Review ArticleDifferent Biological Activities of Substituted 1, 3 Benzothiazole DerivativesMidhula CC*, Akash Marathakam, Baijika P, Shadiha Saheed KDepartment of Pharmaceutical Chemistry, National College of Pharmacy, Manassery, Kozhikode*Corresponding author:Email: [email protected] nucleus plays a major role in heterocyclic chemistry due to its structural simplicity. A series of benzothiazole and its derivatives have been synthesized by using various methods and evaluated for its biological activity. It remains one of the most widely studied heterocyclic compounds due to its wide range of biological activities such as anticancer, antimicrobial, antifungal, antibacterial, anticonvulsant, anthelmintic, anti-tubercular, anti-inflammatory, antipsychotic and anti-diabetic activities. Works of the literature revealed that structural modification of benzothiazole derivatives have improved biological activities and increased a great interest in the research field. The present review focuses on substituted 1, 3 benzothiazoles derivatives with potential activities.Keywords: Heterocyclic compounds, Benzothiazole, Biological activities.Introduction Heterocyclic compounds are cyclic compounds containing one or more atom(s) of other elements along with carbon atoms in the ring system. Nitrogen, sulfur, and oxygen are the most typical heteroatoms. They are widely distributed in nature and are vital to our life.1Heterocyclic compounds may be classified into aliphatic or aromatic. The aromatic heterocyclic compounds are those which have a heteroatom in the ring and resemble benzene in some of their properties. Benzothiazole is aromatic heterocyclic compound. The basic structure of benzothiazole consists of a benzene ring fused with thiazole. Thiazole is a 5 membered ring system contains both nitrogen and sulfur. These two rings together constitute the basic nucleus 1, 3- benzothiazole. The numbering in thiazole starts from sulfur.2 Benzothiazole moiety is an important component of heterocyclic compounds. These compounds possess diverse biological activity such as antimicrobial, antitubercular, antitumor, antimalarial, anticonvulsant, anthelmintic, analgesic and anti-inflammatory activity. Due to their biological and pharmacological properties, they are considered important for the synthesis of the heterocyclic compound.3  Fig. 1: Chemical structure of 1, 3-benzothiazoleBenzothiazole is a bicyclic ring system with chemical formula C7H5NS (Fig. 1). It is a weak base, having a variety of biological activities and still having great scientific interest in modern days. They are widely found in the field of bioorganic and medicinal chemistry with application in new drug development.4The study of these privileged structures in drug discovery is a rapidly emerging in the field of medicinal chemistry. Biological activity Anticancer activity • Eshkil F et al., (2017) synthesized some thiourea derivatives of benzothiazoles and screened for their anticancer activity.5 (a) R = H (b) R = CH3 (c) R = OCH3 (d) R = OEtFig. 2• Uremis MM et al.,(2017) carried out synthesis, characterization, in vitro antiproliferative and cytotoxicity effects of a new class of 2-((1R, 2S) -2-((E)-4- substituted styryl) cyclooctyl)benzodthiazole derivatives by  the reaction of 10-(4-substituted benzylidene)bicyclo6.2 decan-9-ones with 2- aminothiophenol in the presence of p-TsOH.6 (a) R = 4-F (b) R = 4-CH3 (c) R = 4- OCH3Fig. 3• Belal A et al., (2017) designed, synthesized new benzothiazole/benzoxazole-pyrazole hybrids with potential as COX inhibitors and evaluated for anticancer activity.7 (a) X = O, R = CH3; (b) X  = O, R = C6H5; (c) X = S, R = C6H5; (d) X = O, R = CH2Cl; (e) X = S, R = CH2ClFig. 