INTRODUCTION:
A brief Introduction
A thiazole ring is attached to benzene in the bicyclic compound benzothiazole (figure 1). Nine coplanar atoms create benzothiazole1. It's a heterocyclic compound which has anticancer2, anti-diabetic3, hepatoprotective4, antioxidant5,6, analgesic7,8, anti-inflammatory910, antibacterial11, antiviral12, antifungal13, antimicrobial14,15, antituberculosis16 and other properties.
Riluzole17 and Ethoxzolamide18 are benzothiazole derivatives that are widely available. Riluzole is an antidepressant and neuroprotective drug, whereas Ethoxzolamide is a carbonic anhydrase inhibitor.
Structure Activity Relationship:
There are several active sites in the structure of benzothiazole. When different functional groups are substituted at different sites on the benzothiazole molecule, different derivatives are formed. Positions 2, 4, 5, 6, and 7 are active sites for adding different substituents.
In the second position, phenyl and substituted phenyl groups have anticancer, anti-TB, anticonvulsant, and anti-inflammatory properties. Anticonvulsant properties are given by halogen substituents, anti-alzheimer activity is produced by -OCH3 substituents, and anti-inflammatory properties are provided by phenyl group substitutions19.
The second position of the benzothiazole moiety is relevant for substitution. The mercapto and hydrazine groups at the 2nd and 4th positions, respectively, had substantial antibacterial and anti-inflammatory activity, and the replacement of the -OCH3 group at the 4th position significantly increased the antibacterial property of the moiety. When the -OCH3 group was exchanged with -Cl at the 4th position, the antibacterial activity was completely transformed to antifungal activity. The benzothiazole moiety has also received a lot of attention as an anticonvulsant agent, and a thorough investigation by a number of researchers revealed the main characteristics of benzothiazole derivatives that are needed for their action20
The activity of benzothiazole in its second position is strengthened by the thiol group, amino group, pyrazoline moiety, and phenyl with a lipophilic group, such as -NH2, -OH, -CH3, -Cl. The potency of the compound is increased by replacing -H, -Cl, and -F atoms in the 5th position. In the sixth position, -OH, -OCH3, and -CH3 boost the compound's potency21,22.
Mechanism of Action of some Benzothiazole derivatives:
Benzothiazole is such a versatile moiety that gives many biological activities23 that are shown here in the figure below.
Various biological activities of Benzothiazole derivatives:
1. Anti-cancer activity:
Several studies have shown that certain benzothiazole compounds synthesised have biological and pharmacological activity. Prasad et al. synthesised 2-(9-chloro-3-cyano-8-fluoro-2-methylthio-4-oxo-4H-pyrimido [2, 1-b] [1,3] benzothiazole and its 2-substituted derivatives. MTT assay24 method was used to screen derivatives for in-vitro anticancer activity against MCF-7 (Human Breast cancer cell line), Hepg2 (Human Liver cancer cell line), B16(mouse melanoma cells), A-549 (Human lung cancer cell line) and Hela (Human Epithelial cervix cancer cell line) cell lines. As a standard medication, doxorubicin was used25.
Uremis et al. discovered cytotoxic properties in 2-((1S,2S)-2-((E)-4-nitrostyryl)cyclopent-3-en-1-yl)benzo[d] thiazole and 2-((1S,2S)-2-((E)-4-florostyryl)cyclopent-3-en-1-yl)benzo[d] thiazole. The effects of these derivatives on PANC-1 human pancreatic cancer cells after treatment with 5 to 100 M of the compounds for 48 hours were measured using the MTT assay. Synthetic benzothiazole compounds inhibited pancreatic cancer cells more effectively than gemcitabine26.
Sadhasivam et al. synthesised a number of novel substituted benzothiazole compounds, including 4-(Benzo[d]thiazol-2-yl)-N5-phenyl-1H-pyrazole-3,5-diamine and (3-Aminobenzo[d]thiazol-2-yl)-N5-phenyl-1H-pyrazole-3,5-diamine and (3-Amino -4-(benzo[d]thiazol-2-yl) -5-(phenylamino)thiophen-2-yl)-4-(benzo[d]thiazol-2-yl) -5-(phenylamino)thiophen-2-yl) (4-chlorophenyl) -methanone. Both compounds were reported to have good anticancer activity in vitro and in vivo27.
