The Open Medicinal Chemistry Journal




ISSN: 1874-1045 ― Volume 14, 2020
REVIEW ARTICLE

A Review: Medicinally Important Nitrogen Sulphur Containing Heterocycles



Praveen K. Sharma1, *, Andleeb Amin1, M. Kumar2
1 Department of Chemistry, School of of Chemical Engineering and Physical Sciences, Lovely Professional University, Phagwara, Punjab, India
2 Department of Chemistry, University of Rajasthan, Jaipur, India

Abstract

Nitrogen sulphur containing heterocycles have specific properties due to which they can be used as a potential material in a different type of industries such as medicinal/pharmaceutical, paint, packing and textile, required for various chemical, physical operations and their use as products. Especially dyes, paint, agrochemicals, medicine, etc. make them more significant. In present days, Nitrogen-Sulfur heterocycles are repeatedly attracting the interest of chemists due to their exceptional bioactive behavior. The present study is a review of the work carried out by a chemist in the discovery of new, effective, medicinally important heterocyclic compounds. The present review basically focused on nitrogen-sulfur heterocycles of potential therapeutic interest, especially with thiazole, thiazine, pyrimidine, morpholine and piperazine heterosystems, benzothiazines, pyrazole-benzothiazines, morpholine-benzothiazines, piperazine-benzothiazines and pyrimidine-benzothiazoles, mainly due to their unique structural features, which enable them to exhibit a number of biological and pharmacological activities. Due to a novel mode of action, a broad spectrum of activity, lesser toxicity towards mammalian cells, and suitable profiles towards humans have triggered the use of Nitrogen Sulphur containing heterocycles in designing and synthesizing their derivatives with better properties. The overall objective of the review is to discuss the importance of novel biodynamic structurally diverse heterocycles of potential therapeutic interest: pyrimidine, morpholine, piperazine, pyrozole, benothiazoles, pyrimidobenzothiazoles, 4H-1,4-benzothiazines, pyrazolyl-benzothiazines, morpholinyl-benzothiazines and piperazinylbenzothiazines in order to have access to important commercial molecules for the search of better future.

Keywords: Pyrimidobenzothiazoles, Morpholinylbenzothiazines pharmacophores, Antimicrobial, Antiviral, Benzothiazoles, Benzothiazines, Pyrazolylbenzothiazines, Piperainylbenzothiazines.


Article Information


Identifiers and Pagination:

Year: 2020
Volume: 14
First Page: 49
Last Page: 64
Publisher Id: TOMCJ-14-49
DOI: 10.2174/1874104502014010049

Article History:

Received Date: 03/03/2020
Revision Received Date: 29/04/2020
Acceptance Date: 30/04/2020
Electronic publication date: 14/09/2020
Collection year: 2020

© 2020 Sharma et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Chemistry, School of of Chemical Engineering and Physical Sciences, Lovely Professional University, Phagwara, Punjab, India; E-mail: pk_pandit1982@yahoo.com





1. INTRODUCTION

Heterocycles are considered as the largest section of chemistry, especially organic chemistry. A greater part of the natural compounds produced by biotic component has heterocyclic rings as a constitutional part of their molecules. Different types of commercially important compounds alkaloids like vinblastine, reserpine, morphine, ellipticine, antibiotics like cephalosporin, penicillin etc., cardiac glycosides and different type of pesticides are heterocycles of meaning for animal and human health. The majority of the important advances have been developed by synthesizing new heterocycles which imitate natural products with similar biological activities. For that reason, scientists/researchers/chemist communities are on a nonstop search to develop better pesticides, pharmaceuticals, fungicides, compost material, weed killers, insecticides, etc. Heterocycles' role in biological system is very important. Biochemical processes of components of living organisms like RNA, DNA etc. are based on heterocycles. Except for this present life pattern and civilization, there are additional significant applications of heterocycles in the fields of cosmetics, additives, antioxidants, vulcanization accelerators dyestuffs, photographic material, reprography, data storage, solvents, and plastics. Eventually, heterocyclic chemistry is an infinite supply of exceptional compounds. A large number of models of carbon, heteroatoms and hydrogen, can be produced, which have various biological, physical and chemical properties [1Katritzky, A.R.; Rees, C.W. Comprehensive Heterocyclic Chemistry., (1st ed. ), 1984, -7Xu, J.; Stevenson, J. Drug-like index: A new approach to measure drug-like compounds and their diversity. J. Chem. Inf. Comput. Sci., 2000, 40(5), 1177-1187.
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]. The expansion of newly discovered processes and the planned use of recognized procedures for the development of heterocycles continue to strengthen the vast domain of organic chemistry.

