Abstract
HSV disease is distributed worldwide. Anti-herpesvirus drugs are a problem in clinical settings, particularly in immunocompromised individuals undergoing herpes simplex virus type 1 infection. In this work, 4-substituted-1,2,3-1H-1,2,3-triazole linked nitroxyl radical derived from TEMPOL were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. The nitroxide derivatives were characterized by infrared spectroscopy and elemental analysis, and three of them had their crystal structures determined by single-crystal X-ray diffraction. Four hybrid molecules showed important anti-HSV-1 activity with IC50 values ranged from 0.80 to 1.32 µM. In particular, one of the nitroxide derivatives was more active than Acyclovir (IC50 = 0.99 µM). All compounds tested were more selective inhibitors than the reference antiviral drug. Among them, two compounds were 4.5 (IC50 0.80 µM; selectivity index CC50/IC50 3886) and 7.7 times (IC50 1.10 µM; selectivity index CC50/IC50 6698) more selective than acyclovir (IC50 0.99 µM; selectivity index CC50/IC50: 869). These nitroxide derivatives may be elected as leading compounds due to their antiherpetic activities and good selectivity.
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Nicoll MP, Proença JT, Efstathiou S (2012) The molecular basis of herpes simplex virus latency. FEMS Microbiol Rev 36:684–705. https://doi.org/10.1111/j.1574-6976.2011.00320.x
Rajasagi NK, Rouse BT (2019) The role of T cells in herpes stromal keratitis. Front Immunol 10:1–7. https://doi.org/10.3389/fimmu.2019.00512
Zhurilo NI, Chudinov MV, Matveev AV, Smirnova OS, Konstantinova ID, Miroshnikov AI, Prutkov AN, Grebenkina LE, Pulkova NV, Shvets VI (2018) Isosteric ribavirin analogues: synthesis and antiviral activities. Bioorg Med Chem Lett 28:11–14. https://doi.org/10.1016/j.bmcl.2017.11.029
Dheer D, Singh V, Shankar R (2017) Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg Chem 71:30–54. https://doi.org/10.1016/j.bioorg.2017.01.010
Poole CL, James SH (2018) Antiviral therapies for herpesviruses: current agents and new directions. Clin Ther 40:1282–1298. https://doi.org/10.1016/j.clinthera.2018.07.006
Czartoski T, Liu C, Koelle DM, Schmechel S, Kalus A, Wald A (2006) Fulminant, acyclovir-resistant, herpes simplex virus type 2 hepatitis in an immunocompetent woman. J Clin Microbiol 44:1584–1586. https://doi.org/10.1128/JCM.44.4.1584-1586.2006
Chen Y, Scieux C, Garrait V, Socié G, Rocha V, Molina JM, Thouvenot D, Morfin F, Hocqueloux L, Garderet L, Espérou H, Sélimi F, Devergie A, Leleu G, Aymard M, Morinet F, Gluckman E, Ribaud P (2000) Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation. Clin Infect Dis 31:927–935. https://doi.org/10.1086/314052
Reusser P (2002) Management of viral infections in immunocompromised cancer patients. Swiss Med Wkly 132:374–378. https://doi.org/10.4414/smw.2002.09875
Wathen MW (2002) Non-nucleoside inhibitors of herpesviruses. Rev Med Virol 12:167–178. https://doi.org/10.1002/rmv.354
De Clerq E (2003) New inhibitors of human cytomegalovirus (HCMV) on the horizon. J Antimicrob Chemother 51:1079–1083. https://doi.org/10.1093/jac/dkg205
Hammond JL, Koontz DL, Bazmi HZ, Beadle JR, Hostetler SE, Kini GD, Aldern KA, Richman DD, Hostetler KY, Mellors JW (2001) Alkylglycerol prodrugs of phosphonoformate are potent in vitro inhibitors of nucleoside-resistant human immunodeficiency virus type 1 and select for resistance mutations that suppress zidovudine resistance. Antimicrob Agents Chemother 45:1621–1628. https://doi.org/10.1128/AAC.45.6.1621-1628.2001
Mohamed SF, Flefel EM, Amr AEGE, Abd El-Shafy DN (2010) Anti-HSV-1 activity and mechanism of action of some new synthesized substituted pyrimidine, thiopyrimidine and thiazolopyrimidine derivatives. Eur J Med Chem 45:1494–1501. https://doi.org/10.1016/j.ejmech.2009.12.057
