• Monika Maheshwari
  • Anju Goyal


The ultimate beneficiary of scientific advances is discovering new and better therapeutic agents. 1,4-benzothiazine forms an important class of
heterocyclic system, contains both N and S. Consequently, there have been various efforts for the production of novel 1,4-benzothiazine derivatives
possessing various biological activities such as anti-hypertensive, anti-HIV, anti-inflammatory, antimicrobial, anti-rheumatic, ATP-sensitive potassium
channel opener, cardiovascular, cytotoxic, immunomodulator, neuroprotective, antioxidant, antimalarial and aldose reductase inhibitor etc. As a part
of an ongoing effort toward finding novel pharmacological active agents, it was thought worthwhile to synthesize hybrids of 1,4-benzothiazine.
Keywords: 1,4-Benzothiazine, Ring expansion reaction, Biological activity, 2-aminothiophenol.



1. Parai MK, Panda G. A covinient synthesis of chiral amino acid derived 3,4-dihydro-2H-benzo[b][1,4]thiazines and antibiotics levofloxacine. Tetrahedron letters 2009; 50:4703-4705.
2. Fringuelli R, Schiaffella F, Navarro MPU, Milanese L, Santini C, Rapucci M et al. 1,4-Benzothiazine analogues and apoptosis: structure -activity relationship. Bioorg Med Chem 2003; 11:3245-3254.
3. Hori M, Kataoka T, Shmizu H and Imai Y. Ring expansion reactions of benzothizolines to benzothiazine. Chem Pharm Bull 1973; 5:27.
4. Barange DK, Batchu VR, Gorja D., Pattabiraman VR, Tatini LK, Babu JM and Pal M. Rigioselective construction of six-membered fused heterocyclic rings via Pd/ C-mediated C-C coupling followed by iodocyclization strategy: a new entry to 2H-1,2- benzothiazine-1,1-dioxides. Tetrahedron 2007; 63:1775-1789.
5. Bakavoli M, Nikpour M, Rahimizadeh M, Saberi MR and Sadeghian H. Design and synthesis of pyrimido[4,5-b][1,4] benzothiazine derivatives, as potent 15-lipoxygenase inhibitors. Bioorg Med Chem 2007; 15:2120-26.
6. Dabholkar VV and Gavande RP. Synthesis of pyrazolyl 1,4-benzothiazine derivatives. Heteroletters 2011; 1 Suppl 3:255-261.
7. Saadouni M, Gailane T, Baukhris S, Hassikou A, Habbadi N, Gailane T et al. Regeoselective synthesis of new variety of 1,4-Benzothiazines. Org Commun 2014; 7 (2): 77-84.
8. Gurda VL, Perrissin M, Thomasson F, Ximenes AE, Galdino SL, Pitta IR et al. Synthesis of 4-octyl - 2H - 1,4 - benzothiazine-3-ones. Eur J Med Chem 2003; 38:769-773.
9. Cecchetti V, Fravolini A, Pagella PG, Savino A and Tabarrini O. Quinolinecarboxylic acids- synthesis and antibacterial evaluation of 2 - substituted - oxo - 2, 3 - dihydro - 7H-pyrido[1,2,3- de] [1,4] benzothiazine - 6 - carboxylic acids related to rufloxacin. J Med Chem 1993; 36:3449-3454.
10. Sabatini S, Kaatz GW, Rossolini GM, Prandini D and Sravolini A. From Phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the staphylococcus aureus nor a multidrug efflux. J Med Chem 2008; 51 (14):4321-4330.
11. Schiaffella F, Macchiarulo A, Milanese L, Vecchiarelli A and Fringulli R. Novel ketoconazole analogue based on the replacement of 2, 4-dichlorophenyl group with 1, 4-benzothiazine moiety: design, synthesis and microbiological evaluation. Bioorg Med Chem 2006; 14:5196-5203.
12. Macchiarulo A, Costantino G, Fringuelli D, Vecchiarelli A, Schiaffella F and Fringuelli D. 1,4 - benzothiazine and 1, 4- benzoxazine imidazole derivatives with antifungal activity: a docking study. Bioorg Med Chem 2002; 10:3415-3423.
13. Deshmukh MB, Deshmukh SA, Jagtap SS and Mulik AR. Sysnthesis and study of biological activity of some new 1, 4-benzothiazines. Indian J Chem 2007; 1:852-859.
14. Gupta G and Wagh SB. Synthesis and antifungal activity of N-(alkyl/aryl)-2-(3-oxo-1,4-benzothiazine-3-yl)acetamide. Indian J Chem 2006; 45B:697-702.
15. Acharya RC and Saran N. Synthesis and antihypertensive activity of 1,4-benzothiazine derivatives. Indian J Chem. 1985; 29B:299-301.
16. Kajino M, Mizuno K, Tawada H, Shibouta Y, Nishikawa K and Meguro K. Synthesis and biological activities of new 1, 4- benzothiazine derivatives. Chem Pharm Bull 1991; 39 (11):2888-95.
17. Cecchetti V, Schiaffella F, Tabarrini O and Fravolini A. (1,4-Benzothiazinyloxy) alkylpiperazine derivatives as potential antihypertensive agents. Bioorg Med Chem, 2000; 10:465-468.
18. Campiani G, Garofalo A, Fiorini I, Botta M, Nacci V et al. Pyrrolo[2,1-c][1,4]benzothiazine: synthesis, structure-activity relationship, molecular modeling studies and cardiovascular activity. J Med Chem 1995; 38:4393-4410.