A specific class of heterocycles having sulfur-nitrogen heteroatoms includes very important aromatic compounds that show physicochemical properties with significance in the development of futuristic materials such as magnets and molecular conductors. At present, interest has been promptly growing in accepting modifications and the characteristics of sulphur-nitrogen based heterocycles. Aromatic heterocycles containing Nitrogen (N) and sulfur(S) are resulting from aromatic carbocycles with the replacement of one or more carbon by a heteroatom in the ring. Whereas, the occurrence of sulfur and nitrogen atoms in the cyclic ring is usually related to the complexity and instability in the synthesis, however, the established nitrogen and sulfur containing heterocycles with significant properties have repeatedly been synthesized. On account of the availability of electrons (unshared pairs) and the distinction in electronegativity between carbon and heteroatoms, heterocycles are very significant in the cyclic molecular structures. Therefore, the nitrogen-sulphur heterocycles exhibit physicochemical properties and reactivity fairly diverse from the precursor carbocyclic compounds [8Marcos, C.F.; Polo, C.; Rakitin, O.A.; Rees, C.W.; Torroba, T. From Hunig’s Base to Bis([1,2]dithiolo)-[1,4]thiazines in One Pot: The Fast Route to Highly Sulfurated Heterocycles. Angew. Chem., 1997, 36, 281-283.
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2. REVIEW OF LITERATURE

2.1. Medicinally Important Pyrimidine, Benzothiazole Fused Heterosystem: Pyrimidobenzothiazole

Pyrimidine and Thiazole nuclei are treated preferred structures as both these heterocyclic systems constitute the pharmacophore of diverse biological active molecules [13Kappe, C.O. 100 years of the biginelli dihydropyrimidine synthesis. Tetrahedron, 1993, 49, 6937-6963.
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] Fig. (1). In medicinal chemistry, the therapeutic applications of pyrimidine derivatives are well known. RNA and DNA activities are based on nucleic acids Uracil, Thymine and cytosine, which have pyrimidine unit. Pyrimidine nucleus compounds acquire a wide variety of biological activities, like stavudine and zidovudine as antiHIV, sulphamethiazine trimethoprim, and sulphadiazine as antibacterial, idoxuridine and trifluoridine as antiviral, barbiturates e.g. phenobarbitone as sedative, 5-fluorouracil as anticancerprazosin and minoxidil as antihypertensive, hypnotics and anticonvulsant, thionzylamine as H1-antihistamine, and fervennuline and toxoflavin as antibiotics, propylthiouracil as antithyroid, sulphadoxin as antimalarial and antibacterial, etc [20Belema, M.; Bunker, A.; Nguyen, V.; Beaulieu, F.; Ouellet, C.; Marinier, A.; Roy, S.; Yung, X.; Zhang, Y.; Zuci, C. PCT Int. Appl. WO 2003084, Through. Chem. Abstr., 2003, 139337987x]. Pyrimidine and their derivatives are very well known anti-inflammatory, analgesic and antipyretic agents [21Pirisino, R.; Bianchini, F.; Banchelli, G.; Ignesti, G.; Raimondi, L.; Pecori-Vettori, L.; Rafanelli, D. Pharmacological activity of FPP028 (2-phenylpyrazolo-4-ethyl-4,7-dihydro [1,5a]pyrimidin-7-one) a new non-steroid anti-inflammatory agent. Pharmacol. Res. Commun., 1986, 18(3), 241-256.
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].