Shi et al. formulated a series of new 2,6-disubstituted benzothiazol derivatives and studied their anti-cancer efficacy in vitro. According to the results, the cyclohexyl benzene sulphonamide benzothiazole derivative showed significant efficacy against human breast adenocarcinoma (MCF 7), human cervical adenocarcinoma (HeLa), and human osteosarcoma (MG63)28.
Youssef et al. produced a new sequence of seven substituted 2-phenyl-benzothiazole and substituted 1, 3-benzothiazole-2 -yl-4-carbothiaote derivatives and tested them in EAC-bearing mice for anticancer activity. Benzothiazole derivatives minimized tumour volume, packed cell volume, viable cell count, and non-viable cell count as compared to EAC control mice. Benzothiazole derivatives increased the differential count and percentage of neutrophils in benzothiazole derivatives treated mice as compared to EAC control mice, whereas lymphocytes count was decreased in benzothiazole derivatives carrying EAC cell lines29.
Singh et al. synthesised a new benzothiazole-containing amide moiety and screened it for cytotoxicity against two human cervical cancer cell lines by using MTT assay (SiHa and C33-A). Our engineered compounds are significantly more effective on HPV-positive cells (SiHa) than on HPV-negative cells, according to the findings (C33-A)30.
Devmurari et al. synthesised a number of novel benzothiazole-2-thiol derivatives and measured their anti-proliferative properties in vitro using the MTT assay. The pyridinyl-2-amine based benzothiazole-2-thiol compounds demonstrated enhanced anticancer activity on the three human cancer cells examined (SW480, HeLa and HepG2). They had powerful and broad-spectrum anti-proliferative activity against a variety of human cancer cell lines, according to further reports31.
A chain of novel substituted benzothiazoles was synthesised by Zhuang et al. Hydrogen-bonding constrained target-based virtual screening was used in the quest for a novel non-sulfamide NAE inhibitor. N-(6-(2-((3-hydroxyphenyl)thio)acetamido)benzo[d]thiazol-2-yl)-4-(trifluoromethyl)benzamide, N-(6-(2-(naphthalen-2-ylthio)acetamido)benzo[d]thiazol-2-yl) -4-(trifluoromethyl)benzamide and N-(6-(2-((4-aminophenyl) thio)acetamido)benzo[d]thiazol-2-yl)-4-(trifluoromethyl)benzamide provided selective cytotoxicity32.
Kaya et al. examined the cytotoxic activity of new 1,3,4-oxadiazolec-benzothiazole derivatives on human lung carcinoma cell line (A5490), human breast adenocarcinoma cell line (MCF-7), and mouse embryonic fibroblast cell line (NIH/3T3) using 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). N-(6-Methoxybenzothiazol-2-yl)-2-[(5-[(3-methoxyphenoxy) methyl]-1,3,4-oxadiazol-2-yl) thio] acetamide is found to be selective cytotoxic agents against MCF-7 and A549 cell lines, but not against healthy cell lines, according to these findings33.
2. Antidiabetic activity:
Patil et al. designed a list of novel (E)-3-(Benzo [d]thiazol-2-ylamino) phenylprop-2-en-1-ones with potent α-amylase inhibitory properties. These compounds showed promise as glycosidase inhibitors in male Swiss mice. The anti-diabetic efficacy of these compounds was assessed using standard α-amylase inhibition and glucosidase inhibition assays34.
Pattan et al. created a new sequence of 2-amino[5'(4-sulphonylbenzylidine)-2,4-thiazolidinedione]-7-chloro-6-fluoro benzothiazoles, which were tested for anti-diabetic activity in albino rats using the alloxan induced tail tipping process35.
Ahmadi et al. synthesised substituted aminomethyl benzothiazoles and measured blood glucose levels in rats after administration of substituted aminomethyl benzothiazoles to see if they had anti-diabetic activity. The anti-diabetic activity of 2,4-Dichloro-N-[2-[4-[(4,6-dimethyl-2 benzothiazolylamino) sulfamoyl] phenyl]ethyl]benzamide and 2,4-Dichloro-N-[2-[4-[(4-methyl-2-benzothiazolylamino)-sulfamoyl] phenyl]ethyl]benzamide was found to be greater than others36.
