Benzopyran, Benzamidocoumarin, Phenylpyrrolidine, and Barbituric Acid Derivatives as Potential Actives Targeting Endonuclease VIII‐2 ( <i>Nei2</i> ) of <i>Mycobacterium Tuberculosis</i>

Abstract Emerging drug resistance in Mycobacterium tuberculosis ( M. tuberculosis ) has forced us to find novel drug targets. Endonuclease VIII 2 or DNA base excision repair glycosylase, is such an enzyme. Newly synthesized inhibitors derived from benzopyran, benzamidocoumarin, 5‐oxo‐1‐phenylpyrrolidine‐3‐carboxylic acid, their Claisen products, and barbituric acid were evaluated for their potential to inhibit M. tuberculosis Endonuclease VIII 2. Endonuclease VIII 2 (Nei2) structure was modeled and analyzed. An in‐house library of 72 synthetic compounds was prepared and analyzed for drug‐likeness and ADMET properties. Finally, 67 compounds were screened against the active site of Nei2, and on the basis of docking energy, compound 1s [ethyl (4 R )‐4‐(3,5‐dichloro‐2‐hydroxyphenyl)‐5,7‐dihydroxy‐2‐methyl‐4 H ‐1‐benzopyran‐3‐carboxylate] was identified as the most promising drug candidate. The binding energy (Δ G ) and binding affinity ( K a ) of 1s toward the active site of Nei2 were −9.8072 kcal mol −1 and 1.56 × 10 7 m −1 , respectively. The corresponding dissociation constant ( K d ) value of compound 1s was estimated to be 64.1 nM. Compound 1s formed hydrogen bonds and hydrophobic interactions with the key active site residues of Nei2 such as Met1, Pro2, Glu3, Lys51, Leu66, Met68, Val165, and Tyr166. Molecular dynamics simulations suggested the formation of a stable Nei2‐ 1s complex. The analysis of compound 1s for drug‐likeness and ADMET properties established it as a potential drug against TB, pending experimental validation.