In the same way, substituted benzothiazoles show interesting biological activities, like antiviral, anti-inflammatory, anticonvulsant, antitumor, antimicrobial and antagonists, etc [34Sawhney, S.N.; Bhutani, S. Dharamvir. Synthesis of some 2 - (2 - Benzothiazolyl) - 6 2 - (2 - Benzimidazolyl) - 6 - aryl -4,5- dihydro - 3 (211 -) pyridazinones as potential anti-flamatory agents. Indian J. Chem., 1987, 26B, 348-350.-45Sreenivasa, M.V.; Nagappa, A.N.; Nargund, L.V.G. Various benzothiazolotriazole derivatives possess good microbial activity. Indian J. Heterocycl. Chem., 1998, 8, 23-27.]. The adjoining of one biodynamic heterocyclic system with another biodynamic heterosystem results in a molecule with structural variability and improved pharmacological activity. The fusion of heterosystems has been proven to be useful and attractive for the design of new molecular framework of therapeutically interesting drugs. With the object of discovery of exploring new heterocyclic therapeutics, we focused on pyrimidobenzothiazoles, a new class of heterocycles, incorporating two pharmacologically important heterocyclic systems, benzothiazole and pyrimidine [46Gopkumar, P.; Shivakumar, B.; Jayachandran, E.; Nagappa, A.N.; Nargund, L.V.G.; Gurupadaiah, B.M. Synthesis and biological activity of 6-fluoro-7-(substituted)-(2-Np-anilino sulphonamido) benzothiazoles. Indian J. Heterocycl. Chem., 2001, 11, 39-42.-56Hutchinson, I.; Chua, M.S.; Browne, H.L.; Trapani, V.; Bradshaw, T.D.; Westwell, A.D.; Stevens, M.F.G. Antitumor benzothiazoles. 14. Synthesis and in vitro biological properties of fluorinated 2-(4-aminophenyl)benzothiazoles. J. Med. Chem., 2001, 44(9), 1446-1455.
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Pyrimidobenzothiazoles reportedly exhibited an extensive choice of pharmacological and biological activities such as anticonvulsant [57Gineinah, M.M.M. 6-, 7- And 8-(5-Aryl-1-Phenyl-2-Pyrazolin-3-ly)Imidazo- and Pyrimido[2,1-b]Benzothiazoles as Novel Antoconvulsant Agents. Sci. Pharm., 2001, 69(1), 53-61.
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].

2.2. Biodynamic Heterosystem: Benzothiazine and their Derivatives

Benzothiazines are structural analogues of phenothiazines [63Gupta, R.R. Synthetic and spectral investigation of fluorinated phenothiazines and 4H-1,4-benzothiazines as potent anticancer agents. J. Fluor. Chem., 1993, 62, 191-200.
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[http://dx.doi.org/10.1016/S0014-2999(97)01092-3] [PMID: 9300266]
] and exhibit similar structural flexibility along with structural specificity, fold along nitrogen and sulfur axis, as in phenothiazines. The direction of folding and the magnitude of folding angle depend to a larger extent on the position as well as the type of the other substituents on the ring system, which consequently affect the therapeutic activities considerably. The structural specificity along nitrogen-sulfur axis in phenothiazines and 4H-1,4-benzothiazines has been considered as a significant factor to be responsible for their activities and made both the series important from not only structural point of view but also from pharmacological as well as industrial view point [70Schreiber, S.L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science, 2000, 287(5460), 1964-1969.
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]. The structural presentation of phenothiazine and 4H-1,4-benzothiazine ring systems according to Gordon’s model is presented to show the structural similarity of both the heterosystems Fig. (2).

