In Silico Design, Synthesis, Anti-Microbial and Anti-Tubercular Evaluation of New Series of Benzothiazinone Derivatives Containing Triazolo Thiadiazole Moiety

Abstract

\n Tuberculosis has proved harmful to the entire history of mankind from past several decades. Among the strategies for the development of new anti-tubercular lead compounds, Benzothiazinone (BTZ) were studied, with highly selective mechanism of action on DprE1 (Decaprenyl phosphoryl-b-D-ribose 2-epimerase) flavoenzyme. DprE1 is a vital enzyme for cell wall synthesis, plays a crucial role in the formation of D-arabinofuranose, a component of lipo-arabinomannan and arabinogalactam. Formation of covalent and non covalent bond by the interacting ligand with the enzyme causes loss of its catalytic activity which ultimately leads to death of the mycobacterium. The Benzothiazinone derivatives kill the mycobacterium by inhibiting the essential flavoenzyme DprE1. This study involves designing of a series of 16 Benzothiazinone derivatives that binds non covalently to DprE1. These derivatives were subjected to energy minimization and molecular docking studies with Schrodinger software, from which the binding free energy calculations showed that the suggested compounds had better binding affinity with DprE1. Ten compounds were selected for synthesis on the basis of docking score. The synthesized compounds were characterized and evaluated for their antimicrobial and anti-tubercular activity against different strains. Out of 5 evaluated compounds 3 compounds exhibited potent activity against microbial (Staphylococcus Aureus and Escherichia Coli) and tubercular (H37RV) strains. BTZ4 and BTZ10 has shown good activity against anti-microbial strain and BTZ8 has shown good activity against anti-tubercular strain. On the basis of docking results, we concluded that the selected new series of Benzothiazinone hybrid derivatives BTZ4, BTZ7, BTZ8, BTZ9, BTZ10 act on the Enzyme DprE1, against tuberculosis binding protein with PDB ID: 4NCR, as they may have better binding sites and better energy values, when compared with the standard drugs Ampicillin, Isoniazid and Rifampicin. So these derivatives (BTZ4, BTZ8, BTZ10) can be taken as best hit molecule and it could be useful for development of more new antimicrobial and anti-tubercular agents, blocking the mycobacterial cell wall formation.