Wen Y, Zhang Z, Liu N-N, Andrei G, Snoeck R, Xiang Y-H, Schols D, Chen X, Zhang Z-Y, Zhang Q-S, Wu Q-P (2017) Synthesis and antiviral activity of 5-(benzylthio)-4-carbamyl-1,2,3-triazoles against human cytomegalovirus (CMV) and varicella-zoster virus (VZV). Med Chem 13:453–464. https://doi.org/10.2174/1573406413666170307165236
Mohamed SF, Abbas EMH, Khalaf HS, Farghaly TA, Abd El-Shafy D (2017) Triazolopyrimidines and thiazolopyrimidines: synthesis, anti-HSV-1, cytotoxicity and mechanism of action. Mini-Rev Med Chem 18:794–802. https://doi.org/10.2174/1389557518666171207161542
Jordão AK, Ferreira VF, Souza TML, Faria GGS, Machado V, Abrantes JL, de Souza MCBV, Cunha AC (2011) Synthesis and anti-HSV-1 activity of new 1,2,3-triazole derivatives. Bioorg Med Chem 19:1860–1865. https://doi.org/10.1016/j.bmc.2011.02.007
Khan FY, Elhiday A, Khudair IF, Youssef H, Omran AH, Alsamman SH, Elhamid M (2012) Evaluation of the use of piperacillin/tazobactam (Tazocin®) at Hamad General Hospital, Qatar: are there unjustified prescriptions? Infect Drug Resist 5:17–21. https://doi.org/10.2147/idr.s27965
Long TE, Williams JT (2014) Cephalosporins currently in early clinical trials for the treatment of bacterial infections. Expert Opin Investig Drugs 23:1375–1387. https://doi.org/10.1517/13543784.2014.930127
Wheless JW, Vazquez B (2010) Rufinamide: a novel broad-spectrum antiepileptic drug. Epilepsy Curr 10:1–6. https://doi.org/10.1111/j.1535-7511.2009.01336.x
Wang Y, Cong C, Chai WC, Dong R, Jia L, Song D, Zhou Z, Ma S (2017) Synthesis and antibacterial activity of novel 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs. Bioorg Med Chem Lett 27:3872–3877. https://doi.org/10.1016/j.bmcl.2017.06.044
Gonzaga DTG, Souza TML, Andrade VMM, Ferreira VF, da Silva FC (2018) Identification of 1-Aryl-1H-1,2,3-triazoles as Potential New Antiretroviral Agents. Med Chem 14:242–248. https://doi.org/10.2174/1573406413666170906121318
Jordão AK, Ferreira VF, Lima ES, de Souza MCBV, Carlos ECL, Castro HC, Geraldo RB, Rodrigues CR, Almeida MCB, Cunha AC (2009) Synthesis, antiplatelet and in silico evaluations of novel N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides. Bioorg Med Chem 17:3713–3719. https://doi.org/10.1016/j.bmc.2009.03.053
An R, Hou Z, Li J-T, Yu H-N, Mou Y-H, Guo C (2018) Design, synthesis and biological evaluation of novel 4-substituted coumarin derivatives as antitumor agents. Molecules 23:2281–2292. https://doi.org/10.3390/molecules23092281
Kaur P, Chawla A (2018) Green synthesis, structural characterization and pharmacological evaluation for analgesic and anti-inflammatory activities of salicylic acid based triazolothiadiazole derivatives. Eur J Biomed Pharm Sci 5:472–479
Jordão AK, Sathler PC, Ferreira VF, Campos VR, de Souza MCBV, Castro HC, Lannes A, Lourenço A, Rodrigues CR, Bello ML, Lourenço MCS, Carvalho GSL, Almeida MCB, Cunha AC (2011) Synthesis, antitubercular activity, and SAR study of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides. Bioorg Med Chem 19:5605–5611. https://doi.org/10.1016/j.bmc.2011.07.035
Fedoreyev SA, Krylova NV, Mishchenko NP, Vasileva EA, Pislyagin EA, Iunikhina NP, Lavrov VF, Svitich AO, Ebralidze LK, Loenova GN (2018) Antiviral and antioxidant properties of echinochrome A. Mar Drugs 16:509–518. https://doi.org/10.3390/md16120509
Rehman ZU, Meng C, Sun Y, Safdar A, Pasha RH, Munir M, Ding C (2018) Oxidative stress in poultry: lessons from the viral infections. Oxid Med Cell Longev. https://doi.org/10.1155/2018/5123147
Linares E, Giorgio S, Augusto O (2008) Inhibition of in vivo leishmanicidal mechanisms by tempol: Nitric oxide down-regulation and oxidant scavenging. Free Radic Biol Med 44:1668–1676. https://doi.org/10.1016/j.freeradbiomed.2008.01.027
Lewandowski M, Gwozdzinski K (2017) Nitroxides as antioxidants and anticancer drugs. Int J Mol Sci 18:2490–2515. https://doi.org/10.3390/ijms18112490