Benzothiazines have also been established for their pharmacological/biological behavior such as antihypertensive [73Cecchetti, V.; Schiaffella, F.; Tabarrini, O.; Fravolini, A. (1,4-Benzothiazinyloxy)alkylpiperazine derivatives as potential antihypertensive agents. Bioorg. Med. Chem. Lett., 2000, 10(5), 465-468.
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], antiinflammatory [74Turk, C.F.; Egli, P.; Krapcho, J. Synthesis and antiinflammatory activity of the sulfoxides of 4-(3-(dimethylamino)propyl)-3,4-dihydro-2-(1-hydroxyethyl)-3-phenyl-2h -1,4-benzothiazine. J. Heterocycl. Chem., 1977, 14, 1135-1137.
[http://dx.doi.org/10.1002/jhet.5570140702]
], antianginal [75Kanda, A.; Hashimoto, H. Effects of semotiadil fumarate, a novel calcium antagonist, on blood pressure and heart rate in conscious spontaneously hypertensive rats. Jpn. J. Pharmacol., 1993, 63(1), 121-124.
[http://dx.doi.org/10.1254/jjp.63.121] [PMID: 8271524]
], antihistaminic [76Sugimoto, Y.; Tarumi, T.; Zhao, Q.E.; Fujii, Y.; Kamei, C. Effects of antiallergic drugs on histamine release from rat peritoneal mast cells induced by bradykinin. Methods Find. Exp. Clin. Pharmacol., 1998, 20(6), 457-462.
[http://dx.doi.org/10.1358/mf.1998.20.6.485708] [PMID: 9789869]
], antipsychotic [77King, D.J.; Wager, E. Haematological safety of antipsychotic drugs. J. Psychopharmacol. (Oxford), 1998, 12(3), 283-288.
[http://dx.doi.org/10.1177/026988119801200309] [PMID: 10958256]
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], neuroleptic [79Platonov, I.A. [The effect of neuroleptics on blood proteins during development of toxic cerebral edema-brain swelling]. Vopr. Med. Khim., 1995, 41(1), 27-29.
[PMID: 7771085]
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[http://dx.doi.org/10.1139/v94-134]
], antioxidant properties [81Kale, S.B.; Karale, B.K. Synthesis and characterization of some important indazolyl derivatives. J. Heterocycl. Chem., 2007, 44(2), 289-301.
[http://dx.doi.org/10.1002/jhet.5570440203]
], etc. 4H-1,4-Benzothiazines have also been used as colour photographic developers and dye stuffs in the industry [82Aiello, A.; Fattorusso, E.; Luciano, P.; Menna, M.; Esposito, G.; Iuvone, T.; Pala, D. Conicaquinones A and B, two novel cytotoxic terpene quinones from the mediterranean ascidian Aplidium conicum. Eur. J. Org. Chem., 2003, 898-900.
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Fig (1)
Pyrimidobenzothiazole.


Fig (2)
Gordon’s model.


Table 1
Pharmacological activities of Nitrogen-Sulphur containing heterocycles.


2.3. Pharmaceutically Important Pyrazole Derivatives: Pyrazolylbenzothiazine

Pyrazole derivatives, a set of hererocycles, occupy a significant place in pesticide and medicinal chemistry by means of a large collection of bioactivities. Pyrazole derivatives are well known and reported to show antibacterial, fungicidal, herbicidal, antimicrobial, antiinflammatory, and anticancer activities [117Liu, X.H.; Cui, P.; Song, B.A.; Bhadury, P.S.; Zhu, H.L.; Wang, S.F. Synthesis, structure and antibacterial activity of novel 1-(5-substituted-3-substituted-4,5-dihydropyrazol-1-yl)ethanone oxime ester derivatives. Bioorg. Med. Chem., 2008, 16(7), 4075-4082.
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]. Pyrazophos, the fungicide was marketed by Hoechst AG in1974, which have the ability to control powdery mildew in vegetables. The significance like a novel mode of action, broad spectrum of activity, lesser toxicity towards mammalian cells, and suitable profiles towards humans have triggered the use of pyrazole in designing and synthesizing its derivatives with better properties. Recently, pyrazole compounds, like pyraclostrobin (BASF, 2001) and penthiopyrad (Mitsui Toatsu Chemicals, 1995), are found to be latent antifungal agents for the control of various plant diseases. In recent years, researchers have given considerable attention to the synthesis of pyrazole and their derivatives due to their wide ranging bioactivities obtained through modification of structural profile by a change of the substituents in pyrazole ring [128Li, Y.; Zhang, H.Q.; Liu, J.; Yang, X.P.; Liu, Z.J. Stereoselective synthesis and antifungal activities of (E)-alpha-(methoxyimino)benzeneacetate derivatives containing 1,3,5-substituted pyrazole ring. J. Agric. Food Chem., 2006, 54(10), 3636-3640.
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].

In view of the structural relationship with bioactivities, the synthesis of substituted 1,4-benzothiazines Fig. (3), incorporating both benzothiazine and pyrazole heterosystems with this assumption that the synthesized heterocycles will exhibit better features caused by co-existence of two types of pharmacophoric interactions with different action of mechanism have also been reported.

