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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

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Abstract

N′-Substitutedbenzylidene-2-(4-methyl-5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-1(4H)-yl)acetohydrazides (7a–u) were synthesized through a multistep reaction. The final compounds were screened for anti-HIV-1 and cytotoxic activities. Among these compounds, 7l and 7m exhibited the most significant anti-HIV-1 activity with EC50 values of 5.4 and 3.3 μM, respectively, while 7j showed moderate anti-HIV activity with an EC50 value 17.1 μM. Molecular docking into HIV-1 Reverse Transcriptase also showed the best fit for 7l and 7m followed by 7j. In addition, compounds 7b, 7f, 7h, 7k, 7o, and 7s exhibited no toxicity in all the three cell lines used i.e., primary human PBM, CEM, and Vero cells, while 7e, 7g, 7i, 7n, 7p, 7q, and 7t exhibited no cytotoxic activity in primary human PBM cells. Moreover, it was found through molecular docking that compounds 7l, 7m, and 7j bound efficiently in the NTP-binding pocket of HIV-1 Reverse Transcriptase. The structure–activity relationship established on these results would facilitate the further development of new HIV inhibitors based on this skeleton.

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References

  • Ahmad M, Siddiqui HL, Ahmad SM, Parvez M, Tizzard GJ (2010a) Synthesis and crystal structures of a series of pyrazolo[4,3-c][1,2]benzothiazine,2,4-dihydro-3,4-dimethyl-,5,5-dioxide derivatives. J Chem Crystallogr 40:1188–1194

    Article  CAS  Google Scholar 

  • Ahmad M, Siddiqui HL, Azam M, Bukhari IH, Parvez M (2010b) 2-(2-Oxo-2-phenylethyl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide. Acta Cryst E 66:o616

    Article  CAS  Google Scholar 

  • Ahmad M, Siddiqui HL, Rizvi UF, Ahmad S, Parvez M (2010c) 3-Benzoyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide. Acta Cryst E 66:o862

    Article  CAS  Google Scholar 

  • Ahmad M, Siddiqui HL, Zia-ur-Rehman M, Parvez M (2010d) Antioxidant and antibacterial activities of novel N′-arylmethylidene-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2] benzothiazin-2-(4H)-yl) acetohydrazides. Eur J Med Chem 45:698–704

    Article  CAS  PubMed  Google Scholar 

  • Ahmad M, Rizvi SUF, Siddiqui HL, Ahmad S, Parvez M, Suliman R (2012) Antioxidant and antimicrobial studies of novel N-(substituted-2-chloroquinolin-3-yl)methylidene-4-hydroxy-2H-1,2-benzothiazine-3-carbohydrazides-1,1-dioxides. Med Chem Res 21(9):2340–2348

    Article  CAS  Google Scholar 

  • Ahmad M, Siddiqui HL, Gardiner JM, Parvez M, Aslam S (2013a) Synthesis and antioxidant studies of novel N-substituted benzyl/phenyl-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides. Med Chem Res 22:794–805

    Article  CAS  Google Scholar 

  • Ahmad M, Aslam S, Bukhari MH, Montero C, Detorio M, Parvez M, Schinazi RF (2013b) Synthesis of novel pyrazolobenzothiazine 5,5-dioxide derivatives as potent anti-HIV-1 agents. Med Chem Res. doi:10.1007/s00044-013-0718-x

    Google Scholar 

  • Altomare A, Cascarano M, Giacovazzo C, Guagliardi A (1993) SIR92. J Appl Cryst 26:343

    Article  Google Scholar 

  • Aslam S, Ahmad M, Zia-ur-Rehman M, Montero C, Detorio M, Parvez M, Schinazi RF (2013) Synthesis and anti-HIV-1 screening of novel N′-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides. Arch Pharm Res. doi:10.1007/s12272-013-0200-9

    PubMed  Google Scholar 

  • Barrd-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blein C, Vdzinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L (1983) Isolation ofa T-lymphotrophic retro-virus from a patient at risk for Acquired Immune Deficiency Syndrome (AIDS). Science 220:868–871

    Article  Google Scholar 

  • Barreca ML, Manfroni G, Leyssen P, Winquist J, Kaushik-Basu N, Paeshuyse J, Krishnan R, Iraci N, Sabatini S, Tabarrini O, Basu A, Danielson UH, Neyts J, Cecchetti V (2013) Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication. J Med Chem 56:2270–2282

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Belen’kii MS, Schinazi RF (1994) Multiple drug effect analysis with confidence interval. Antiviral Res 25:1–11

    Article  PubMed  Google Scholar 

  • Beurskens PT, Admiraal G, Beurskens G, Bosman WP, de Gelder R, Israel R, Smits JMM (1994) The DIRDIF-94 program system technical report of the crystallography laboratory. University of Nijmegen, Nijmegen

