Denovo Drug Design, Synthesis and Biological Activity Evaluation of Certain Novel Benzothiazole Derivativesa

The present work was focused on the insilico studies, synthesis and evaluation of benzothiazole derivatives as DprE1 inhibitors. Step I: LITERATURE REVIEW: Literature review showed that benzothiazoles are having potent antitubercular and antibacterial activity. Step II: IDENTIFICATION OF DRUG TARGET AND SELECTION OF LEAD: The drug target was identified as DprE1 and the lead moiety was selected as benzothiazole based on the extensive literature survey. Step III: LEAD OPTIMISATION: Lead optimisation was done by observing in silico ADME studies and computation of drug like properties. All the ligands had showed druglikness and acceptable pharmacokinetic parameter. Hence would be further studied for biological activities. Step IV: DOCKING: Docking studies were carried out using Schrodinger Release 2020-3 Life Science Suite. Docking study was done for 25 lead compounds which showed best binding energy with the DprE1 enzyme. The compounds B1-B8 showed good binding score when compared to standard BTZ-043. Step V: SYNTHESIS: In the present work, eight new compounds with good docking score were synthesised. Synthesis involves the formation of N=CH bond followed by thiazolidinone formation by cyclisation using thiolactic acid. Step VI: CHARACTERISATION: All the synthesized compounds were characterised by melting point, Rf values, percentage yield and solubility. The structural determination was done by spectral studies including UV, IR, 1H NMR and Mass spectroscopy. Step VII: ANTIMICROBIAL ACTIVITES: 1. Antitubercular activity: The compounds B3, B5, B6, B7 and B8 showed good antitubercular activity. These compounds showed better binding (binding energy around -7.0 to -8.0 kcal/mol) towards the target enzyme DprE1 in docking study. 2. Antibacterial activity: The compounds B4, B6 and B8 showed antibacterial activity against gram-positive Staphylococcus aureus and gram-negative Escherichia coli. CONCLUSION: The present study had proved to be a tool in minimising tedious drug discovery process and delivers new drug candidate more quickly. • DprE1, critical enzyme for the cell wall synthesis of Mycobacterium tuberculosis was chosen after the review of literature. • A database of 25 molecules with high probability of inhibiting the target DprE1 was chosen by making changes to a known inhibitor scaffold i.e., aryl substituted benzothiazole nucleus was chosen for the study. • The in silico ADME studies and drug likeness score established for the 25 compounds are proven to be pharmacokinetically active. The binding energies obtained from the docking studies for all 25 compounds further confirmed the synthesis of lead compounds. • Using the developed schemes, only eight benzothiazole derivatives were prepared in good yield and their structures were established based on spectral data. • The synthesized compounds were evaluated for their antitubercular and antibacterial activity. The antitubercular study establishes a good correlation with the docking score. • Few of the synthesized compounds also showed good to moderate antibacterial properties. • Five synthesized derivatives (B3, B5, B6, B7 and B8) showed moderate antitubercular activity compared to the standards at concentration of 25μg/ml. Three synthesized derivatives (B1, B2 and B4) exhibited antitubercular activity at a concentration of 50μg/ml. • It is concluded that the synthesized benzothiazole derivatives might effectively inhibit the chosen target DprE1 which is essential for the Mycobacterial tuberculosis and act as a potential lead moiety