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)

• Published in: PloS one 2015-10, Vol.10 (10), p.e0139798-e0139798
• Main Authors: Anusha, Sebastian, Cp, Baburajeev, Mohan, Chakrabhavi Dhananjaya, Mathai, Jessin, Rangappa, Shobith, Mohan, Surender, Chandra, Paricharak, Shardul, Mervin, Lewis, Fuchs, Julian E, M, Mahedra, Bender, Andreas, Basappa, Rangappa, Kanchugarakoppal S
• Format: Article
• Language: English
• Subjects: Adamantane - chemistry; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Aromatic compounds; Aspergillus fumigatus - drug effects; Biology; Catalysis; Chemical synthesis; Chemistry; Chemistry Techniques, Synthetic; Ciprofloxacin; College campuses; Crystallography; Drug Discovery; Drugs; Green Chemistry Technology; Informatics; Ionic liquids; Ionic Liquids - chemistry; Laboratories; Magnesium Oxide - chemistry; Minimum inhibitory concentration; Models, Molecular; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Nanostructures - chemistry; Pharmaceutical sciences; Predictions; Protein Conformation; Pyrazinamide; Single crystals; Solvents; Sterol 14-Demethylase - chemistry; Sterol 14-Demethylase - metabolism; Sterols; Streptomycin; Thiadiazoles; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Tuberculosis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0139798

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 M. tuberculosis, 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 (3f) showed potent inhibitory activity towards M. tuberculosis with an MIC value of 8.5 μM. The inhibitory effect of this molecule against M. tuberculosis was comparable to the standard drugs such as Pyrazinamide, Streptomycin, and Ciprofloxacin drugs. Mechanistically, an in silico analysis predicted sterol 14α-demethylase (CYP51) as the likely target and experimental activity of 3f in this system corroborated the in silico target prediction. In summary, we herein report the synthesis and biological evaluation of novel AITs against M. tuberculosis that likely target CYP51 to induce their antimycobacterial activity.