Exploring Potential of 1,5-Benzothiazepines: A Brief Review
A. P. G Nikalje*, M. Ghodke, S. Tiwari
Department of Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy. Dr. Rafiq Zakaria Campus, Aurangabad. 431001.(MS) India.
*Corresponding Author E-mail: ana@k.st
ABSTRACT:
Benzothiazepines are fused heterocyclic compounds. They are claimed of various therapeutic activities and hence, they are utilized in drug research. Recently, attention is being directed to their synthetic methods, chemical and biological properties. Benzothiazepines posses wide variety of biological activities like anticonvulsant, CNS depressant, Ca++ channel blockers, calcium channel modulator, calcium channel antagonist, anticancer, anti fungal antimicrobial, anti‐HIV and anti-anginal.
KEYWORDS: 1,5-benzothiazepine, CNS, Green synthesis, Microwave –assisted.
Benzothiazepine is a heterocyclic compound that contains a benzene ring fused with, a seven membered ring, having nitrogen and sulphur. Benzothiazepine derivatives are of two types; 1) 1,4-benzothiazepine and 2) 1,5-benzothiazepine, as shown in Fig. 1.
1, 4-Benzothiazepine
1,5-Benzothiazepine
Fig.1 Types of benzothiazepines
Benzothiazepines exists in two tautomeric forms i.e imino and enamino structure. as shown in Fig. 2.
Imino
Enamino
Fig.2 Tautomeric forms of benzothiazepins
In the imino structure of 2, 4-substituted-1,5-benzothiazepines, C2 is the chiral centre having methine proton and C3 is a prochiral centre bearing two methylene protons, where HA and HB are the two hydrogen, one of which is equatorial and the other is axial. The hydrogen gives peculiar pattern in PMR spectra and appear as double doublets .Substitutions on this hydrogens produces isomers. The enamino form has one methine proton at C2 chiral center, but has only one proton at C3 and be easily distinguished by appearance of only doublet for C2 and C3 proton.
Benzothiazepines have been claimed of various therapeutic activities, but the investigation of their chemistry commenced rather slowly. Benzothiazepines posses wide variety of activities like anticonvulsant, CNS depressant, Ca++ channel blockers, anticancer, anti fungal, antiviral, antitumor, anti-HIV, antimicrobial, etc. The molecule has structural resemblance to benzodiazepam, established CNS depressant and hence can be used as its bioisosteric replacement. However there are less reports on the CNS action specially anticonvulsant and CNS depressant activity. This review article aims to cover many previous as well as latest research explaining synthetic protocols and diverse biological activities. The comprehensive literature survey of 1,5-benzothiazepines will help the upcoming researchers to synthesize the novel derivatives possessing various therapeutic effects
Synthesis of 1, 5-Benzothiazepines:
Several methods for synthesis are available in literature which involves conventional, microwave as well as combinatorial synthetic methods. Benzothiazepine are prepared by condensation of 2-aminothiophenol with carbonyl compounds. Various research groups have reported methods of synthesis for 1, 5-benzothiazepines. Following are some of the methods reported:
i) Hideg K. and Hankovszky1 have synthesized 4-substituted-1,5-benzothiazepines by the condensation of 2-aminothiophenols with open chain or alicyclic β-amino ketones in neutral medium, as shown in Fig.3 .
ii) 3-Hydroxy-1,5- benzothiazepine-4-ones were prepared by the reaction of 2-aminothiophenol with an epoxyalkane carboxylic esters., as reported by Kugita et al2 and shown in Fig.4.
iii) Acrylic acids like ά-phenyl crotonic acid, sorbic acid were used by Krapcho and Turk3, and adamantly acrylic acids when reacted with 2-aminothiphenol gives 1, 5-benzothiazepin-4-one, as shown in Fig.5.
iv) 2, 4-Disubstituted-2, 3- dihydro-1, 5- benzothiazepine are obtained by cyclo condensation of 2-amino thio phenols with ά-β-unsaturated carbonyls in neutral medium.
