricl, S.; Serra, A.; Carta, E.; Loddo, R.; Giliberti, G. Quinoxaline derivatives as new inhibitors of coxsackievirus B5. Eur. J. Med. Chem., 2018, 145, 559-569.
[] [PMID: 29339251]
Ibba, R.; Corona, P.; Carta, A.; Giunchedi, P.; Loddo, R.; Sanna, G.; Delogu, I.; Piras, S. Antiviral Activities of 5-Chlorobenzotriazole Derivatives. Monatsh. Chem., 2018, 149(7), 1247-1256.
Piras, S.; Sanna, G.; Carta, A.; Corona, P.; Ibba, R.; Loddo, R.; Madeddu, S.; Caria, P.; Aulic, S.; Laurini, E.; Fermeglia, M.; Pricl, S. Dichloro-phenyl-benzotriazoles: A new selective class of human respiratory syncytial virus entry inhibitors. Front Chem., 2019, 7, 247.
[] [PMID: 31041309]
Loddo, R.; Novelli, F.; Sparatore, A.; Tasso, B.; Tonelli, M.; Boido, V.; Sparatore, F.; Collu, G.; Delogu, I.; Giliberti, G.; La Colla, P. Antiviral activity of benzotriazole derivatives. 5-[4-(Benzotriazol-2-yl)phenoxy]-2,2-dimethylpentanoic acids potently and selectively inhibit Coxsackie Virus B5. Bioorg. Med. Chem., 2015, 23(21), 7024-7034.
[] [PMID: 26443549]
Loddo, R.; Briguglio, I.; Corona, P.; Piras, S.; Loriga, M.; Paglietti, G.; Carta, A.; Sanna, G.; Giliberti, G.; Ibba, C.; Farci, P.; La Colla, P. Synthesis and antiviral activity of new phenylimidazopyridines and N-benzylidenequinolinamines derived by molecular simplification of phenylimidazo[4,5-g]quinolines. Eur. J. Med. Chem., 2014, 84, 8-16.
[] [PMID: 25014745]
Fiore, L.; Buttinelli, G.; Fiore, S. 2013 Available at:.
Carta, A.; Loriga, G.; Piras, S.; Paglietti, G.; Ferrone, M.; Fermeglia, M.; Pricl, S.; La Colla, P.; Secci, B.; Collu, G.; Loddo, R. Synthesis and in vitro evaluation of the anti-viral activity of N-[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkylcarboxamides. Med. Chem., 2006, 2(6), 577-589.
[] [PMID: 17105439]
Carta, A.; Loriga, M.; Piras, S.; Paglietti, G.; Ferrone, M.; Fermeglia, M.; Pricl, S.; La Colla, P.; Collu, G.; Sanna, T.; Loddo, R. Synthesis and anti-picornaviridae in vitro activity of a new class of helicase inhibitors the N,N′-bis[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl] alkyldicarboxamides. Med. Chem., 2007, 3(6), 520-532.
[] [PMID: 18045201]
Carta, A.; Briguglio, I.; Piras, S.; Corona, P.; Boatto, G.; Nieddu, M.; Giunchedi, P.; Marongiu, M.E.; Giliberti, G.; Iuliano, F.; Blois, S.; Ibba, C.; Busonera, B.; La Colla, P. Quinoline tricyclic derivatives. Design, synthesis and evaluation of the antiviral activity of three new classes of RNA-dependent RNA polymerase inhibitors. Bioorg. Med. Chem., 2011, 19(23), 7070-7084.
[] [PMID: 22047799]
Nieddu, M.; Boatto, G.; Pirisi, M.A.; Azara, E.; Marchetti, M. LC-MS analysis of trimethoxyamphetamine designer drugs (TMA series) from urine samples. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2008, 867(1), 126-130.
[] [PMID: 18417429]
Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter, J.; De Clercq, E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods, 1988, 20(4), 309-321.
[] [PMID: 2460479]
Sanna, G.; Farci, P.; Busonera, B.; Murgia, G.; La Colla, P.; Giliberti, G. Antiviral properties from plants of the Mediterranean flora. Nat. Prod. Res., 2015, 29(22), 2065-2070.
[] [PMID: 25613403]

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