Moreno-Daz et al. synthesised a new sequence of N-(6-substituted-1,3-benzothiazol-2 yl) benzene sulfonamides and tested them for in vivo antidiabetic activity in a non-insulin-dependent diabetes mellitus rat model. Several compounds produced in this model significantly lowered plasma glucose levels. As a possible mode of action, the compounds were investigated in vitro as 11b hydroxysteroid dehydrogenase type 1 (11b-HSD1) inhibitors37.
Kharbanda et al. synthesised 28 benzothiazole-based sulfonylureas/sulfonylthioureas and tested their antidiabetic effect in a normoglycemic rat model using an in vivo oral glucose tolerance test (OGTT). Ten active compounds were tested in vitro for PPAR-g transactivation and found to have potent anti-diabetic properties. These ten active compounds were also discovered to transactivate PPAR, so they were tested for their anti-diabetic ability in a diabetic model induced by streptozotocin (STZ). {2-[3-(4-Chloro-phenyl)-5-phenyl-4,5-dihydro-pyrazol-1-yl]-benzothiazole-6-sulfonylN0-benzylthiourea is the most powerful compound. The OGTT was used to test the effect of {2-[3-(4-Chloro-phenyl)-5-phenyl-4,5-dihydro-pyrazol-1-yl]-benzothiazole-6-sulfonylN0-benzylthiourea a on PPAR-g gene expression activity38.
Sadhasivam et al. synthesised a new sequence of benzothiazole derivatives and used the α-amylase assay to assess their anti-diabetic activity. By inhibiting the α-amylase enzyme, (2E)-N-(2-acetamido-1,3-benzothiazol-6-yl)-3-(2- furyl)acryl amide, N-(6-{[(4-fluorophenyl)carbamoyl]amino}-1,3-benzothiazol-2-yl)acetamide and N-(6-{[(3-methoxy phenyl)carbamoyl]amino}-1,3-benzothiazol-2-yl) acetamide showed potent antidiabetic activity by inhibition of α-amylase enzyme demonstrated potent antidiabetic activity39.
Puranik et al. synthesised benzothiazole derivatives and tested their anti-diabetic efficacy using -glucosidase, α -amylase, non-enzymatic glycosylation of haemoglobin, and advanced glycation end product inhibition assays. The most active compound was discovered to be 2-(4'-(N,N-Dimethylamino) phenyl)-1,3-benzothiazole. Non-bonded interactions were formed by the enzymes α -glucosidase and α -amylase with 2-(4'-(N,N-Dimethylamino) phenyl)-1,3-benzothiazole40.
3. Hepatoprotective activity:
Kim et al. created 2,4-dihydroxyphenyl benzothiazole, which when given orally to old rats significantly reduced aging-induced hepatic steatosis without affecting body weight or serum levels of liver injury markers. It also increased mRNA expression of fatty acid oxidation-related genes. To see whether 2,4-dihydroxyphenyl benzothiazole had a direct effect on the liver, researchers used the LXR agonist T0901317 to induce lipid aggregation in HepG2 cells. T0901317 is a well-known stimulator of hepatic steatosis by inducing de novo lipogenesis. In HepG2 cells, the synthesised compound decreased triglyceride accumulation induced by T0901317 more than WY14643. The synthesized compound showed antiinflammatory effects in old rat liver. Thus 2,4-dihydroxyphenyl benzothiazole showed hepatoprotective activity in rat liver41.
4. Analgesic and anti-inflammatory activity:
2-[(2-methoxy-6-pentadecylphenyl)-methyl]-thio]-benzothiazole was synthesised by Paramashivappa et al. and it was tested in a human whole blood assay for its ability to inhibit human cyclooxgenase-2 (COX-2) enzyme, whereas the more active compounds were tested for cyclooxgenase-1 (COX-1) inhibition. In the cyclooxygenase inhibition assay, Rofecoxib was used as an active control42.
Verma et al. synthesised 2-(6-acetamidobenzo[d]thiazol-2-ylcarbamoyl)benzoic acid and its derivatives and used the carrageenan mediated paw oedema process and Eddy's hot plate method to test their anti-inflammatory and analgesic efficacy in albino rats. Many of the compounds that were synthesised had outstanding anti inflamatory and analgesic properties43.