v) Hideg and Hankovszky4 and Levai and Bognar5 have synthesized benzothiazepines by reaction of 2-aminothiophenol with chalcones in alcohol-acetic acid mixture or xylene instead of isolating thio propeophenone intermediates, Fig.6.
vi) Stephens and Field6 have used piperidine as catalyst for the condensation of 2-amino thio phenols with ά-β-unsaturated carbonyls and also isolated β- phenyl – β ( 2-aminophenyl thio)- propeophenones as intermediates, these when reacted with acetic acid gave 2,3- dihydro-1,5- benzothiazepine.
vii) Murata et al7 have synthesized the optically active trans-isomers of diltiazem and their cardiovascular effects and Ca-antagonistic activity.
Apart from these various conventional methods reported earlier, the following are the recent synthetic methodology and biological activities , reported by various researchers.
LITERATURE SURVEY:
1) Sharma et al.8have synthesized new 1,5 -benzothiazepine Derivatives as Analogues of Anticancer Drugs. (±) cis-2-(4-Methoxyphenyl)-3-hydroxy/methoxy-2,3-dihydro-1,5-benzothiazepin-4 [ 5H/5- chloroacetyl/5-(4'-methylpiperazino-1')acetyl]-ones have been synthesized by the condensation of 2- aminobenzene thiols with methyl(±)trans-3-(4-methoxyphenyl) glycidate in xylene. The synthesized compounds have been characterized by elemental analyses and spectral data and screened for their antimicrobial activity.
2) Pant et al 9 have synthesized 8-substituted-2,5-dihydro-2-(4-N-dimethyl amino phenyl)- 4-(4- methoxy phenyl) -1,5-benzothiazepines by reacting 5-substituted-2-aminobenzene-thiols with 4-N dimethyl amino benzal- 4-methoxy acetophenone in dry ethanol saturated with hydrogen chloride gas.
3) Grandolini et al.10 have synthesized some new 1, 4-benzothiazine and 1,5-benzothiazepine tricyclic derivatives with structural analogy with TIBO and their screened for anti-HIV activity, Fig 7.
Fig.7 1,4-Benzothiazine and 1,5-benzothiazepine tricyclic derivatives
4) Yuan and Yuan et al11 have synthesized a steric structure of 1, 5-Benzothiazepine-Phenyl-β-Lactams.In this method 1, 5-Benzothiazepines were reacted with phenylacetyl chloride to give the title compounds.
5) Ali et al.12 have synthesized 1,5-benzothiazepin-4-ones by ring transformation of 5-ylidene-1,3-dioxan-4-ones with 2-aminothiophenol. Here author described stereo selective conjugate addition of the –SH group of 2-aminothiophenol to the Michael system of the chiral 5-ylidene-1,3-dioxan-4-one, catalyzed by BuLi, gave adducts. The stereo chemical- mode of attack can be rationalized by hydrogen bonding of the attacking 2-aminothiophenolate with the oxygen atoms of the dioxanone ring. Treatment of the adducts with ethyl magnesium bromide afforded ring transformation by attack of the amino group at the carbonyl carbon atom cleaving the dioxanone ring. The resulting 3-(1-hydroxyethyl)-1, 5-benzothiazepin-4-ones represent structural analogues of Diltiazem®, a widely used drug in the treatment of hypertension.
6) Micheli et al.13 have synthesized [1,5] Benzothiazepine derivatives as potential antibacterial agents and reports the exploration of this scaffold for the generation of combinatorial libraries both in solution and on solid phase, Fig. 8
Fig.8 2,4-disubstituted-1,5-benzothiazepine derivatives
7) Nikalje et al.14 have synthesized new chromonyl/ thiochromonyl 1,5- benzothiazepines and evaluated for their antimicrobial activity. In this method, 3-formyl chromones were synthesized by using Vilsmeire-Haack reaction and were then converted to respective 2-propane-1-ones by claisen condensation of this compound with 2-amino benzenethiol gave 2-chromonyl-4-substituted phenyl -2,3- dihydro-1,5-benzothiazepine, as shown in Fig. 9 The 1,5-benzothiazepine and P2S5 when refluxed in pyridine gives thiochromonyl 1,5- benzothiazepines.
