In-Silico and In-Vitro Approaches to Screen the Antituberculosis Activity of Benzothiazole Analogs

Benzothiazole (1, 3-benzothiazole) is one of the important fused heterocyclic compounds, which is a weak base having varied biological activities. The unique methyne center present in the thiazole ring makes benzothiazole as the most bioactive heterocyclic compound. The benzothiazole subunit is the commonly found in many natural bioactive compounds and semisynthetic drugs. Benzothiazole and its analogous found to exhibit variety of bio-activities, also with less toxic effect and their derivatives showed the enhanced activities, which has proven Benzothiazole scaffold is one of the prominant moiety in the medicinal chemistry, presence of hetero atoms such as sulphur and nitrogen makes the receptor cite in the parent moiety for the observed activity. Benzothiazole derivatives possess various pharmacological activities such as anti-viral, anti-microbial, anti-allergic, anti-diabetic, anti-tumor, anti-inflammatory, anthelmitic and anti-cancer activities. Which makes chemistry of benzothiazole is makes the prominent, rapidly developing and interesting field in the medicinal chemistry. In this chapter, briefly explained the importance, common methods of synthesis of the benzothiazole scaffold and also explained the popular benzothiazole molecules which have applications in various fields of the chemistry. Main objective of this chapter to explore various pharmacological activities containing benzothiazole moieties and rationalized the activities based on the structural variations with respect to the tuberculosis activity. The studies on benzothiazole derivatives reveal that, substitution on the C-2 and C-6 positions are the reasons for variety of biological activities.

Bioactivity of the synthesized compounds depends upon the molecular morphology of the compounds. The presence of the number of heteroatoms and ring size and shape of the molecules influences the corresponding biological activity. To predict the biological activity, structural activity relationship is one of the traditional non-computational method and from this methods, activity relation with structure can correlate. In this chapter discussed the source of the SAR, reliability of the method and general information. To predict the activity of the molecule, various computational methods were also developed, this method is called in-silico method. In continuation of this chapter, molecular docking, source of molecular docking, different types of docking, various interactions, docking process and applications are discussed.

Tuberculosis is a most infectious dangerous health problems caused by the Mycobacterium tuberculosis, the species mainly affects the lungs, it can also spreads to various parts of the body like the brain and the spine and second biggest killer in the world. In this chapter, we have discussed about the Mycobacterium tuberculosis and its various types and symptoms of the tuberculosis diseases. Detailed history of the evolution of the tuberculosis treatment has been discussed, followed by the prominent drug molecules and their classification. To screen the molecules to tuberculosis, different methodologies are required; here various in-vitro and in-vivo methods have been discussed in-order to evaluate the drug capacity against the tuberculosis.

Synthesis of diamide derivatives are carried out by the phenylalanine initially phenylalanine reacts with the aromatic amine by the acid amine coupling followed by de-protection of the boc and further reacts with the benzothiazole carboxylic acid by the formation of the amide coupling in the presence HATU as coupling reagent. Further series of the diamide benzothiazole derivative compounds were screened for the in-silico and in-vitro anti TB activity. In in-silico method compounds show a good docking score with respect to the standard drug. In-vitro Alamar blue assay demonstrate some of the compounds marked for the superior activity with minimum inhibitory concentration 1.6 μg/mL.

Compounds containing CN3 group in the open chain or in the ring system are called guanidine and are found in a variety of compounds occurring in natural and synthetic sources. The presence of the guanidine sub unit in the synthesized compound helps to enhance the activity, which helps to interact with the various organisms through the hydrogen bonding. A series of Guanidinyl benzothiazole derivatives were synthesized and evaluated for their anti-mycobacterial activity and cytotoxicity. Antimycobacterial study indicates that all the synthesized compounds were appreciably active and many of the compounds have MIC values lower than the standard drugs. The guanidinyl group and electron donating group present in the molecule interacts with the microorganism and arrest the further growth, so synthesized compounds exhibit the excellent activity and some of the compound has MIC at 1.6 μg/mL. In order to rationalize the biological results of the synthesized compounds, molecular docking studies with enoyl acyl carrier reductase (InhA) of M. tuberculosis were performed and the synthesized compounds shows the remarkable docking score -5.85 to -9.27, which can be compared with the standard drug Isoniazid (INH) with -6.61 as docking score.

Hybrid derivatives have advantage over the other compounds, because they exhibit the enhanced bioactivity. In this chapter benzothiazole conjugated pyrazole hybrid compounds are taken the study. Pyrazole and benzothiazole scaffolds have their own advantage in the field of medicinal chemistry. In the present study, two series of the pyrazole conjugated benzothiazole derivatives were synthesized by Vilsmeier- Haack reaction, followed by the Schiff’s base formation. The newly synthesized compounds were screened for the in-vitro and in-silico anti-TB activities. They show moderate antibacterial and antioxidant activities. Compounds containing OH, CH3 and Cl groups exhibit the superior antibacterial activity in the series. Majority of the compounds exhibit the excellent in-vitro anti-TB activity, showing the MIC values up to 1.6 μg/mL. Some compounds were show the superior activity compared to the standard (INH and Cfx) and molecular docking studies were also carried out to know the molecular interaction with InhA protein.