Synthesis and Biological Importance of 2-(thio)ureabenzothiazoles

Abstract

The (thio)urea and benzothiazole (BT) derivatives have been shown to have a broad spectrum of biological activities. These groups, when bonded, result in the 2-(thio)ureabenzothizoles (TBT and UBT), which could favor the physicochemical and biological properties. UBTs and TBTs are compounds of great importance in medicinal chemistry. For instance, Frentizole is a UBT derivative used for the treatment of rheumatoid arthritis and systemic lupus erythematosus. The UBTs Bentaluron and Bethabenthiazuron are commercial fungicides used as wood preservatives and herbicides in winter corn crops. On these bases, we prepared this bibliography review, which covers chemical aspects of UBTs and TBTs as potential therapeutic agents as well as their studies on the mechanisms of a variety of pharmacological activities. This work covers synthetic methodologies from 1935 to nowadays, highlighting the most recent approaches to afford UBTs and TBTs with a variety of substituents as illustrated in 42 schemes and 13 figures and concluded with 187 references. In addition, this interesting review is designed on chemical reactions of 2-aminobenzothiazoles (2ABTs) with (thio)phosgenes, iso(thio)cyanates, 1,1'-(thio)carbonyldiimidazoles [(T)CDI]s, (thio)carbamoyl chlorides, and carbon disulfide. This topic will provide information of utility for medicinal chemists dedicated to the design and synthesis of this class of compounds to be tested with respect to their biological activities and be proposed as new pharmacophores.

Keywords: (thio)carbonyldiimidazoles; (thio)phosgene; (thio)ureabenzothiazoles; 2-aminobenzothiazoles; carbamoyl chlorides; carbon disulfide; iso(thio)cyanates.

Figure 1

UBT and TBT derivatives with biological activities.

Scheme 1

UBTs and TBTs synthesized by Kaufmann.

Scheme 2

UBTs and TBTs from the Kaufmann method.

Figure 2

Substituted UBTs 9 from 2ABTs and alkyl-, -aryl-isocyanates, and carbamoyl chloride.

Scheme 3

4,6-disubstituted-β-bromo-propionyl-UBTs 10 and 4,6-disubstituted-ethenoyl-UBTs 11 to produce dihydrouracils 12.

Scheme 4

Phenyl-UBT 13 from Pd catalyzed C–N coupling of BT-2-ol with phenyl urea or from 2ABT with phenyl-isocyanate.

Scheme 5

6-substituted-UBTs from alkyl-, aryl-isocianates, or phenyl chloroformate.

Scheme 6

6-(2,6-dichlorobenzoamidyl)-alkyl UBTs 15 from the corresponding 2ABT.

Scheme 7

Synthesis of substituted hepta-O-Acetyl-β-D-lactosyl-TBTs.

Figure 3

Use of CDI or TCDI to afford substituted-aryl-UBTs 17,19,20 and -aryl-TBTs 18.

Figure 3

Use of CDI or TCDI to afford substituted-aryl-UBTs 17,19,20 and -aryl-TBTs 18.

Scheme 8

Phenyl-TBT 21 from rearrangement of 3-phenylamino-5-phenylimino-1,2,4-dithiazole.

Scheme 9

6-substituted and 5,6-disubstituted Aryl-UBTs from 2ABTs and arylisocyanates.

Figure 4

N-bis(trifluoromethyl)alkyl-UBTs 23a–c from 2ABT and fluoroalkyl isocyanates.

Figure 5

6-trifluoromethoxy-TBTs 24a–f derived from Riluzole.

Scheme 10

Synthesis of 4/6-substituted-phenylTBTs 25 to afford the thiobarbituric acid derivatives 26.

Scheme 11

Reaction of 4,7-disubstituted-2ABT with a phenyl chloroformate to synthetize 4,7-disubstituted-piperidineUBTs 27a–c.

Scheme 12

The 6-substituted benzyl-UBTs 28a–g from 6-substituted-2ABT and the in situ generated benzyl-isocyanates.

Scheme 13

Synthesis of substituted-(phenyl)-methyl-phosphonate-TBTs 30a–p from substituted 2ABTs and thiocyanates.

Scheme 14

The 6-substituted Aryl-UBTs 31a–e and 32a–e from 6-substituted 2ABTs with aryl-isocyanates.

Figure 6

The 4/6-arylsubstituted-TBTs from 4/6-substituted 2ABT and aryl isothiocyanates.

Scheme 15

Synthesis of aryl-UBTs from 2ABT and aryl-isocyanates.

Scheme 16

UBT 36a and TBT 36b from 6-methoxy-2ABT and the cleavage of the methoxy groups.

Figure 7

Di- and tri-substituted ethyl-UBTs 37–42 from 5,6-, 5,7-, or 4-F,5,7-dihalogenide ethyl-UBTs derived from the corresponding 2ABT and ethyl-isocyanate.