2.4. Medicinally Important Morpholine/Piperazine and their Derivatives: Morpholinyl/Piperazinylbenzothiazines

The systems containing morpholine fragments have attracted interest as potential biologically active compounds [129Mashkovskii, M.D. Lekarstvennye sredstva (Drugs), 2002, 1, 253-263.-135Abdel-Jalil, R.J.; Ali Shah, S.T.; Khan, K.M.; Voelter, W. A novel route towards the synthesis of stereospecific n-substituted chiral morpholines. Lett. Org. Chem., 2005, 2, 306-308.
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[http://dx.doi.org/10.1002/ps.2780150311]
]. Reboxetine acts as an antidepressant drug and is applied to treat panic disorder, clinical depression, hyperactivity disorder [137Wong, E.H.F.; Sonders, M.S.; Amara, S.G.; Tinholt, P.M.; Piercey, M.F.P.; Hoffmann, W.P.; Hyslop, D.K.; Franklin, S.; Porsolt, R.D.; Bonsignori, A.; Carfagna, N.; McArthur, R.A. Reboxetine: A pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor. Biol. Psychiatry, 2000, 47(9), 818-829.
[http://dx.doi.org/10.1016/S0006-3223(99)00291-7] [PMID: 10812041]
]. Fenpropimorph is a broadly used leaf fungicide and is predominantly used to limit fungal diseases in cereals [138Dieckmann, H.; Stockmaier, M.; Kreuzig, R.; Bahadir, M.F. Simultaneous determination of fenpropimorph and the corresponding metabolite fenpropimorphic acid in soil. J. Anal. Chem., 1993, 345, 784-786.]. Trioxazine, ofloxacin, ethmosine, dextromoramide, etc. containing morpholine nucleus have also found their applications in medicine. Morpholine derivatives have been the area of interest for the pharmaceutical industry as these act as bioactive compounds and effective substrates for further elaboration. In this regard, a number of patents elucidating the biological significance of such compounds have been published [139Kaiho, T.; Kusano, K.; Taniyama, T. Benzyl alcohol derivatives or salts thereof. WO 2005023235 A1, 2005.-143Sugihara, Y.; Iizawa, Y.; Baba, M. Cyclic amine compound, process for producing the same, and use. WO 2004026833A1, 2004.]. The literature survey reveals that the compounds with morpholine Fig. (4) show enormous therapeutic uses that include antimalarial [144Singh, N.; Sijwali, P.S.; Pandey, K.C.; Rosenthal, P.J. Plasmodium falciparum: Biochemical characterization of the cysteine protease falcipain-2′. Exp. Parasitol., 2006, 112(3), 187-192.
[http://dx.doi.org/10.1016/j.exppara.2005.10.007] [PMID: 16337629]
], antibacrerial [145Hirokawa, Y.; Kinoshita, H.; Tanaka, T.; Nakamura, T.; Fujimoto, K.; Kashimoto, S.; Kojima, T.; Kato, S. Pleuromutilin derivatives having a purine ring. Part 3: Synthesis and antibacterial activity of novel compounds possessing a piperazine ring spacer. Bioorg. Med. Chem. Lett., 2009, 19(1), 175-179.
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], antimicrobial [146Fung, H.B.; Kirschenbaum, H.L.; Ojofeitimi, B.O. Linezolid: an oxazolidinone antimicrobial agent. Clin. Ther., 2001, 23(3), 356-391.
[http://dx.doi.org/10.1016/S0149-2918(01)80043-6] [PMID: 11318073]
], anticonvulsant agents, antidepressant [147Takeuchi, H.; Yatsugi, S.; Hatanaka, K.; Nakato, K.; Hattori, H.; Sonoda, R.; Koshiya, K.; Fujii, M.; Yamaguchi, T. Pharmacological studies on YM992, a novel antidepressant with selective serotonin re-uptake inhibitory and 5-HT2A receptor antagonistic activity. Eur. J. Pharmacol., 1997, 329(1), 27-35.
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], lukemia [148a)Szulawska, A.; Arkusinska, J.; Czyz, M. Accumulation of gamma-globin mRNA and induction of irreversible erythroid differentiation after treatment of CML cell line K562 with new doxorubicin derivatives. Biochem. Pharmacol., 2007, 73(2), 175-184.
[http://dx.doi.org/10.1016/j.bcp.2006.09.028] [PMID: 17097070] b)Jakubowska, J.; Wasowska-Lukawska, M.; Czyz, M. STI571 and morpholine derivative of doxorubicin collaborate in inhibition of K562 cell proliferation by inducing differentiation and mitochondrial pathway of apoptosis. Eur. J. Pharmacol., 2008, 596(1-3), 41-49.
[http://dx.doi.org/10.1016/j.ejphar.2008.08.021] [PMID: 18782571]
], tranqulizer s [149Mesropyan, E.G.; Galstyan, A.S.; Avetisyan, A.A. Syntheses on the basis of 4-(Oxiran-2-ylmethyl)morpholine. Russ. J. Org. Chem., 2006, 42(12), 1845-1847.
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] and antituberculous agents [150Daryaee, F.; Kobarfard, F.; Khalaj, A.; Farnia, P. Synthesis and evaluation of in vitro anti-tuberculosis activity of N-substituted glycolamides. Eur. J. Med. Chem., 2009, 44(1), 289-295.
[http://dx.doi.org/10.1016/j.ejmech.2008.02.022] [PMID: 18436347]
].

