SpringerLink
Log in

Synthesis of novel pyrazolobenzothiazine 5,5-dioxide derivatives as potent anti-HIV-1 agents

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

A new series of pyrazolobenzothiazine-based carbohydrazides was prepared in a facile way, starting with commercially available sodium saccharine. The final products were sufficiently characterized by spectroscopic techniques. In addition, compound 5k was confirmed with X-ray crystallography as well. All the compounds were screened for anti-HIV-1 and cytotoxicity activities. Overall, out of 15 compounds, seven exhibited good activity with EC50 values <20 μM. Compounds 5c, 5d, 5g, 5j and 5k appeared as the potent anti-HIV-1 agents with EC50 values <5.0 μM. The structure–activity relationship would facilitate the discovery of new molecules with better profile of HIV inhibition activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ahmad M, Siddiqui HL, Ahmad S, 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 E66:o862

    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[4,3c][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 (2013) 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 

  • 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 

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

    Article  PubMed  Google Scholar 

  • Berryman KA, Edmunds JJ, Bunker AM, Haleen S, Bryant J, Welch KM, Doherty AM (1998) Endothelin receptor antagonists: synthesis and structure–activity relationships of substituted benzothiazine-1,1-dioxides. Bioorg Med Chem 6:1447–1456

    Article  CAS  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 

  • Bihovsky R, Tao M, Mallamo JP, Wells GJ (2004) 1,2-Benzothiazine 1,1-dioxide α-ketoamide analogues as potent calpain I inhibitors. Bioorg Med Chem Lett 14:1035–1038

    Article  CAS  PubMed  Google Scholar 

  • Bukhari MH, Siddiqui HL, Ahmad M, Hussain T, Moloney MG (2012) Synthesis and anti-bacterial activities of some novel pyrazolobenzothiazine-based chalcones and their pyrimidine derivatives. Med Chem Res 21(10):2885–2895

    Article  CAS  Google Scholar 

  • Coffin J, Haase A, Levy JA, Montagnier L, Oroszlan S, Teich N, Temin H, Toyoshima K, Varmus H, Vogt P (1986) What to call the AIDS virus? Nature 321:10

    CAS  PubMed  Google Scholar 

  • De Clercq E (2006) From adefovir to AtriplaTM via tenofovir VireadTM and TruvadaTM. Future Virol 1:709–715

    Article  Google Scholar 

  • De Clercq E (2007a) The design of drugs for HIV and HCV. Nat Rev 6:1001–1018

    Google Scholar 

  • De Clercq E (2007b) Anti-HIV drugs. K Verh Acad Geneesk Belg 64:81–104

    Google Scholar 

  • Farrugia LJ (1997) ORTEP-3 for windows—a version of ORTEP-III with a graphical user interface (GUI). J Appl Cryst 30:565

    Article  CAS  Google Scholar 

  • Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, Lu B, McColl D, Chuck S, Enejosa J, Toole JJ, Cheng AK (2006) Tenofovir DF emtricitabine, and efavirenz vs zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354:251–260

    Article  CAS  PubMed  Google Scholar 

  • Gupta RR, Dev PK, Sharma ML, Rajoria CM, Gupta A, Nyati M (1993) Anticancer activities of 2,3-dihydro-1,4-benzothiazines, and of their 4-(N-alkyl amides) and 4-(N-alkyl N-nitrosoamides). Anticancer Drugs 4:589–592

    Article  CAS  PubMed  Google Scholar 

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

  • Lomabardino JG, Wiseman EH, Mclamore W (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 

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

    Google Scholar 

  • Mitsuya H, Weinhold KJ, Furman PA, St. Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S (1985) 3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human t-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA 82(20):7096–7100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Otwinowski Z, Minor W (1997) Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol 276:307–326

    Article  CAS  Google Scholar 

  • Pozniak AL, Gallant JE, DeJesus E, Arribas JR, Gazzard B, Campo RE, Chen SS, McColl D, Enejosa J, Toole JJ, Cheng AK (2006) Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naïve patients. J Aquir Immune Defic Syndr 43:535–540

    CAS  Google Scholar 

  • Rizvi SUF, Ahmad M, Bukhari MH, Montero C, Chatterjee P, Detorio M, Schinazi RF (2013) Anti-HIV-1 screening of (2E)-3-(2-chloro-6-methyl/methoxyquinolin-3-yl)-1-(aryl)prop-2-en-1-ones. Med Chem Res. doi:10.1007/s00044-013-0652-y

    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 

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

    Article  Google Scholar 

  • 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 

  • 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 

Download references

Acknowledgments

The authors (MA, SA, and MHB) 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 compounds has been deposited at Cambridge Crystallographic Data Centre with CCDC numbers 881054.

Author information

Authors and Affiliations

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

    Matloob Ahmad

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

    Sana Aslam & Mujahid Hussain Bukhari

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

    Sana Aslam

  4. 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

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

    Masood Parvez

Authors
  1. Matloob Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sana Aslam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mujahid Hussain Bukhari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Catherine Montero
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mervi Detorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masood Parvez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raymond F. Schinazi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matloob Ahmad.

Additional information

This research article is dedicated to the late professor Dr. Hamid Latif Siddiqui, our honorable teacher (MA, SA and MHB) and friend (MP and RFS).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (RTF 21498 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmad, M., Aslam, S., Bukhari, M.H. et al. Synthesis of novel pyrazolobenzothiazine 5,5-dioxide derivatives as potent anti-HIV-1 agents. Med Chem Res 23, 1309–1319 (2014). https://doi.org/10.1007/s00044-013-0718-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-013-0718-x

Keywords

Search

Navigation