Synthesis and Structural Elucidation of Novel Benzothiazole Derivatives as Anti-tubercular Agents: In-silico Screening for Possible Target Identification

Author(s): Katharigatta N. Venugopala*, Sandeep Chandrashekharappa, Melendhran Pillay, Subhrajyoti Bhandary, Mahmoud Kandeel, Fawzi M. Mahomoodally, Mohamed A. Morsy, Deepak Chopra, Bandar E. Aldhubiab, Mahesh Attimarad, Osama I. Alwassil, Sree Harsha, Koleka Mlisana, Bharti Odhav.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 3 , 2019

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Abstract:

Background: Benzothiazole derivatives are known for anti-TB properties. Based on the known anti-TB benzothiazole pharmacophore, in the present study, we described the synthesis, structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives (BNTZ 1–7 and BNTZ 8–13).

Objective: The study aims to carry out the development of benzothiazole based anti-TB compounds.

Methods: Title compounds are synthesized by microwave method and purified by column chromatography. Characterization of the compounds is achieved by FT-IR, NMR (1H and 13C), LCMS and elemental analysis. Screening of test compounds for anti-TB activity is achieved by Resazurin Microplate Assay (REMA) Plate method.

Results: It was noted that the BNTZ compound with an isoquinoline nucleus (BNTZ 9) exhibited remarkable anti-tubercular activity at 8 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of Mycobacterium tuberculosis. On the other hand, the BNTZ compound with a naphthalene nucleus (BNTZ 2) revealed anti-tubercular activity at 6 µg/mL and 11 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of M. tuberculosis, respectively. One of the selected BNTZ derivatives BNTZ 13 was used for single crystal X-ray studies.

Conclusion: To identify the appropriate target for potent BNTZ compounds from the series, molecular modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium lysine-ɛ-aminotransferase and decaprenyl-phosphoryl-β-D-ribose 2'-oxidase. The interaction is derived by forming favorable hydrogen bonds and stacking interactions. This new class of BNTZ compounds gave promising anti-tubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-tubercular drugs.

Keywords: Benzothiazole derivatives, characterization, whole cell anti-TB screening, in-silico screening for targets, single crystal X-ray studies, one-pot synthesis, microwave method, multidrug resistant tuberculosis.

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Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [311 - 326]
Pages: 16
DOI: 10.2174/1573406414666180703121815
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