Gurupadayya et al. formulated and tested anti-inflammatory activity of various 7-chloro-6-fluoro-2-arylidenylaminobenzo(1,3)thiazoles using a rat hind paw edoema model caused by carrageenan. The hot plate device is also used to monitor for analgesic activity. Anti-inflammatory and analgesic effects are found in the synthesised compounds44.
Ugwu et al. created twelve new benzothiazole derivatives bearing benzene sulphonamide and carboxamide and tested their anti-inflammatory and analgesic activity in vivo. They tested the anti-inflammatory activity of the synthesised compounds using a paw edema model and celecoxib as the standard medication. They also used the Cayman colorimetric COX (ovine) inhibitor screening assay to assess compounds' ability to inhibit cyclooxygenase enzymes. They used the hot plate method on albino rats to assess novel compounds' analgesic efficacy. N-(1,3-Benzothiazol-2-yl)-4-hydroxy-1-(4-methylbenzenesulfonyl)pyrrolidine-2-carboxamide and N-(1,3-Benzothiazol-2-yl)-3-(1H-indol-2-yl)-2-[N-(4-nitrobenzenesulfonyl)-1-phenyl formamido]propenamide are the most potent anti-inflammatory agents, with excellent enzyme inhibition and analgesic properties45.
Russol et al. synthesised a sequence of substituted analogues based on the novel 4H-thieno[2',3': 4,5]pyrimido[2,1-b]benzothiazole and 4H-thieno[2',3': 4,5]pyrimido[2,1-b]benzoxazole ring systems and examined them for anti-inflammatory behaviour in a carrageenan-induced rat paw Tetrahydro-12H-benzothieno[2'3': 4,5] pyrimido]2,1-b]benzoxazole-12-one was the most active compound in the sequence46.
Tariq
et al. created novel
N-(benzothiazol/oxazol-2-yl)-2-[(5-(phenoxymethyl)-4-aryl-4H-1,2,4-triazol-3-yl)thio]
acetamide derivatives and tested their anti-inflammatory and p38
MAP kinase inhibitory activity in vitro. Using a
carrageenan-induced paw edema model, the anti-inflammatory function of novel
compounds was investigated. The most effective anti-inflammatory compound was
N-(Benzothiazol-2-yl)-2-[(4-(4-fluorophenyl)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio]acetamide47.
Kumar et al. synthesised a novel sequence of 2-(5-substituted-1,3,4-oxadiazole-2-yl)-1,3-benzathiazole derivatives and tested them for anti-inflammamtory activity in a carrageenan-induced paw edema model as well as analgesic activity using the Eddy's hot plate process. The compound with the 1, 3-benzothiazole-2-carboxyhydrazide substitution at the 5th position of the oxadiazole ring showed excellent analgesic efficacy, according to the findings48.
Shafi et al. created a targeted library of novel bis-heterocycles, including 2-mercapto benzothiazole and 1,2,3-triazoles. The anti-inflammatory activity of the synthesised compounds was tested using biochemical cyclooxygenase (COX) activity assays and carrageenan-induced hind paw edema. As a common medication, ibuprofen was used. 2-((1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methylthio) benzo[d]thiazole, 2e((1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methylthio)benzo[d]thiazole, 2-((1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)methylthio)benzo[d]thiazole and 2-((1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methylthio) benzo[d]thiazole demonstrated strong anti-inflammatory and analgesic activity. 2-((1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methylthio)benzo[d]thiazole inhibited COX 2 effectively without inducing ulceration49.
5. Anticonvulsant activity:
Siddiqui et al. created 3, 4-disubstituted benzaldehyde-N-(6-substituted-1,3-benzothiazol-2-yl) semicarbazones, which were tested for anticonvulsant activity in laboratory animals by their ability to suppress experimentally induced convulsions. The maximum electroshock seizures test (MES), which is similar to electrical induction tests, was used. To assess the potential neurotoxic effects, the Rotorod test method was used. Experimental animals were Swiss albino mice of either sex50.
Nath et al. synthesised a series of N-(substituted benzothiazole-2-yl)-2-(2,3-dioxoindolin-1-yl)acetamides and tested them for anticonvulsant function and neurotoxicity in mice using the maximal electroshock test (MES), subcutaneous pentylenetetrazole (scPTZ) seizures, and a motor dysfunction model. The most powerful anticonvulsant compound was N-(5-chlorobenzo[d]thiazol-2-yl)-2-(2,3-dioxoindolin-1-yl)acetamide, which showed strong anticonvulsant activity in both MES and scPTZ screens51.