Similarly, the piperazine ring is a preferrable heterosystem in medicinal-pharmaceutical chemistry and is frequently found in the structure of various enzyme inhibitors as well as clinical therapeutics [151Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; Vacca, J.P.; Guare, J.P.; Darke, P.L.; Zugay, J.A.; Emini, E.A.; Schleif, W.A.; Quintero, J.C.; Anderson, P.S.; Huff, J.R.L. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J. Med. Chem., 1994, 37(21), 3443-3451.
[http://dx.doi.org/10.1021/jm00047a001] [PMID: 7932573]
]. Piperazine and its derivatives act as useful synthetic building blocks and have been regularly used in the preparation of important biologically active compounds. Piperazine and its derivatives have also been shown to exhibit a wide spectrum of pharmacological and biological activities such as, antibacterial [152Thomas, R.C.; Cleek, G.J.; Hutchinson, D.K.; Yamada, H. Oxazolidinone antibacterial agent with tricyclic substituents. U.S. Patent 5, 1999., 153Davies, D.T.; Markwell, R.E.; Pearson, N.D.; Takle, A.K. Quinoline derivatives as antibacterials. U.S. Patent 6,911,442, 2005.], antineoplastic [154Erskine, S.G.; Gwynn, M.; Pearson, N.D.; Wilding, E.I. Compounds and methods for the treatment of neoplastic disease. U.S. Patent 6, 803, 369, 2004.], antinociceptive [155Naylor, A.; Judd, D.B.; Lloyd, J.E.; Scopes, D.I.C.; Hayes, A.G.; Birch, P.J. A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines. J. Med. Chem., 1993, 36(15), 2075-2083.
[http://dx.doi.org/10.1021/jm00067a004] [PMID: 8393489]
], antimalarial [156Cunico, W.; Gomes, C.R.B.; Facchinetti, V.; Moreth, M.; Penido, C.; Henriques, M.G.; Varotti, F.P.; Krettli, L.G.; Krettli, A.U.; da Silva, F.S.; Caffarena, E.R.; de Magalhães, C.S. Synthesis, antimalarial evaluation and molecular modeling studies of hydroxyethylpiperazines, potential aspartyl protease inhibitors, part 2. Eur. J. Med. Chem., 2009, 44(9), 3816-3820.
[http://dx.doi.org/10.1016/j.ejmech.2009.03.041] [PMID: 19403210]
], antiproleferative activity [157Ananda Kumar, C.S.; Benaka Prasad, S.B.; Vinaya, K.; Chandrappa, S.; Thimmegowda, N.R.; Kumar, Y.C.; Swarup, S.; Rangappa, K.S. Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines. Eur. J. Med. Chem., 2009, 44(3), 1223-1229.
[http://dx.doi.org/10.1016/j.ejmech.2008.09.025] [PMID: 18973966]
], Na channel blocker [158Drizin, I.; Gregg, R.J.; Scanio, M.J.; Shi, L.; Gross, M.F.; Atkinson, R.N.; Thomas, J.B.; Johnson, M.S.; Carroll, W.A.; Marron, B.E.; Chapman, M.L.; Liu, D.; Krambis, M.J.; Shieh, C.C.; Zhang, X.; Hernandez, G.; Gauvin, D.M.; Mikusa, J.P.; Zhu, C.Z.; Joshi, S.; Honore, P.; Marsh, K.C.; Roeloffs, R.; Werness, S.; Krafte, D.S.; Jarvis, M.F.; Faltynek, C.R.; Kort, M.E. Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain. Bioorg. Med. Chem., 2008, 16(12), 6379-6386.
[http://dx.doi.org/10.1016/j.bmc.2008.05.003] [PMID: 18501613]
], antitumor [159Shami, P.J.; Saavedra, J.E.; Bonifant, C.L.; Chu, J.; Udupi, V.; Malaviya, S.; Carr, B.I.; Kar, S.; Wang, M.; Jia, L.; Ji, X.; Keefer, L.K. Antitumor activity of JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and related O2-aryl diazeniumdiolates in vitro and in vivo. J. Med. Chem., 2006, 49(14), 4356-4366.
[http://dx.doi.org/10.1021/jm060022h] [PMID: 16821795]
], antagonistic [160Li, J.B.; Xia, L.; Wu, B.; Wang, T.; Jiang, Z.Z. Design, synthesis and biological estimation of 1-(benzoxazole-2-yl)piperazine and 4-(benzoxazole-2-yl)piperidine derivatives as potential α1-AR antagonists. Chin. Chem. Lett., 2008, 19, 1193-1195.
[http://dx.doi.org/10.1016/j.cclet.2008.06.042]
], antimicrobial [161Masson, M.; Holappa, J.; Hjalmarsdottir, M.; Runarsson, O.V.; Nevalainen, T.; Jarvinen, T. Antimicrobial activity of piperazine derivatives of chitosan. Carbohydr. Polym., 2008, 74, 566-571.
[http://dx.doi.org/10.1016/j.carbpol.2008.04.010]
], etc.

