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Medicinal Chemistry

Editor-in-Chief

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

Research Article

Piroxicam Analogs: Design, Synthesis, Docking Study and Biological Evaluation as Promising Anti-HIV-1 Agents

Author(s): Ali Imani, Sepehr Soleymani, Rouhollah Vahabpour, Zahra Hajimahdi* and Afshin Zarghi*

Volume 18 , Issue 2 , 2022

Published on: 25 January, 2021

Page: [209 - 219] Pages: 11

DOI: 10.2174/1573406417666210125141639

Price: $65

Abstract

Objective: In this study, we describe the synthesis, docking study and biological evaluation of 1,2-benzothiazines 1,1-dioxide derivatives.

Methods: Taking the well-known drug, Piroxicam as a lead compound, we designed and synthesized two series of 1,2-benzothiazines 1,1-dioxide derivatives to assay their ability in inhibition of HIV-1 replication in cell culture.

Results: Most of the new compounds were active in the cell-based anti-HIV-1 assay with EC50 < 50 μM. Among them, compound 7g was found to be the most active molecule.Docking study using 3OYA pdb code on the most active molecule 7g with EC50 values of 10 μM showed a similar binding mode to the HIV integrase inhibitors.

Conclusion: Since all the compounds showed no remarkable cytotoxicity (CC50> 500 μM), the designed scaffold is promising structure for the development of new anti-HIV-1 agents.

Keywords: Synthesis, docking, autodock vina, 1, 2-benzothiazines 1, 1-dioxide, piroxicam, anti-HIV-1, integrase.