Thomas K, Moody TW, Jensen RT, Tong J, Rayner CL, Barnett NL, Fairfull-Smith KE, Ridnour LA, Wink DA, Bottle SE (2018) Design, synthesis and biological evaluation of hybrid nitroxide-based non-steroidal anti-inflammatory drugs. Eur J Med Chem 147:34–47. https://doi.org/10.1016/j.ejmech.2018.01.077
Nunes DVQ, Costa CA, De Bem GF, Cordeiro VSC, Santos IB, Carvalho LCRM, Jordão AK, Cunha AC, Ferreira VF, Moura RS, Resende AC, Ognibene DT (2018) Tempol, a superoxide dismutase-mimetic drug, prevents chronic ischemic renal injury in two-kidney, one-clip hypertensive rats. Clin Exp Hypertens 40:721–729. https://doi.org/10.1080/10641963.2018.1425423
Queiroz RF, Jordão AK, Cunha AC, Ferreira VF, Brigagão MRPL, Malvezzi A, de Amaral AT, Augusto O (2012) Nitroxides attenuate carrageenan-induced inflammation in rat paws by reducing neutrophil infiltration and the resulting myeloperoxidase-mediated damage. Free Radic Biol Med 53:1942–1953. https://doi.org/10.1016/j.freeradbiomed.2012.09.001
Wang H, Gao P, Jing L, Qin X, Sun X (2012) The heart-protective mechanism of nitronyl nitroxide radicals on murine viral myocarditis induced by CVB3. Biochimie 94:1951–1959. https://doi.org/10.1016/j.biochi.2012.05.015
Soule BP, Hyodo F, Matsumoto K-I, Simone NL, Cook JA, Krishna MC, Mitchell JB (2007) The chemistry and biology of nitroxide compounds. Free Radic Biol Med 42:1632–1650. https://doi.org/10.1016/j.freeradbiomed.2007.02.030
Wilcox CS (2010) Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther 126:119–145. https://doi.org/10.1016/j.pharmthera.2010.01.003
Howieson VM, Tran E, Hoegl A, Fam HL, Fu J, Sivonen K, Li XX, Auclair K, Saliba KJ (2016) Triazole substitution of a labile amide bond stabilizes pantothenamides and improves their antiplasmodial potency. Antimicrob Agents Chemother 60:7146–7152. https://doi.org/10.1128/AAC.01436-16
Bahia SBBB, Reis WJ, Jardim GAM, Souto FT, de Simone CA, Gatto CC, Menna-Barreto RFS, de Castro SL, Cavalcanti BC, Pessoa C, Araújo MH, da Silva Júnior EN (2016) Molecular hybridization as a powerful tool towards multitarget quinoidal systems: synthesis, trypanocidal and antitumor activities of naphthoquinone-based 5-iodo-1,4-disubstituted-, 1,4- and 1,5-disubstituted-1,2,3-triazoles. MedChemComm 7:1555–1563. https://doi.org/10.1039/c6md00216a
Lutz WB, Lazarus S, Meltzer RI (1962) New derivatives of 2,2,6,6-tetramethylpiperidine. J Org Chem 27:1695–1703. https://doi.org/10.1021/jo01052a050
Rauckman EJ, Rosen GM, Abou-Donia MB (1975) Improved methods for the oxidation of secondary amines to nitroxides. Synth Commun 5:409–413. https://doi.org/10.1080/00397917508065573
Zhou B-H, Chen Y-F, Yin G-D, Wu A-X (2006) Synthesis and crystal structure of 4-azido-2,2,6,6-tetramethylpiperidine-1-oxyl free radical. Chinese J Struct Chem 25:127–130
Sheldrick GM (2015) Crystal structure refinement with SHELXL. Acta Cryst Section C Struct Chem C71:3–8. https://doi.org/10.1107/S2053229614024218
Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P, Desmyter J, De Clercq E (1988) Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 20:309–321. https://doi.org/10.1016/0166-0934(88)90134-6
Acknowledgements
Fellowships granted by CAPES and by CNPq (Brazil) are gratefully acknowledged. This work was partially supported by CNPq, FINEP, FAPERJ and UFF. The authors acknowledge LDRX-UFF for using its laboratory facilities.
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Cunha, A.C., Ferreira, V.F., Vaz, M.G.F. et al. Chemistry and anti-herpes simplex virus type 1 evaluation of 4-substituted-1H-1,2,3-triazole-nitroxyl-linked hybrids. Mol Divers 25, 2035–2043 (2021). https://doi.org/10.1007/s11030-020-10094-2
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DOI: https://doi.org/10.1007/s11030-020-10094-2