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.

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
Price: $95

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