4 (a) X = O, R = NO2, (b) X = S, R = NO2, (c) X = O, R = Cl, (d) X = S, R = ClFig, 5• Osmaniye D et al., (2017) synthesized some novel benzothiazole-thiazolidine derivatives and evaluated its anticancer activity.8 Fig. 6• Shaik TB et al., (2017) synthesized a series of 2-anilinopyridinyl-benzothiazole Schiff bases as antimitotic agents and were rationally designed by performing molecular modeling experiments.9 Fig. 7• Dipesh K et al., (2016) reported the synthesis, characterization of some benzothiazole derivatives bearing oxindole moiety and evaluated for their potential anticancer activity.10 Fig. 8R1 R2 R3 R4CH3 H H CH3CH3 Cl H HCl H H ClCl H Cl ClCl H Cl HTable 1• Abdelgawad MA et al., (2016) synthesized new series of quinolone derivatives linked to benzothiazole or benzoxazole moieties and evaluated for anti-cancer and anti-oxidant activities.11 Fig. 9• Prabhu PP et al., (2015) synthesized a novel series of 2-(3-(4-oxo-2-substituted phenyl thiazolidin-3-yl) phenyl) benzod thiazole-6-carboxylic acid derivatives by various benzothiazole Schiff’s bases by reaction with thioglycolic acid. All the synthesized compounds were screened for their in vitro anticancer activity by 3-(4,5-dimethyl thiazole-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay on human cervical cancer cell line (HeLa) cell lines.12 R = H, p-Cl, m-F, p-NO2, p-OCH3, p-CH3, p-OHFig. 10Antimicrobial activity• Sharma PC et al., (2017) synthesized a new series of N-(6-methoxybenzodthiazol-2-yl)-2-substituted phenyl-1H-benzdimidazole-1-carbothioamide derivatives  and evaluated for antibacterial, antifungal and antimalarial effects.13 Fig. 11R1 R2 R3 R4H NH2 H HCl H H HH OCH3 OCH3 OCH3H H OCH3 OCH3H H Cl HF H H HH H NH2 HH H NO2 NO2Table 2• Saraf DV et al., (2017) carried out synthesis, characterization, antibacterial and antifungal studies on metal complexes with Schiff bases of benzothiazole by the reaction of Schiff bases with the Co and Fe metal acetates.14 Fig. 12R1 R2H  H  Table 3• Incerti M et al., (2017) synthesized a series of N?-(halophenylmethylidene)-1,2-benzothiazole-3-acetohydrazides, novel N-2-phenyl-4-oxo-1,3-thiazolidin-3-yl-1,2-benzothiazole-3-carboxamides/ acetamides and evaluated for their antimicrobial activity.15 Fig.13• Verma AK et al., (2014) synthesized parent benzothiazole nucleus by para amino acetanilide, then treatment with various substituted aromatic aldehydes to get the corresponding Schiff’s bases followed by treatment with the pthalic anhydride to form 2-(6-acetamidobenzodthiazol-2ylcarbamoyl)benzoic acid. The structures of synthesized compounds were confirmed by various spectroscopic methods such as IR, 1H NMR, and mass spectroscopy and the products were evaluated for their antibacterial activity.16 Fig. 14                                                                                                                         X = p-chloro, p-methoxy, 3-nitro, p-methyl                                                                     Fig. 15                                                                                           Fig. 16• Sarkar S et al., (2015) synthesized a novel series of azetidinone derivatives from 2, 3, 4 (trisubstituted benzaldehyde)-N-(6, 7 substituted-1, 3-benzothiazol-2-yl) semicarbazone. All of the synthesized compounds were confirmed by elemental analyses, IR and 1H NMR spectral data. These newly synthesized compounds were screened for their antibacterial activity.17 Fig. 17R R1 R2F Cl 2-CH3F Cl 4-OCH3F H 4-OCH3F H 2-CH3H Cl 4-OCH3H Cl 2-CH3Table 4Anti-fungal activity• Pejchalová M et al., (2017) synthesized a new series of 1-(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl- 3-substituted phenyl diamides, structurally evaluated and screened for antifungal activity against a variety of Candida strains.18 Fig. 18• Kukreja S et al., (2016) synthesized some novel series of fluorinated 1, 2, 4-triazolo 3, 4-b benzothiazoles and evaluated for antifungal activity.19 Ar = C6H5, 2’Cl-C6H4, 