Graphical Abstract
[1]
Gallo, R.C.; Sarin, P.S.; Gelmann, E.P.; Robert-Guroff, M.; Richardson, E.; Kalyanaraman, V.S.; Mann, D.; Sidhu, G.D.; Stahl, R.E.; Zolla-Pazner, S.; Leibowitch, J.; Popovic, M. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science, 1983, 220(4599), 865-867.
[http://dx.doi.org/10.1126/science.6601823] [PMID: 6601823]
[2]
Chun, T.W.; Fauci, A.S. HIV reservoirs: pathogenesis and obstacles to viral eradication and cure. AIDS, 2012, 26(10), 1261-1268.
[http://dx.doi.org/10.1097/QAD.0b013e328353f3f1] [PMID: 22472858]
[3]
Zhang, F.H.; Debnath, B.; Xu, Z.L.; Yang, L.M.; Song, L.R.; Zheng, Y.T.; Neamati, N.; Long, Y.Q. Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction. Eur. J. Med. Chem., 2017, 125, 1051-1063.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.045] [PMID: 27810592]
[4]
Barton, K.M.; Burch, B.D.; Soriano-Sarabia, N.; Margolis, D.M. Prospects for treatment of latent HIV. Clin. Pharmacol. Ther., 2013, 93(1), 46-56.
[http://dx.doi.org/10.1038/clpt.2012.202] [PMID: 23212106]
[5]
Porter, K.; Babiker, A.; Bhaskaran, K.; Darbyshire, J.; Pezzotti, P.; Porter, K.; Walker, A.S. CASCADE Collaboration. Determinants of survival following HIV-1 seroconversion after the introduction of HAART. Lancet, 2003, 362(9392), 1267-1274.
[http://dx.doi.org/10.1016/S0140-6736(03)14570-9] [PMID: 14575971]
[6]
Ray, M.; Logan, R.; Sterne, J.A.; Hernández-Díaz, S.; Robins, J.M.; Sabin, C.; Bansi, L.; van Sighem, A.; de Wolf, F.; Costagliola, D.; Lanoy, E.; Bucher, H.C.; von Wyl, V.; Esteve, A.; Casbona, J.; del Amo, J.; Moreno, S.; Justice, A.; Goulet, J.; Lodi, S.; Phillips, A.; Seng, R.; Meyer, L.; Pérez-Hoyos, S.; García de Olalla, P.; Hernán, M.A. HIV-CAUSAL Collaboration The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS, 2010, 24(1), 123-137.
[http://dx.doi.org/10.1097/QAD.0b013e3283324283] [PMID: 19770621]
[7]
Levy, J.A. Pathogenesis of human immunodeficiency virus infection. Microbiol. Rev., 1993, 57(1), 183-289.
[http://dx.doi.org/10.1128/MR.57.1.183-289.1993] [PMID: 8464405]
[8]
Gordon, C.P.; Griffith, R.; Keller, P.A. Control of HIV through the inhibition of HIV-1 integrase: a medicinal chemistry perspective. Med. Chem., 2007, 3(2), 199-220.
[http://dx.doi.org/10.2174/157340607780059558] [PMID: 17348857]
[9]
Craigie, R. The molecular biology of HIV integrase. Future Virol., 2012, 7(7), 679-686.
[http://dx.doi.org/10.2217/fvl.12.56] [PMID: 23024700]
[10]
Hazuda, D.J. HIV integrase as a target for antiretroviral therapy. Curr. Opin. HIV AIDS, 2012, 7(5), 383-389.
[http://dx.doi.org/10.1097/COH.0b013e3283567309] [PMID: 22871634]
[11]
Pommier, Y.; Johnson, A.A.; Marchand, C. Integrase inhibitors to treat HIV/AIDS. Nat. Rev. Drug Discov., 2005, 4(3), 236-248.
[http://dx.doi.org/10.1038/nrd1660] [PMID: 15729361]
[12]
McColl, D.J.; Chen, X. Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy. Antiviral Res., 2010, 85(1), 101-118.
[http://dx.doi.org/10.1016/j.antiviral.2009.11.004] [PMID: 19925830]
[13]
Wang, L.D.; Liu, C.L.; Chen, W.Z.; Wang, C.X. Constructing HIV-1 integrase tetramer and exploring influences of metal ions on forming integrase-DNA complex. Biochem. Biophys. Res. Commun., 2005, 337(1), 313-319.
[http://dx.doi.org/10.1016/j.bbrc.2005.08.274] [PMID: 16188234]
[14]
Delelis, O.; Carayon, K.; Saïb, A.; Deprez, E.; Mouscadet, J.F. Integrase and integration: biochemical activities of HIV-1 integrase. Retrovirology, 2008, 5, 114.
[http://dx.doi.org/10.1186/1742-4690-5-114] [PMID: 19091057]
[15]
Lesbats, P.; Engelman, A.N.; Cherepanov, P. Retroviral DNA Integration. Chem. Rev., 2016, 116(20), 12730-12757.
[http://dx.doi.org/10.1021/acs.chemrev.6b00125] [PMID: 27198982]
[16]
Maertens, G.N.; Hare, S.; Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature, 2010, 468(7321), 326-329.
[http://dx.doi.org/10.1038/nature09517] [PMID: 21068843]
[17]
Tandon, V. Urvashi; Yadav, P.; Sur, S.; Abbat, S.; Tiwari, V.; Hewer, R.; Papathanasopoulos, M.A.; Raja, R.; Banerjea, A.C.; Verma, A.K.; Kukreti, S.; Bharatam, P.V. Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors. ACS Med. Chem. Lett., 2015, 6(10), 1065-1070.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00230] [PMID: 26487913]
[18]
Carcelli, M.; Rogolino, D.; Sechi, M.; Rispoli, G.; Fisicaro, E.; Compari, C.; Grandi, N.; Corona, A.; Tramontano, E.; Pannecouque, C.; Naesens, L. Antiretroviral activity of metal-chelating HIV-1 integrase inhibitors. Eur. J. Med. Chem., 2014, 83, 594-600.
