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)

Sebastian Anusha; Baburajeev Cp; Chakrabhavi Dhananjaya Mohan; Jessin Mathai; Shobith Rangappa; Surender Mohan; Chandra; Shardul Paricharak; Lewis Mervin; Julian E Fuchs; Mahedra M; Andreas Bender; Basappa; Kanchugarakoppal S Rangappa

doi:10.1371/journal.pone.0139798

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)

PLoS One. 2015 Oct 15;10(10):e0139798. doi: 10.1371/journal.pone.0139798. eCollection 2015.

Authors

Affiliations

¹ Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College campus, Palace Road, Bangalore, 560 001, India.
² Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570 006, India.
³ Centre for Advanced Biomedical Research and Innovation, Gulf Medical University, Ajman, United Arab Emirates.
⁴ Frontier Research Center for Post-genome Science and Technology, Hokkaido University, Sapporo, 060-0808, Japan.
⁵ Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India.
⁶ Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore, 570 006, India.
⁷ 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.
⁸ Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, United Kingdom.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adamantane / chemistry*
Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology
Aspergillus fumigatus / drug effects
Catalysis
Chemistry Techniques, Synthetic
Drug Discovery
Green Chemistry Technology
Ionic Liquids / chemistry*
Magnesium Oxide / chemistry*
Models, Molecular
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Nanostructures / chemistry
Protein Conformation
Sterol 14-Demethylase / chemistry
Sterol 14-Demethylase / metabolism*
Thiadiazoles / chemical synthesis
Thiadiazoles / chemistry*
Thiadiazoles / pharmacology*

Substances

Antitubercular Agents
Ionic Liquids
Thiadiazoles
Magnesium Oxide
Sterol 14-Demethylase
Adamantane

Grants and funding

This research was supported by University Grants Commission (41-257-2012-SR), Vision Group Science and Technology, Department of Science and Technology (NO. SR/FT/LS-142/2012). KSR thanks Institution of Excellence, University of Mysore for funding. AB thanks Unilever and the European Research Commission (ERC Starting Grant 2013) for funding. SP thanks the Netherlands Organization for Scientific Research (NWO, grant number NWO-017.009-065) and the Prins Bernhard Cultuurfonds for funding. CDM thanks University of Mysore for Department of Science and Technology-Promotion of University Research and Scientific Excellence (DST-PURSE) Research Associate fellowship.