Scheme 17

The 6- and 5-substituted ethyl UBTs and ethyl-substituted-UBTs.

Scheme 18

The 5,7-disubstituted ethyl-UBTs 49–51 from 5-OBn, 7-Bromo-ethylUBTs 46.

Figure 8

The 5-substituted alcohol-containing ethyl-UBTs 52a–s, 53a–g, and 54a–k.

Figure 8

The 5-substituted alcohol-containing ethyl-UBTs 52a–s, 53a–g, and 54a–k.

Figure 9

Tolyl UBTs 56 from the respective tolyl-isocyanate.

Scheme 19

The 6-bromo ethyl-substituted-UBTs 56 from 6-bromo-2ABT and CDI then substituted ethylamine to be N-aryl-sulfonated.

Figure 10

The 6-(2-Ome, 3-substituted Pyridine 2-morpholinethylUBTs for comparative activities.

Scheme 20

Synthesis of 6-sulfonamide-BisTBTs 61a,b and 6-sulfonamide-bis-MeisoTBTs 63a,b 6-sulfonamide-2ABT and CS₂/NaOH then dimethyl-sulfate.

Scheme 21

Three ways to synthesize picolinamide based UBTs 64a, 64b, ethyl TBT 65, and UBTs 66a–n.

Scheme 21

Three ways to synthesize picolinamide based UBTs 64a, 64b, ethyl TBT 65, and UBTs 66a–n.

Scheme 22

Substituted 1,1,1-trifluoroethylUBTs 67a–d from substituted 2ABT and tri-fluoroethyl-isocyanate.

Scheme 23

UBTs 68 and 69 from o-amino-thiophenol disulfide, copper cyanide, and aryl cyanates.

Scheme 24

Substituted benzene-sulfonamide-TBTs 70a–c from substituted 2ABTs and 4-isothiocyanatobenzenesulfonamide.

Scheme 25

UBTs and TBTs 71a–v from 6-substituted 2ABTs and alkyl/cycloalkyl/aryl isocyanates or isothiocyanates.

Scheme 26

UBTs 72a–m with a pyridyl-amide moiety by ether linkage at the 6-position of BT.

Scheme 27

UBTs 73a and 73b from an in situ generated 2-isocyanateBT and anilines.

Scheme 28

TBT 74 from ammonium thiocyanate in acid media.

Scheme 29

Synthesis of 6-substituted aryl-UBTs 75a–zb and Frentizole based aryl-UBTs 75zc–zt.

Scheme 30

The 6-substituted UBTs, TBTs, and GBT from 6-substituted 2ABTs and CDI or TCDI.

Scheme 31

The 5-substituted TBTs from CS₂ in basic media then dimethyl-sulfate and ammonia.

Scheme 32

The 6-substituted-luoroquinolone-TBT derivatives 78a–n from 6-substituted-2ABTs, fluoroquinolones and CS₂ in basic medium.

Scheme 33

Substituted-TBTs 79 from alkyl- or aryl-isothiocyanates to be cyclized to compounds 80.

Scheme 34

Synthesis of BMZ-TBTs 81 from 6OMe-2ABT, 2-aryl-BMZs, and CS₂ in basic media.

Scheme 35

The 6-substituted-substitutedUBTs 83 from 6-methoxy-2ABT and phenylisocyanates and their modified compounds 83–85.

Scheme 36

Synthesis of 6-amino-ethylUBT to be transformed to 6-substituted ethyl-UBTs 86c–e, 86g.

Figure 11

The 6-substituted-arylUBTs 87a–l, 88a–g, and 89a–d from CDI and the corresponding substituted aniline.

Scheme 37

The 6-substituted-TUBTs as intermediates to be cyclized to compounds 90 and 91.

Scheme 38

Substituted-UBTs 94a–f derived from α-amino-acids from di-thiomethyl-carboimidate-BT 92.

Scheme 39

The 6-substituted-p-methoxybenzylUBTs 95a–j from 6-substituted-2ABTs and the N-(4-methoxybenzyl) carbamoyl-imidazole.

Figure 12

Substituted UBTs 96a–zzc and TBT 97 from substituted 2ABTs, CDI, or TCDI and aniline derivatives.

Figure 13

General structure of tested Frentizole derivatives.

Scheme 40

Chiral UBT 99a and TUBTs 99b,c from chiral isocyanate or thiocyanate.

Scheme 41

Substituted aryl-UBTs 100xY from aryl-isocyanates in ketone.

Scheme 42

The 6-substituted-substituted UBTs 101a–i from iodine catalyzed reaction of 6-substituted 2ABTs with isocyanides.

Scheme 43

Amination-desulfurization of substituted-ary TBTs 102 to afford GBTs 103.

Figure 14

Substituted-sugar-TBTs 104 used as intermediates in the synthesis of substituted-sugar-GBTs.