title: 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: 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.
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College campus, Palace Road, Bangalore, 560 001, India.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Anusha
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College campus, Palace Road, Bangalore, 560 001, India.
authors.forename: Baburajeev
authors.initials: B
authors.lastname: Cp
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570 006, India.
authors.forename: Chakrabhavi Dhananjaya
authors.initials: CD
authors.lastname: Mohan
authors.affiliation: Centre for Advanced Biomedical Research and Innovation, Gulf Medical University, Ajman, United Arab Emirates.
authors.forename: Jessin
authors.initials: J
authors.lastname: Mathai
authors.affiliation: Frontier Research Center for Post-genome Science and Technology, Hokkaido University, Sapporo, 060-0808, Japan.
authors.forename: Shobith
authors.initials: S
authors.lastname: Rangappa
authors.affiliation: Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India.
authors.forename: Surender
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore, 570 006, India.
authors.lastname: Chandra
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom; Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300, RA Leiden, The Netherlands.
authors.forename: Shardul
authors.initials: S
authors.lastname: Paricharak
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom.
authors.forename: Lewis
authors.initials: L
authors.lastname: Mervin
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Fuchs
authors.affiliation: Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore, 570 006, India.
authors.forename: Mahedra
authors.initials: M
authors.lastname: M
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College campus, Palace Road, Bangalore, 560 001, India.
authors.lastname: Basappa
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570 006, India.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D000218:Adamantane / Q000737:chemistry*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D055808:Drug Discovery; D055772:Green Chemistry Technology; D052578:Ionic Liquids / Q000737:chemistry*; D008277:Magnesium Oxide / Q000737:chemistry*; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D049329:Nanostructures / Q000737:chemistry; D011487:Protein Conformation; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D052578:Ionic Liquids; D013830:Thiadiazoles; D008277:Magnesium Oxide; D058886:Sterol 14-Demethylase; D000218:Adamantane