[http://dx.doi.org/10.1016/j.ejmech.2014.06.055] [PMID: 24996145]
[19]
Hajimahdi, Z.; Zarghi, A. Progress in HIV-1 integrase inhibitors: A review of their chemical structure diversity. Iran. J. Pharm. Res., 2016, 15(4), 595-628.
[PMID: 28243261]
[20]
Maurin, C.; Bailly, F.; Cotelle, P. Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions. Curr. Med. Chem., 2003, 10(18), 1795-1810.
[http://dx.doi.org/10.2174/0929867033456981] [PMID: 12871105]
[21]
Kirschberg, T.; Parrish, J. Metal chelators as antiviral agents. Curr. Opin. Drug Discov. Devel., 2007, 10(4), 460-472.
[PMID: 17659488]
[22]
Cocohoba, J.; Dong, B.J. Raltegravir: the first HIV integrase inhibitor. Clin. Ther., 2008, 30(10), 1747-1765.
[http://dx.doi.org/10.1016/j.clinthera.2008.10.012] [PMID: 19014832]
[23]
Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D.J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M.V.; Rowley, M. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem., 2008, 51(18), 5843-5855.
[http://dx.doi.org/10.1021/jm800245z] [PMID: 18763751]
[24]
Sato, M.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.; Kawakami, H.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Ikeda, S.; Kodama, E.; Matsuoka, M.; Shinkai, H. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J. Med. Chem., 2006, 49(5), 1506-1508.
[http://dx.doi.org/10.1021/jm0600139] [PMID: 16509568]
[25]
Shimura, K.; Kodama, E.N. Elvitegravir: a new HIV integrase inhibitor. Antivir. Chem. Chemother., 2009, 20(2), 79-85.
[http://dx.doi.org/10.3851/IMP1397] [PMID: 19843978]
[26]
Johns, B.A.; Kawasuji, T.; Weatherhead, J.G.; Taishi, T.; Temelkoff, D.P.; Yoshida, H.; Akiyama, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Jeffrey, J.; Foster, S.A.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Johnson, M.N.; Garvey, E.P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J. Med. Chem., 2013, 56(14), 5901-5916.
[http://dx.doi.org/10.1021/jm400645w] [PMID: 23845180]
[27]
Kawasuji, T.; Johns, B.A.; Yoshida, H.; Weatherhead, J.G.; Akiyama, T.; Taishi, T.; Taoda, Y.; Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Garvey, E.P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J. Med. Chem., 2013, 56(3), 1124-1135.
[http://dx.doi.org/10.1021/jm301550c] [PMID: 23316884]
[28]
Marinello, J.; Marchand, C.; Mott, B.T.; Bain, A.; Thomas, C.J.; Pommier, Y. Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. Biochemistry, 2008, 47(36), 9345-9354.
[http://dx.doi.org/10.1021/bi800791q] [PMID: 18702518]
[29]
Quashie, P.K.; Mesplède, T.; Han, Y-S.; Veres, T.; Osman, N.; Hassounah, S.; Sloan, R.D.; Xu, H.T.; Wainberg, M.A. Biochemical analysis of the role of G118R-linked dolutegravir drug resistance substitutions in HIV-1 integrase. Antimicrob. Agents Chemother., 2013, 57(12), 6223-6235.
[http://dx.doi.org/10.1128/AAC.01835-13] [PMID: 24080645]
[30]
Supuran, C.T.; Innocenti, A.; Mastrolorenzo, A.; Scozzafava, A. Antiviral sulfonamide derivatives. Mini Rev. Med. Chem., 2004, 4(2), 189-200.
[http://dx.doi.org/10.2174/1389557043487402] [PMID: 14965291]
[31]
Lebegue, N.; Gallet, S.; Flouquet, N.; Carato, P.; Pfeiffer, B.; Renard, P.; Léonce, S.; Pierré, A.; Chavatte, P.; Berthelot, P. Novel benzopyridothiadiazepines as potential active antitumor agents. J. Med. Chem., 2005, 48(23), 7363-7373.
[http://dx.doi.org/10.1021/jm0503897] [PMID: 16279796]
[32]
Wells, G.J.; Tao, M.; Josef, K.A.; Bihovsky, R. 1,2-Benzothiazine 1,1-dioxide P2-P3 peptide mimetic aldehyde calpain I inhibitors. J. Med. Chem., 2001, 44(21), 3488-3503.
[http://dx.doi.org/10.1021/jm010178b] [PMID: 11585453]
[33]
Tawada, H.; Sugiyama, Y.; Ikeda, H.; Yamamoto, Y.; Meguro, K. Studies on antidiabetic agents. IX. A new aldose reductase inhibitor, AD-5467, and related 1,4-benzoxazine and 1,4-benzothiazine derivatives: synthesis and biological activity. Chem. Pharm. Bull. (Tokyo), 1990, 38(5), 1238-1245.
[http://dx.doi.org/10.1248/cpb.38.1238] [PMID: 2118427]
[34]
Aslam, S.; Ahmad, M.; Athar, M.M.; Ashfaq, U.A.; Gardiner, J.M.; Montero, C. Synthesis, molecular docking and antiviral screening of novel N′-substitutedbenzylidene-2-(4-methyl-5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-1(4H)-yl)acetohydrazides. Med. Chem. Res., 2014, 23(6), 2930-2946.
[http://dx.doi.org/10.1007/s00044-013-0879-7]
[35]