    Google Scholar 

  • Broder S, Gallo RC (1984) A pathogenic retrovirus (HTLV-III) linked to AIDS. N Engl J Med 311(20):1292–1297

    Article  CAS  PubMed  Google Scholar 

  • Bukhari MH, Siddiqui HL, Ahmad M, Hussain T, Moloney MG (2011) Synthesis and anti-bacterial activities of some novel pyrazolobenzothiazine-based chalcones and their pyrimidine derivatives. Med Chem Res 21(10):2885–2895

    Article  Google Scholar 

  • Caruso I, Montrone F, Boari L (1994) Lornoxicam versus diclofenac in rheumatoid arthritis: a double-blind, multicenter study. Adv Ther 11:132–138

    Google Scholar 

  • Constantine JW (1967) Aggregation and adhesion of rat platelets. Nature 214:1084–1086

    Article  CAS  PubMed  Google Scholar 

  • Engelhardt G, Homma D, Schlegel K et al (1995) Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new nonsteroidal anti-inflammatory agent with favourable gastrointestinal tolerance. Inflamm Res 44:422–433

    Google Scholar 

  • Farrugia LJ (1997) J Appl Cryst 30:565

    Article  CAS  Google Scholar 

  • Feriono PM, Jaffe HW, Palmer E, Peterman TA, Francis DP, Kalyanaraman VS, Weinstein RA, Stoneburner RL, Alexander WJ, Raevsky C, Gethchell JP, Warfield D, Haverkos HW, Kilbourne BW, Nicholson JKA, Curran JW (1985) Transfusion-associated acquired immunodeficiency syndrome: evidence for persistent infection in blood donors. N Engl J Med 312:1293–1296

    Article  Google Scholar 

  • Francis DP, Curran JW, Essex M (1983) Epidemic acquired immune deficiency syndrome: epidemiologic evidence for a transmissible agent. J Natl Cancer Inst 71(1):1–4

    CAS  PubMed  Google Scholar 

  • Giuseppe M, Arnaldo F, Patrizia T (1987) Derivatives of pyridobenzothiazine with high anti-microbial activity. US Patent 4,668,784, 26 May 1987

  • Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A (1981) Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 305(24):1425–1431

    Article  CAS  PubMed  Google Scholar 

  • Hooft R (1998) Collect. Nonius B V, Delft

    Google Scholar 

  • Ikeda T, Kakegawa H, Miyataka H, Matsumoto H, Satoht T (1992) Anti-allergic and anti-inflammatory actions of 20-(tetrazole-5-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxanilide-1,1-dioxide. Biorg Med Chem Lett 2:709–714

    Article  CAS  Google Scholar 

  • Klatzman D, Barrd-Sinoussi F, Nugeyre MT, Dauguet C, Vilmer E, Griscelli C, Brun-Vdzinet F, Rouzioux C, Gluckman JC, Chermann JC, Montagnier L (1984) Selective tropism of lymphadenopathy associated virus (LAV) for helper-inducer T-lymphocytes. Science 225:59–63

    Article  Google Scholar 

  • Krapcho J (1973) Benzothiazine derivatives. 3,725,403, 3 Apr 1973

  • Krapcho J, Turk CF (1975) 1-Substituted-4-phenyl-4H-[1,2,4]triazolo[3,4-c][1,4] benzothiazines or benzoxazines. US Patent 3,929,783, 30 Dec 1975

  • Lomabardino JG, Wiseman EH, McLamore WM (1971) Synthesis and antiinflammatory activity of some 3-carboxamides of 2-alkyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide. J Med Chem 14:1171–1175

    Article  Google Scholar 

  • Lombardino JG, Wiseman EH, Chiaini J (1973) Potent antiinflammatory N-heterocyclic 3-carboxamides of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide. J Med Chem 16:493–496

    Article  CAS  PubMed  Google Scholar 

  • Marfat A (1985) Anti-inflammatory 2-methyl-2H-1,2-benzo-(o-thieno-)thiazine-3-carboxamide-1,1-dioxide derivatives, compositions, and method of use therefor.US Patent 4,551,452, 5 Nov 1985

  • Masur H, Michelis MA, Greene JB, Onorato I, Vande Stouwe RA, Holzman RS, Wormser G, Brettman L, Lange M, Murray HW, Cunningham-Rundles S (1981) An outbreak of community-acquired pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 305(24):1431–1438

    Article  CAS  PubMed  Google Scholar 

  • McCormick JB, Getchell JP, Mitchell SW, Hicks DR (1984) Ribavirin suppresses replication of lymphadenopathy-associated virus in cultures of human adult T lymphocytes. Lancet 2(8416):1367–1369

    Article  CAS  PubMed  Google Scholar 

  • Myung PS, Soon KK (2000) Dehydration of alcohols; synthesis of 3-alkoxy-3-methylcarboxyl-4-oxo-1,2-benzothiazine derivatives. Bull Korean Chem Soc 21(12):1249–1250