Chopade and colleagues developed a new class of 3-(6-substituted-benzothiazol-2-yl)-6-phenyl-[1,3]-oxazinane-2-thiones. All of the title compounds were tested for anticonvulsant activity in a mouse model of Maximal Electroshock (MES) induced seizures, and the most active compounds were also tested in a subcutaneous pentylene tetrazole (sc PTZ) induced seizures model. The most effective anticonvulsant compounds were 3-(6-Methyl-benzothiazol-2-yl)-6-phenyl-[1,3] -oxazinane-2-Thiones, 3-(6-Ethyl-benzothiazol-2-yl)-6-phenyl-[1,3] -oxazinane-2-thiones and 3-(6-Hydroxybenzothiazol-2-yl) -6-phenyl-[1,3] -oxazinane-2-thiones52.
Ali et al. developed a new class of 3-(2-(substitutedbenzylidene)hydrazinyl)-N-(substituted benzo[d]thiazol-2-yl)-propanamides. The two most commonly used seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ)., were used for preliminary in vivo anticonvulsant screening (phase I). The results revealed that two compounds, 3-[2-(2-Hydroxybenzylidene) hydrazinyl]-N-(6-methoxybenzo[d]thiazol -2-yl)propanamides and N-(6-Methoxybenzo[d]thiazol-2-yl)-3-[2-(4-methylbenzylidene)hydrazinyl]-propanamides which were found to be equivalent to the normal drugs phenytoin (PHY) and carbamazepine (CBZ)53.
Amir et al. produced a new sequence of N-(6-chlorobenzothiazol-2-yl)-2-substituted-acetamides and N-(6-chlorobenzothiazol-2-yl)-2-(substituted-benzylidene) hydrazine carbothioamides. Maximal electroshock seizure (MES) and subcutaneous pentylene tetrazole were used to test the anticonvulsant efficacy of compounds. The most effective anticonvulsant compounds they discovered were N-(6-chlorobenzothiazol-2-yl)-2-morpholinoacetamide and N-(6-chlorobenzothiazol-2-yl)-2-(1H-imidazol-1-yl)54.
Amnerkar et al. synthesised and tested sequence of 6-substituted-[3-substituted-prop-2-eneamido]benzoth iazole and 6-substituted-2-[(1-acetyl-5-substituted)-2-py razolin-3-yl]aminobenzothiazoles for anticonvulsant effects using the maximal electroshock seizure (MES) technique. The most effective anti -convulsant compound was 6-methyl-2-[(1-acetyl-5-(4-chlorophenyl))-2-pyrazol in-3-yl] amino benzothiazole55.
CONCLUSION:
Benzothiazole derivatives can affect blood sugar levels, microtubules, liver damage, bacterial, fungi, and virus development, inhibition of the cyclooxygenase enzyme, and convulsions, among other things. The significance of various functional groups for different activities of benzothiazole derivatives was revealed by SAR data for benzothiazole derivatives. The mercapto group in the second position, for example, has antibacterial activity, while the hydrazine group in the second position has anti-inflammatory activity. If we substitute methoxy group with -Cl at the 4th position, we get antibacterial activity, and if we substitute methoxy group with -Cl at the 4th position, we get antifungal activity. The anticonvulsant properties of N'-substituted acetohydrazide and 2-substituted hydrazinyl of 2-amino benzothiazoles have been demonstrated. Thiol group, amino group, pyrazoline moiety, phenyl with lipophilic group, including -NH2, -OH, -CH3, -Cl, increase several folds of action for anticancer agents containing benzothiazole moiety at its second place. The substitution of -H, -Cl, and -F atoms in the 5th position increases the compound's potency. -OH, -OCH3, and -CH3 increase the compound's potency in the sixth position.
CONFLICT OF INTEREST:
The authors declare no conflict of interest.
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Received on 06.02.2021 Modified on 26.04.2021
Accepted on 23.06.2021 © RJPT All right reserved
Research J. Pharm.and Tech 2022; 15(4):1901-1909.
DOI: 10.52711/0974-360X.2022.00317