Fig.9 3-Substituted chromonyl-1,5-benzothiazepine derivatives
8) Mistry and Desai et al 15 have synthesized 1,5-benzothiazepine using Microwave assisted rapid and efficient method.1,5-Benzothiazepines have been synthesized in 75-90% yield by a microwave promoted condensation of 2-aminothiophenol and various chalcones in the presence of catalytic amount of glacial acetic acid using methanol as a reaction mediator. The work-up is simple and involves treatment with ice-cold water. All the compounds of this series have been evaluated for their antibacterial activity.
9) Nikalje et al.16 have synthesized New 1,5-Benzothiazepines as prospective antimicrobial agents. In this, new 3-substituted benzoyl-1,5-benzothiazepine have been obtained by refluxing 1-[4,substituted phenyl]-2-[2’-hydroxy-5’-CH3/ Cl- benzoyl]-3-[4’-substituted phenyl]-propen-1-one with 2-amino thiophenols in ethanol ethanol using piperidine and acetic acid as catalyst,as shown in Fig.10. Further 3-substituted benzoyl-1,5-benzothiazepine converted to their 1,1-dioxides and evaluated for their antimicrobial activity.
Fig.10 2 –Aryl ,3-substituted benzoyl-1,5-benzothiazepine derivatives
10) Nikalje et al. 17 have synthesized new 4-thiazolidinoyl-1, 5- benzothiazepines and evaluated for their antimicrobial activity. In this method 2-[substituted phenyl]-4-[2’-hydroxy-3’/5’- substituted phenyl] 2,3-dihydro-1,5-benzothiazepines were formylated using Vilsmeier-Haack reagent. The 3-formyl-1, 5-benzothiazepines were condensed with aromatic amines to give Schiff’s bases, which were cyclo condensed with mercapto acetic acid by refluxing in dry benzene, using anhydrous zinc chloride as a catalyst, to give 4-thiazolidinoyl-1, 5- benzothiazepines, Fig. 11.
Fig.11 4-Thiazolidinoyl-1, 5- benzothiazepines derivatives
11) Nikalje et al18 have synthesised new 2-[substituted thiochromonyl-3’-yl]-4-[2’-hydroxy-3’/5’- substituted phenyl]2,3-dihydro-1,5-benzothiazepines and screened these compounds for their CVS and CNS activity.
12) Gan and Ma19 reported solution-phase parallel synthesis of 2, 3-Dihydro-1,5-benzothiazepin-4(5H)-ones. As shown in Fig. 12 two types of derivatives are obtained.
Fig.12. 2, 3-Dihydro-1,5-benzothiazepin-4(5H)-ones
This benzothiazepin-4(5H)-one skeleton possesses three or four diversity points. Furthermore, three novel tricycles integrating a benzothiazepin-4(5H)-one scaffold with other privileged structures, such as benzimidazole, benzimidazolone, and thio-benzimidazole, were also developed, Fig.8. The synthetic strategy provides an efficient way to access the benzothiazepinone core, starting from commercially available 1,5-difluoro-2,4- dinitrobenzene (DFDNB), and also allows further derivation of the strategically anchored functionalities.
13) Levai and Kiss-Szikszai 20 have synthesized an optically active 1,5-benzothiazepines. In this review article, they discussed in detail about the optically active 2,3-dihydro- 1,5-benzothiazepin-4(5H)-ones, their 3-amino and 3-hydroxy derivatives, comprising the most important groups of these benzothiazepines and also the less known optically active 1,5-benzothiazepines. Some of them possess important bioactivities.
