Benzothiazole: Different Methods of Synthesis and Diverse Biological Activities
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Available online at www.ijpsdr.com International Journal of Pharmaceutical Sciences and Drug Research 2011; 3(1): 01-07 Review Article ISSN 0975-248X Benzothiazole: Different Methods of Synthesis and Diverse Biological Activities P S Yadav*, Devprakash, Senthilkumar G P Bharathi College of Pharmacy, Bharathinagara, Mandya, Karnataka- 571422, India ABSTRACT Substituted 1, 3-benzothiazole derivatives are an important class of heterocyclic compounds. In recent years heterocyclic compounds analogues and derivatives have attracted strong interest due to their biological and pharmacological properties. The benzothiazole nucleus containing compounds involved in research aimed at evaluating new products that possess biological activities, such as antimicrobial, anticancer, antifungal, anthelmintic, anti-diabetic, amyloid imagining agents and anticancer agents. The present review focus on the different methods of synthesis of substituted benzothiazoles with potential activities that are now in developing phase. Keywords: Substituted benzothiazole derivatives, antibacterial activity, anticancer activity, anti-diabetic activity. INTRODUCTION amino benzothiazole scaffold is one of privileged structure in A heterocyclic compound is one which possesses a cyclic medicinal chemistry [3, 5] and reported cytotoxic on cancer structure with at least two different kinds of hetero atoms in cells. [5] It must be emphasized that combination of 2- the ring. Nitrogen, oxygen, and sulphur are the most common aminobenzothiazoles with other heterocyclic is a well known heteroatoms. Heterocyclic compounds are very widely approach to design new drug like molecules, which allows distributed in nature and are essential to life in various ways. achieving new pharmacological profile, action, toxicity Most of the sugars and their derivatives, including vitamin C, lowering. The 2-(4-aminophenyl) benzothiazoles are novel for instance, exist in the form of five-membered (furan) or class of potent and selective antitumor agents and display six-membered (pyran) rings containing one oxygen atom. characteristic profile of cytotoxic response across the cell Most member of vitamin B group possess heterocyclic ring lines. In addition, benzothiazole ring is present in various containing nitrogen. One example is vitamin B6 (pyridoxine), marine or terrestrial natural compounds, which have useful which is a derivative of pyridine, essential in amino acid biological properties. In last few years it was reported that metabolism. [1] benzothiazole, its bioisosters and derivatives had Benzothiazole is a heterocyclic compound, weak base, antimicrobial activities against Gram-negative, having varied biological activities and still of great scientific Gram positive bacterias (e.g., Enterobacter, Pseudomonas interest now a days. They are widely found in bioorganic and aeruginosa, E. coli, and Staphylococcus epidermidis etc.) and medicinal chemistry with application in drug discovery. the yeast‐ (e.g., Candida albicans). Benzothiazole moites are part of compounds showing Benzothiazoles are fused membered rings, which contain the numerous biological activities such as antimicrobial [6-10] heterocycles bearing thiazole. Sulphur and nitrogen atoms anticancer [11-13, 27], anthelmintic [15], anti-diabetic [16] constitute the core structure of thiazole and many activities. They have also found application in industry as pharmacologically and biologically active compounds. anti-oxidants, vulkanisation accelerators. Various benzothiazoles such as 2-aryl benzothiazole received much N N attention due to unique structure and its uses as radioactive amyloid imagining agents [3], and anticancer agents. [4] Benzothiazoles are bicyclic ring system with multiple S S applications. In the 1950s, a number of [1] [2] 2 aminobenzothiazoles were intensively studied, as the 2- Thiazole (1) is structurally related to thiophene and *Corresponding‐ author: Mr. P S Yadav, Bharathi College pyridine, but in most of its properties it resembles to the of Pharmacy, Bharathinagara, Mandya, Karnataka- 571422, latter. Thiazole was first described by Hantzsch and Waber India; E-mail: [email protected] in 1887. Popp confirmed its structure in 1889.The numbering 1 Yadav et al. / Benzothiazole: Different Methods of Synthesis and Diverse ……………. in thiazole starts from the sulphur atom. Structure (2) is O benzothizole. The basic structure of benzothiazole consist of N CH3 NH O benzene ring fused with 4, 5 position of thiazole. The two S Cl rings together constitute the basic nucleus 1, 3-benzothiazle. 