3’Cl-C6H4, 4’Cl-C6H4, 4’F-C6H4, 2’OH-C6H4, 3’OH-C6H4, 4’OH-C6H4, 4’OCH3-C6H4 , 2’NO2-C6H4, 3’NO2-C6H4, 4’NO2-C6H4, 3’OCH3, 4’OCH 3-C6H3, 3’OCH3, 4’OH-C6H3 3’OCH2CH3, 4’OH-C6H3, 4’N(CH3)2-C6H4, 3’OCH3,4’OCH3,5’OCH 3-C6H2 3’OCH3,4’OH,5’OCH ,3-C 6H2 ,C4H3O ,-CH=CH-C6H5.Fig. 19• Maddila S et al., (2016) synthesized  a new series of 5-amino-6-(benzodthiazol-2-yl)-2-(2-(substituted benzylidene)hydrazinyl)-7-(4-chlorophenyl)pyrido2,3-dpyrimidin-4(3H)-one derivatives. All the newly synthesized compounds were screened for their in vitro antibacterial activity and for antifungal activity.20  R = H, 4-Cl, 2-Cl, 4-CH3, 4-CH3O, 4-F, 4-NO2, 2, 4-(CH3)2, 4-NH2, 4-C2H5, 4-CH (CH3)2Fig. 20Anticonvulsant activity • Siddiqui N et al., (2017) reported the synthesis and docking study of 2-(6-substituted benzodthiazol-2-yl carbamoyl) methyl-1-(4-substituted phenyl) isothiourea derivatives and evaluated its anticonvulsant activity.21 R & R1 = H, 4-CH3, 4-OCH3, 4-Br, 4-ClFig. 21• Saleh OA et al., (2016) synthesized N-(6-substituted benzod thiazol-2-yl)-2-(4-substituted piperazin-1-yl) acetamides and evaluated for anticonvulsant activity.22 Fig. 22R1 R2Br C2H5Cl C2H5CH3 C2H5Br CH2C6H5Cl CH2C6H5CH3 CH2C6H5Table 5• Singh R et al., (2014) synthesized a new series of 2-amino-6-substituted benzothiazole by using 4-substituted aniline and potassium thiocyanate in presence of bromine in glacial acetic acid which further treated with various substituted aromatic aldehydes in presence of glacial acetic acid to get the 2-iminobenzothiazole derivatives. 23  R = Cl, F, Br, NO2Fig. 23 R= Cl, N (CH3)2, OCH3, CH3Fig. 24Anti-inflammatory activity• Patil V et al., (2015) synthesized 2-amino-6-methoxy benzothiazole derivative by simple condensation of benzothiazole with chloroethyl acetate and further treated with hydrazine hydrate to obtain hydrazino benzothiazole. The compounds were screened for their anti-inflammatory activity.24                                                                                 Fig. 25• Kharbanda C et al., (2014) synthesized pyrazolines bearing benzothiazole and evaluated for their anti-inflammatory potential using carrageenan-induced paw edema model.25 X = Cl/ Br.,Ar = Fig. 26MISCELLANEOUS • Charehsaz M et al., (2017) carried out Toxicological Evaluation of Benzothiazole Derivatives Carrying Piperazine Ring.26  R = Benzoyl, 2-FluroylFig. 27• Faraji L et al., (2017) synthesized, characterized a series of novel benzimidazole and benzothiazole derivatives bearing a 1, 2, 3-triazole ring system and their acetyl cholinesterase inhibitory activity and evaluated for in- vitro acetyl cholinesterase (AChE) inhibitory activity.27 Fig. 28• Thakkar SS et al., (2017) reported synthesis, characterization and biological activities of benzothiazole. Invitro antimalarial and antimicrobial activities were studied. The molecules were characterized by IR, Mass, 1 H NMR, 13C NMR and elemental analysis.28 R =3- NO2, 4-Cl, 2-NO2, 3, 4-di Cl, 4-Br, 4-OH, 4-FFig. 29 R1 = O, S, NHFig. 30• Telvekar VN et al., (2012) designed and synthesized a novel series of substituted 2-(2-(4-aryloxybenzylidene) hydrazinyl) benzothiazole derivatives incorporating 2-hydrazinyl benzothiazole and 4-(aryloxy) benzaldehyde using molecular hybridization approach. All the synthesized compounds exhibited promising activity against Mycobacterium tuberculosis H37Rv strains using REMA.29  Fig. 31CONCLUSIONFrom the above literature review concluded that the benzothiazoles and their derivatives have shown a wide spectrum of biological activities. Researchers have been synthesized different derivatives due to its structural simplicity. The benzothiazole moiety has a greater significance of in the area of drug discovery. REFERENCES1. RG I, Marathe RP. Review on literature study of benzothiazole. 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