Taking into account the significance of piperazine scaffold in a wide range of applications [162Sharma, P.K. Antifungal, Antibacterial and Antioxidant activities of substituted Morpholinylbenzothiazine. Der Pharmacia Lettre., 2016, 8(11), 140-142.-174Sharma, P.K. Synthesis of 2,4-diaryl-2, 3-dihydro-1, 5-benzothiazepines. Heterocycl. Commun., 2008, 14(3), 155-160.], we apprehended that it might be worthwhile to incorporate the piperazine heterosystem alongwith 1,4-benzothiazine Fig. (5), to synthesize therapeutically interesting heterocycles with structural diversity [175Sharma, P.K. Synthesis, spectral, energetic and reactivity properties of phenothiazines: Experimental and computational approach. J. Chem. Pharm. Res., 2015, 7(11), 462-473.-179Jampilek, J. Heterocycles in Medicinal Chemistry. Molecules, 2019, 24(21), 3839.
[http://dx.doi.org/10.3390/molecules24213839] [PMID: 31731387]
].

Fig (3)
Pyrazolylbenzothiazine.


Fig (4)
Morpholinylcarbonyl-4H-1,4-benzothiazines.


Fig (5)
Piperazinylcarbonyl-4H-1,4-benzothiazines.


CONCLUSION

Literature reveals that nitrogen and sulphur containing heterosystems are truly important for the development of human and associated society. These heterosystems play an important and key role in curing process against life threating diseases, which directly influence the growth of humans and animals. The overall objective of the review is to discuss the importance of novel biodynamic structurally diverse heterocycles of potential therapeutic interest, pyrimidine, morpholine, piperazine, pyrozole, benothiazoles, pyrimidobenzothiazoles, 4H-1,4-benzothiazines, pyrazolyl-benzothiazines, morpholinyl-benzothiazines and piperazinylbenzothiazines in order to have access to important commercial molecules for the search of better future.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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