Chemistry and Pharmacological diversity of Benzothiazepine - Excellent pathway to drug discovery

Abstract

In this era of sporadic advancement in science and technology, a substantial amount of intervention is being set in motion to reduce health-related diseases. Discoveries from researchers have pinpointed the usefulness of heterocyclic compounds, amongst which benzothiazepine (BTZ) derivatives have been synthesized for their various pharmacological activities. This also contributes to their undeniable application in therapeutic medicine for the development of efficacious drugs. BTZs are compounds with a benzene ring fused with a thiazepine ring. This work contains several methods that have been used to synthesize 1,3-, 1,4-, 1,5-, and 4-1-benzothiazepine derivatives. In addition, up-to-date information about the crucial pharmacological activities of BTZ derivatives has been reviewed in this present study to appreciate their druggable potential in therapeutic medicine for drug development. Drug design and development have further been simplified with the implementation of computer aided approaches to predict biological interactions which can help in the design of several derivatives. Hence, the structural activity relationship (SAR), ADMET and the molecular docking studies of BTZ derivatives were discussed to further establish their interactions and safety in biological systems. This present work aims to expound on the reported chemistry and pharmacological propensity of BTZ moiety in relation to other relevant moieties to validate their potential as excellent pharmacophores in drug design and development.

Keywords: ADMET; Drug design; Heterocyclic compounds; Medicinal properties; Molecular docking; Synthesis.

Figure 1:

Different forms of the benzothiazepine ring

Figure 2:

Structures of benzothiazepine with anti-tumor properties

Figure 3:

Structures of benzothiazepine with anti-malaria properties

Figure 4:

Structures of benzothiazepine with anti-bacterial properties

Figure 5:

Structures of benzothiazepine with anti-fungal properties

Figure 6:

Structures of benzothiazepine with anti-cancer properties

Figure 7:

Structures of benzothiazepine with anti-protozoal properties

Figure 8:

Structures of benzothiazepine with anti-diabetic properties

Figure 9:

Structures of benzothiazepine with anti-oxidant properties

Figure 10:

Structures of benzothiazepine with anti-anti-inflammatory properties

Figure 11:

Structures of benzothiazepine with anti-leishmanial properties

Figure 12:

SAR of 1,5-benzothiazepine derivatives containing pyridine moiety the antiviral activity

Figure 13:

SAR of carbazole incorporated 1,5-benzothiazepine the antimalarial and antimicrobial activity

Figure 14:

2D ligand interaction of compounds (a) 85 and (b) 86 against helicase of Zika virus protein.

Figure 15:

2D ligand interaction (c) of compound 87 against EGFR kinase domain.

Figure 16:

2D ligand interaction (d) of compound 88 against Tubulin.

Scheme 1:

Microwave synthesis of 1,4 benzothiazepine derivative

Scheme 2:

Microwave synthesis of 1,4-benzothiazepine derivative

Scheme 3:

Microwave synthesis of 1,5-benzothiazepine

Scheme 4:

Ultrasonic synthesis of 1,5-benzothiazepine

Scheme 5:

Ultrasonic synthesis of 2,4-substituted 1,5-benzothiazepine

Scheme 6:

Ultrasonic synthesis of 1,5-benzothiazepine

Scheme 7:

Solvent-free synthesis of 1,5-benzothiazepine derivatives

Scheme 8:

Synthesis of 1,5-benzothiazepine derivatives

Scheme 9:

Combinatorial synthetic route for 1,5-benzothiazepine derivatives

Scheme 10:

Synthesis of 1,3-Benzothiazepines derivative

Scheme 11:

Synthesis of 4,1-Benzothiazepines derivative

Scheme 12:

Rh-catalyzed reaction route of 1,5-Benzothiazepine derivatives

Scheme 13:

Synthesis of the 1,2-Benzothiazepine 1-Oxides derivative using Rh-catalyst

Scheme 14:

A 1,3 dipolar cycloaddition synthetic route for 1,5-benzothiazepine derivatives

Scheme 15:

Synthetic route for chloropyrazine conjugated 1,5-benzothiazepine derivatives

Scheme 16:

Synthetic route for furan attached to 1,4 benzothiazepine ring