A Nano-MgO and Ionic Liquid-Catalyzed ‘Green’ Synthesis Protocol for the Development of Adamantyl-Imidazolo-Thiadiazoles as Anti-Tuberculosis Agents Targeting Sterol 14α-Demethylase (CYP51)

Abstract

<div><p>In this work, we describe the ‘green’ synthesis of novel 6-(adamantan-1-yl)-2-substituted-imidazo[2,1-b][1,3,4]thiadiazoles (AITs) by ring formation reactions using 1-(adamantan-1-yl)-2-bromoethanone and 5-alkyl/aryl-2-amino1,3,4-thiadiazoles on a nano material base in ionic liquid media. Given the established activity of imidazothiadiazoles against <i>M</i>. <i>tuberculosis</i>, we next examined the anti-TB activity of AITs against the H₃₇Rv strain using Alamar blue assay. Among the tested compounds 6-(adamantan-1-yl)-2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole (<b>3f</b>) showed potent inhibitory activity towards <i>M</i>. <i>tuberculosis</i> with an MIC value of 8.5 μM. The inhibitory effect of this molecule against <i>M</i>. <i>tuberculosis</i> was comparable to the standard drugs such as Pyrazinamide, Streptomycin, and Ciprofloxacin drugs. Mechanistically, an <i>in silico</i> analysis predicted sterol 14α-demethylase (CYP51) as the likely target and experimental activity of <b>3f</b> in this system corroborated the <i>in silico</i> target prediction. In summary, we herein report the synthesis and biological evaluation of novel AITs against <i>M</i>. <i>tuberculosis</i> that likely target CYP51 to induce their antimycobacterial activity.</p></div