Barreca, M.L.; Manfroni, G.; Leyssen, P.; Winquist, J.; Kaushik-Basu, N.; Paeshuyse, J.; Krishnan, R.; Iraci, N.; Sabatini, S.; Tabarrini, O.; Basu, A.; Danielson, U.H.; Neyts, J.; Cecchetti, V. Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication. J. Med. Chem., 2013, 56(6), 2270-2282.
[http://dx.doi.org/10.1021/jm301643a] [PMID: 23409936]
[36]
Zia-ur-Rehman, M.; Choudary, J.A.; Ahmad, S.; Siddiqui, H.L. Synthesis of potential biologically active 1,2-benzothiazin-3-yl-quinazolin-4(3H)-ones. Chem. Pharm. Bull. (Tokyo), 2006, 54(8), 1175-1178.
[http://dx.doi.org/10.1248/cpb.54.1175] [PMID: 16880664]
[37]
Zia-ur-Rehman, M.; Choudary, J.A.; Elsegood, M.R.; Siddiqui, H.L.; Khan, K.M. A facile synthesis of novel biologically active 4-hydroxy-N'-(benzylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxides. Eur. J. Med. Chem., 2009, 44(3), 1311-1316.
[http://dx.doi.org/10.1016/j.ejmech.2008.08.002] [PMID: 18804313]
[38]
Christofis, P.; Katsarou, M.; Papakyriakou, A.; Sanakis, Y.; Katsaros, N.; Psomas, G. Mononuclear metal complexes with piroxicam: synthesis, structure and biological activity. J. Inorg. Biochem., 2005, 99(11), 2197-2210.
[http://dx.doi.org/10.1016/j.jinorgbio.2005.07.020] [PMID: 16176832]
[39]
Cini, R. Anti-Inflammatory Compounds as Ligands in Metal Complexes as Revealed in X-Ray Structural Studies. Comments Inorg. Chem., 2006, 22(3-4), 151-186.
[http://dx.doi.org/10.1080/02603590008050867]
[40]
Cini, R.; Giorgi, G.; Cinquantini, A.; Rossi, C.; Sabat, M. Metal Complexes of the Antiinflammatory Drug Piroxicam. Inorg. Chem., 1990, 29(5), 197-5200.
[http://dx.doi.org/10.1021/ic00351a012]
[41]
Safakish, M.; Hajimahdi, Z.; Aghasadeghi, M.R.; Vahabpour, R.; Zarghi, A. Design, synthesis, molecular modeling and anti-HIV assay of novel quinazolinone incorporated coumarin derivatives. Curr. HIV Res., 2020, 18(1), 41-51.
[http://dx.doi.org/10.2174/1570162X17666191210105809] [PMID: 31820700]
[42]
Hajimahdi, Z.; Zabihollahi, R.; Aghasadeghi, M.R.; Zarghi, A. Design, synthesis, docking studies and biological activities novel 2,3-diaryl-4-quinazolinone derivatives as anti-HIV-1 agents. Curr. HIV Res., 2019, 17(3), 214-222.
[http://dx.doi.org/10.2174/1570162X17666190911125359] [PMID: 31518225]
[43]
Hajimahdi, Z.; Zabihollahi, R.; Aghasadeghi, M.R.; Zarghi, A. Design, synthesis and docking studies of new 4-hydroxyquinoline-3-carbohydrazide derivatives as anti-HIV-1 agents. Drug Res. (Stuttg.), 2013, 63(4), 192-197.
[http://dx.doi.org/10.1055/s-0033-1334964] [PMID: 23487403]
[44]
Hajimahdi, Z.; Zarghi, A.; Zabihollahi, R.; Aghasadeghi, M.R. Synthesis, biological evaluation, and molecular modeling studies of new 1,3,4-oxadiazole- and 1,3,4-thiadiazole-substituted 4-oxo-4H-pyrido[1,2-a]pyrimidines as anti-HIV-1 agents. Med. Chem. Res., 2013, 22, 2467-2475.
[http://dx.doi.org/10.1007/s00044-012-0241-5]
[45]
Hajimahdi, Z.; Zabihollahi, R.; Aghasadeghi, M.R.; Ashtiani, S.H.; Zarghi, A. Novel quinolone-3-carboxylic acid derivatives as anti-HIV-1 agents: design, synthesis, and biological activities. Med. Chem. Res., 2016, 25, 1861-1876.
[http://dx.doi.org/10.1007/s00044-016-1631-x]
[46]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[47]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[48]
HyperChem(TM) Professional 8.0, Hypercube, Inc, , 2009.
[49]
Safakish, M.; Hajimahdi, Z.; Zabihollahi, R.; Aghasadeghi, M.R.; Vahabpour, R.; Zarghi, A. Design, synthesis, and docking studies of new 2-benzoxazolinone derivatives as anti-HIV-1 agent. Med. Chem. Res., 2017, 26, 2718-2726.
[http://dx.doi.org/10.1007/s00044-017-1969-8]
[50]
Parizadeh, N.; Alipour, E.; Soleymani, S.; Zabihollahi, R.; Aghasadeghi, M.R.; Hajimahdi, Z. Synthesis of novel 3-(5-(alkyl/arylthio)-1,3,4-oxadiazol-2-yl)-8-phenylquinolin-4(1H)-one derivatives as anti-HIV agents. Phosphorus Sulfur Silicon Relat. Elem., 2018, 193, 225-231.
[http://dx.doi.org/10.1080/10426507.2017.1394302]
[51]
Hare, S.; Gupta, S.S.; Valkov, E.; Engelman, A.; Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature, 2010, 464(7286), 232-236.
[http://dx.doi.org/10.1038/nature08784] [PMID: 20118915]
[52]
Ferro, S.; De Luca, L.; Lo Surdo, G.; Morreale, F.; Christ, F.; Debyser, Z.; Gitto, R.; Chimirri, A. A new potential approach to block HIV-1 replication via protein-protein interaction and strand-transfer inhibition. Bioorg. Med. Chem., 2014, 22(7), 2269-2279.
[http://dx.doi.org/10.1016/j.bmc.2014.02.012] [PMID: 24618511]

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