    Google Scholar 

  • Otwinowski Z, Minor W (1997) Methods Enzymol 276:307–326

    Article  CAS  Google Scholar 

  • Rosenbaum W, Dormont D, Spire B, Vilmer E, Gentilini M, Griscelli C, Montagnier L, Barre-Sinoussi F, Chermann JC (1985) Antimoniotungstate (HPA 23) treatment of three patients with AIDS and one with prodrome. Lancet 1(8426):450–451

    Article  Google Scholar 

  • Sandstrom EG, Kaplan JC, Byington RE, Hirsch MS (1985) Inhibition of human T-cell lymphotropic virus type III in vitro by phosphonoformate. Lancet 1(8444):1480–1482

    Article  CAS  PubMed  Google Scholar 

  • Schinazi RF, Sommadossi PJ, Cannon DL, **e MY, Hart GC, Smith JA, Hahan EF (1990) Activities of 3′-azido-3′-deoxythymidine nucleotide dimers in primary lymphocytes infected with human Immunodeficiency virus type 1. Antimicrob Agents Chemother 34:1061–1067

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shaw GM, Harper ME, Hahn BH, Epstein LG, Gajdusek DC, Price RW, Navia BA, Petito CK, O’Hara CJ, Groopman JE, Cho ES, Oleske JM, Wong Staal F, Gallo RC (1985) HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science 227(4683):177–182

    Article  CAS  PubMed  Google Scholar 

  • Sheldrick GM (2008) A short history of SHELX. Acta Cryst A64:112–122

    Article  Google Scholar 

  • Siegal FP, Lopez C, Hammer GS, Brown AE, Kornfeld SJ, Gold J, Hassett J, Hirschman SZ, Siegal M, Cunningham-Rundles S, Adelsberg BR (1981) Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 305(24):1439–1444

    Article  CAS  PubMed  Google Scholar 

  • Soler JE (1986) Derivatives of oxazinobenzothiazine-6,6-dioxide US Patent 4,563,452, 7 Jan 1986

  • Stuyver LJ, Lostia S, Adams M, Mathew SJ, Pai SB, Grier J, Tharnish MP, Choi Y, Chong Y, Choo H, Chu KC, Otto JM, Schinazi FR (2002) Antiviral activities and cellular toxicities of modified 2′,3′-dideoxy-2′,3′-didehydrocytidine analogues. Antimicrob Agents Chemother 46:3854–3860

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Suh JJ, Hong YH, Kim BC (1987) Synthesis and antiinflammatory activity of 4-substituted-1,2-benzothiazine-3-carboxamide-1,1-dioxides. J Kor Pharm Sci 17(2):61–65

    CAS  Google Scholar 

  • Turck D, Busch U, Heinzel G, Narjes H, Nehmiz G (1995) Effect of food on the pharmacokinetics of meloxicam after oral administration. Clin Drug Invest 9:270–276

    Article  Google Scholar 

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Acknowledgments

The authors (SA and MA) are grateful to Higher Education Commission, Pakistan and Institute of Chemistry, University of the Punjab, Lahore, for financial assistance. We are also thankful to International Centre for Chemical and Biological Sciences, HEJ Research Institute of Chemistry, University of Karachi, Karachi, for spectral measurements. This work was also supported in part by NIH grant 2P30-AI-050409 and the Department of Veterans Affairs (RFS), USA. The X-ray coordinate of the compound has been deposited at Cambridge Crystallographic Data Centre with CCDC number 915138.

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Authors and Affiliations

  1. Department of Chemistry, Government College Women University, Faisalabad, Pakistan

    Sana Aslam

  2. Institute of Chemistry, University of the Punjab, Lahore, 54590, Pakistan

    Sana Aslam & Muhammad Makshoof Athar

  3. Department of Chemistry, Government College University, Faisalabad, 38000, Pakistan

    Matloob Ahmad

  4. Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, 38000, Pakistan

    Usman Ali Ashfaq

  5. School of Chemistry and Manchester Institute of Biotechnology, University of Manchester, Manchester, M1 7DN, UK

    John M. Gardiner

  6. Laboratory of Biochemical Pharmacology, Emory University School of Medicine/Veterans Affairs Medical Center, 1760 Haygood Drive, Atlanta, GA, 30322, USA

    Catherine Montero, Mervi Detorio & Raymond F. Schinazi

  7. Department of Chemistry, The University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada

    Masood Parvez

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  1. Sana Aslam
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Corresponding author

Correspondence to Matloob Ahmad.

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This research article is dedicated to Dr. Hamid Latif Siddiqui (Institute of Chemistry, University of the Punjab, Lahore-Pakistan), our honorable teacher (SA and MA), our friend and colleague (MMA, JMG, MP, and RFS) who passed away on July 26, 2012.

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Aslam, S., Ahmad, M., Athar, M.M. et al. 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 23, 2930–2946 (2014). https://doi.org/10.1007/s00044-013-0879-7

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