14) Arya and Dandia21 have synthesized 1,5-benzothiazepines as a family of cytotoxic drugs. The author reported and synthesized 1,5-benzothiazepines using LaY zeolite under stirring condition and screened for cytotoxic activity, Fig.7. The reaction produces the product in relatively low yields and requires a long time when they were performed in various solvents under conventional and microwave irradiation. Thus, the procedure provides a simple and green synthetic methodology under environmentally friendly conditions.
Fig. 13 2,4-Disustituted -1,5-benzothiazepine derivatives
15) Cherkupally et al.22 have synthesized and studied novel methylene-bis-benzofuranyl- [1,5]-benzothiazepines.
A series of novel methylene-bis-[1,5]-benzothiazepines and methylene-bis-benzofuranyl-[1,5]-benzothiazepines were prepared by the reaction of methylene-bis-chalcones with 2-aminothiophenol followed by the condensation with α-bromoacetophenone. All the synthesized compounds were tested for their antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. Similarly these compounds showed potent antifungal effect against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum, and Trichophyton mentagrophytes. It is interesting to note that the compounds with heterocyclic ring substituents at the 4th position of benzothiazepine system displayed notable antibacterial activity, almost equal to that of streptomycin and penicillin
16) Raval et al23 have synthesized 2, 3-dihydro-2-aryl-4-[4-(2–oxo–2H–chromen–3–yl)–1,3-thiazol–2–ylamino]-1,5–benzothiazepines were synthesized from N-[4-(2-oxo-2H-chromen-3-yl)-1,3-thiazol-2-yl]-cinnamamide derivatives, by microwave assisted and conventional method and studied their antimicrobial activity.
17) Nikalje AG et al.24 have synthesized novel 1, 5-benzothiazepines and evaluated for anticonvulsant activity. 1,3-substituted-prop-2-en-1-one were synthesized by microwave –assisted Claisen-Schmidt condensation of acetylated a-naphthol with aldehydes in presence of alkali and ethanol. Synthesis of 2,3-dihydro-2-substituted-4- (naphthalen-2’-ol)-yl -1,5-benzothiazepines was carried out by cyclo condensation of 1,3-substituted -prop-2-en-1-one with 2-aminothiophenol in presence of ecofriendly catalyst zinc acetate in the solvent free condition under microwave irradiation, Fig.14. The compounds were evaluated for their anticonvulsant and CNS depressant activity.
18) Nikalje and Vyawahare25 have reported eco friendly synthesis of 2, 4-substituted -2, 3- dihydro -1,5-benzothiazepine derivatives as novel anticonvulsant and central nervous system (CNS) depressant agents having lesser side effects, as shown in Fig.15. The products were obtained in shorter reaction time and in better yields as compared with the conventional synthesis. Their anticonvulsant activities were evaluated by the maximal electroshock test and CNS depressant activity was evaluated by sleep deprivation test. The compounds have shown moderate CNS depressant activity and anticonvulsant activity.
Fig.15 2, 4-Substituted -2, 3- dihydro -1,5-benzothiazepine
The literature survey reveals that the 1,5-benzothiazepine molecule can be synthesized by various methods and exhibits diverse biological potential and the easy synthetic routes for synthesis have taken attention of the chemists, pharmacologists and researchers. The anticancer and anti HIV activities are the most encouraging activities for the pharmacists. Also the research in anticonvulsant and CNS depressant activity has given positive results. By the present scenario it can be concluded that 1, 5-benzothiazepines have a great potential as a therapeutic agent and which still remains to be explored.
The authors are grateful to the Chairman of the Maulana Azad Education Trust and Principal Dr. M.H Dehghan for encouragement and support.
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Received on 22.01.2013 Modified on 08.02.2013
Accepted on 18.02.2013 © AJRC All right reserved
Asian J. Research Chem. 6(2): February 2013; Page 182-186