1 Benzothiazole may be prepared by action of acid anhydrides (or) chlorides on o-aminophenols and formic acid in presence Cl O CH3 of acetic anhydride. [28] (CH CO) O N NH2 3 2 O O O + + H2O OH S CH N CH3 N 3 SH N N N N Benzothiazoles are also formed by action of phosphorus NH NH [28] S S pentasulfide on o-acylaminophenoles. Cl Cl 3 OH 2 P2S5 N Me S NH S NHCOMe N N 2-mercaptobenzothiazole is vulkanisation accelerator it may NH OH [28] be prepared as follows. S 4 NH2 N (CH3CO)2O CS SH H2O + 2 + S NH S OH N N NH O S IR SPECTROSCOPIC STUDIES CH3 The IR spectrum of the compound showed absorption peak at 5 -1 -1 -1 -1 Minor modification of dihydroxyphenyl group, removal of 3344cm , 3025cm , 1630cm , 690cm due to stretching of fluro group or its replacement with other halogens had a N-H, C-H, C=N, C-S. IR spectra (KBr) were recorded on [29] profoundly dyschemotherapeuitic effect with respect to in Shimadzu IR spectrophotometer. vitro cancer cell growth inhibitory activity. [21] SAR STUDY F OH Presence of hydrophobic moieties in molecule is conductive for cytotoxic activity of benzothiazole derivitives against N cancer cell lines. The amino, hydroxyl, and chloro group OH containing benzothiazole shows better anticancer activity. S [13] The thiazole ring has been extensively studied and it N forms a part of vitamin B, penicillins and the antibacterial 4 R thiazoles. Given below is a brief account of various structural S modifications done on benzothiazole ring and their associated biological activities. R= -NH3, -OH, -Cl The substituents at second position of benzothiazole ring like SYNTHESIS mercapto group and hydrazine group are responsible for Many methods had been reported in literature. Some methods marked bactericidal activity and anti-inflametory activity. [22] were listed in this study. 1) Scheme1: Solvent free synthesis N N 2 2 Synthesis of 2-substituted benzothiazoles by condensation of SH NHNH2 S S 2-aminothiophenol with various saturated and olefinic fatty acids under microwave in solvent free condition (path-A) Introduction of methoxy group (-OCH ) at position 4 of 2- 3 with the use of catalyst P S in (path-B), the reaction was mercaptobenzothiazole increase antibacterial activity and 4 10 successful in terms of yield and was completed within 3-4 introduction of chloro group (-Cl) at same position increase min. [2] antifungal activity. [8] O SH OCH Cl 3 R + OH NH 4 4 2 N N 1 a-f 2 SH SH S S Anticancer activity of compounds (1,5) are due to substituent MW S MW nd R at position 2 of aminobenzothiazole. Compound 1 with Solvent-free N P4S10 prop-2-enamido derivative and p-hydroxyphenyl substitution Solvent-free demonstrate most marked effect and possess significant 3 a-f anticancer activity. Compounds with pyrazoline and thiazole 1 , 3 substitution (2,3,4,5) were tending to have moderate a anticancer activity. Heterocyclic rings, 1-acetyl-pyrazoline 11 and thiazole do not support eminently for anticancer activity (2,3). Chloro substituted amino benzothiazoles were found to have encouraging sensitivity to cancer cell lines compared to b fluro substituted benzothiazoles. [20] 13 IJPSDR January-March, 2011, Vol 3, Issue 1 (01-07) 2 Yadav et al. / Benzothiazole: Different Methods of Synthesis and Diverse ……………. 2) Scheme2: Synthesis of cynosubstituted conjugated O O O benzothiazoles OH a Cl b N They explored synthesis of benzothiazole based organic S 1 2 nano-particles. The elaboration of conjugated system was 3 performed by reacting equimolar quantities of 4 and 5 in dry c O THF and terbutyl alcohol at 50ºC while a small amount of S O S terbutylammonium hydroxide was slowly dropped in NH mixture. [3] N d NH NH N 5 NH2 H C 3 4 + e S SH 2 3 N 1 NH2 R S N 6 CN S 5) Scheme5 4 Development of simple procedure to prepare a series of pyrimido[2,1-b]benzothiazoles by the conjugation addition of N + O the imino nitrogen of 2-aminobenzothiazoles to alkyne β- [6] S carbon atom of acetylinic acid followed by ring closure. H R4 5 R4 R R 3 3 S - S COOH + O NH2 NH2 + R5 N N R2 OH R2 R1 R1 R5 N CN S S R4 R4 R3 R3 S H S 6 + COOH N N NH - N O N R2 R2 H 3) Scheme3: Suzuki-Miyaura coupling reaction R1 OH R1 R5 Development of microwave promoted Suzuki-Miyaura R5 reaction 2-chlorobenzothiazole with phenyl boronic acid was carrid out using Pb(PPh3)4 as a catalyst. This reaction -H2O provides the adduct 6a with excellent regioselectivity. The bis adduct 2,6-diphenyl benzothiazole(7) by the catalysis of 2,6-dichloro benzothiazole with excess of phenyl boronic R4 [4] R acid. 3 S PhB(OH) N Cl 2 Cl S S N O Pd(PPh3)4 R2 Cl R1 ligand Na CO R N 2 3 N 5 dioxane/H O 2 6a 3 6) Scheme-6 + Synthesis of substituted 2-mercaptobenzothiazoles by varying substituents at 4, 5, and 6-position in the S benzothiazole ring system. The synthesis of final compounds involves two steps- 1) Substituted anilines were converted to its hydrochloride salts. 2) This aniline hydrochloride salt was N then cyclized to substituted 2-mercaptobenzothiazoles by reacting with carbon disulphide in presence of sulfur in an 7 [8] alkaline medium. R1 R R1 1 R 4) Scheme 4: Solid phase synthesis- NH NH2HCl 2 2 R N R2 2 CS , KOH, S Conversion of resin bound isothiocynate 3 was to N-acyl, N- conc.