19. Watanabe, Osanai K, Nishi T, Miyawaki N and Shii D. Synthesis as azido derivatives of semotiadil, a novel 1,4-benzothiazine calcium antagonist for photoaffinity probe4s of calcium channels. Bioorg Med Chem 1996; 6 (16):1923-1926.
20. Fujita M, Ito S, Ota A, Kato N, Yamamoto K, Kawashiwa Y et al. Synthesis and Ca+ antagonistic activity of 2-2[(aminoalkyl)oxy]5-methoxyphenyl]3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazines. J Med Chem 1990; 33:1898-1905.
21. Kaneko T, Clark RSJ, Ohi N and Akamatsu H. Inhibitors of adhesion molecules expression; the synthesis and pharmacological properties of 10-H - pyrazino[2,3-b] [1,4] benzothiazine derivatives. Chem Pharm Bull 2002; 50 (7): 922-929.
22. Turk CF and Krapcho J. 4-(3-(Dimethyl amin)propyl-3,4-dihydro-2(1-hydroxyethyl)3-phenyl-2H-1,4-benzothiazine and related compounds: A new class of anti-inflammatory agents. J Med Chem 1973; 16 (1):776-779.
23. Sarri WS, Cochran DW, Lee YC, Cresson EL, Springer JP, Williams M et al. 10-[3- (Dimethyl amino) - 1- propyl] 10H – pyrazine [2, 3 - b] [1,4] benzothiazines as potential neuroleptics. J Med Chem 1983; 26:564-569.
24. Grandolini G, Rossi C, Tiralti MC, Rossi C and Ambrogi V. Synthesis of new series of 1 or 2-substituted-4H-s-triazolo[3,4-c]-1,4-benzothiazines and related compounds with potential CNS activity. Farmaco 1987; 42 (1):43-60.
25. Duro F and Condorelli P. N-dialkylaminoalkyl derivatives of 2-carboethoxy and 2-carbomethoxy-4H-1, 4-benzothiazine. Farmaco 1972; 27(8):656-662.
26. Matsuoka H, Ohi N, Mishra M, Suzuki H, Miyamoto K, Maru Ya N et al. Antireumatic agents : novel methotrexate derivatives bearing benzoxazine or benzothiazine moiety. J Med Chem 1997; 40:105-111.
27. Aotsuka T, Hosono H, Kurihara T, Nakamura Y, Matasui T and Kobayashi F. Novel and potent aldose reductase inhibitor: 4-benzly and 4-(benzothiazol-2-ylmethyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-acetic acid derivatives. Chem Pharm Bull 1994; 42 (4):1264-71.
28. Schou SC, Hansen HC, Tagmose TM and Boonen HCM. Synthesis and pharmacological evaluation of 4H-1,4-Benzothiazine-2-carbonotril1,1-dioxide and N-(2-cyanomethylsulfonyl phenyl) acylamide derivaties as potential activatore of ATP sensitive potassium channels. Bioorg Med Chem 2005; 13:141-155.
29. Vincenzo C, Robert OS, Alma M, Giuseppe M, Lara T, Stesano S, Oriana T and Violetta C. Novel 1,4-benzothiazine derivatives as large conductance Ca++ activated potassium channel opener. J Med Chem 2008; 51 (16):5085-5092.
30. Gautam N, Ajmera N, Gupta S and Gautam DC. Synthesis, spectral characterization and biological evaluation of 4H‐1,4‐benzothiazines, their sulfones and ribofuranosides. Eur J Chem 2012; 3 (1):106-111.
31. Deshmukh MB, Mulik AR and Desai SD. Sysnthesis of some new 2-methyl-1, 4-benzothiazin-3-(1H)-one derivatives as potential vasodilator. E J Chem 2004; 1 (4):206-210.
32. Barazarte A, Lobo G, Gamboa N and Rodrigues JR. Synthesis and antimalarial activity of pyrazolo and pyrimido benzothiazine dioxide derivatives. Eur J Med Chem 2008; 30:1-8.
33. Grandolini G, Luana P and Ambrogi V. Synthesis of some new 1,4-benzothiazine and 1,5-benzothiazepine tricyclic derivatives with structural analogy with TIBO and their screening for anti-HIV activity. Eur J Med Chem 1999; 34:701-709.
34. Gomez-Gonazalez JC, Santana L, Uriarte E, Brea J, Villazon M, Loza MI et al. New arylpiperazine derivatives with high affinity for 1A, D2 and 5 - HT2A receptors. Bioorg Med Chem 2003; 13:175-178.
35. Shastri CVR, Kondaiah K and Sai GST. Synthesis and anthelmintic activity of [5(6)(3-oxo-1,4-benzothiazin-7yl-oxy)-benzimidazole]2-carbamates. Indian J Chem 1990; 29B:297-299.
36. Varnano F, Catarzi D, Colotta V, Filacchiono and Cecchi L. Synthesis of 2-substituted-6,8-dichloro-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-1,1-dioxide and -1-oxide as glycibe -NMDA receptor antagonist. Farmaco 1998; 53:752-757.
631 Views | 1827 Downloads
How to Cite
Maheshwari, M., and A. Goyal. “A REVIEW: SYNTHESIS AND MEDICINAL IMPORTANCE OF 1,4-BENZOTHIAZINE ANALOGUES”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 8, no. 2, Mar. 2015, pp. 41-46, https://innovareacademics.in/journals/index.php/ajpcr/article/view/4445.
Review Article(s)