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United States Department of Agriculture

Agricultural Research Service

Research Project: DISCOVERY AND DEVELOPMENT OF NATURAL PRODUCT-BASED WEED MANAGEMENT METHODS

Location: Natural Products Utilization Research

Title: Synthesis, Antitubercular Activity and Docking Study of Novel Cyclic Azole Substituted Diphenyl Ether Derivatives

Authors
item Kini, Suvarna - DEPT PHARMA CHEM, INDIA
item Bhat, Anilchandra - DEPT PHARMA CHEM, INDIA
item Bryant, Byron - UNIVERSITY OF MISSISSIPPI
item Williamson, John - UNIVERSITY OF MISSISSIPPI
item DAYAN, FRANCK

Submitted to: European Journal of Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 8, 2008
Publication Date: January 8, 2009
Repository URL: http://www.sciencedirect.com
Citation: Kini, S.G., Bhat, A.R., Bryant, B., Williamson, J.S., Dayan, F.E. 2009. Synthesis, Antitubercular Activity and Docking Study of Novel Cyclic Azole Substituted Diphenyl Ether Derivatives. European Journal of Medicinal Chemistry. 44(2):492-500.

Interpretive Summary: The reemergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of heterocyclic o/m/p substituted diphenyl ether derivatives and determine their activity against H37Rv strain of Mycobacterium. All ten compounds inhibited the growth of the H37Rv strain of mycobacterium at concentrations as low as 1 ug/mL. This level of activity was found comparable to the reference drugs rifampicin and isoniazid at the same concentration. Molecular modeling of the binding of the diphenyl ether derivatives on enoyl-ACP reductase (ENR), the molecular target site of triclosan, indicated that these compounds fit within the binding domain occupied by triclosan. While the antimicrobial activity of other diphenyl ether structural analogues, such as triclosan, is associated with the inhibition of ENR, the synthesized cyclic azole substituted diphenyl ether derivatives did not affect this enzyme activity in spite of structural similarity with triclosan. Therefore, these bioactive compounds appear to have a novel mechanism of action against M. tuberculosis, and their structural features should be studied further for their potential use as new antitubercular drugs.

Technical Abstract: Tuberculosis is a global health problem. New of heterocyclic diphenyl ether derivatives were tested against the Mycobacterium in laboratory settings. All ten compounds inhibited the growth of the mycobacterium at concentrations as low as 1 ug/mL. This level of activity was found comparable to reference drugs included in the project. Molecular modeling of the binding of the diphenyl ether derivatives on its target site indicated that these compounds fit within the binding domain occupied by triclosan. While the antimicrobial activity of other diphenyl ether structural analogues, such as triclosan, is associated with the inhibition of ENR, the synthesized cyclic azole substituted diphenyl ether derivatives did not affect this enzyme activity in spite of structural similarity with another know diphenyl ether known to inhibit this site. Therefore, these bioactive compounds appear to have a novel mechanism of action that may be useful as potential new antitubercular drugs.

Last Modified: 9/10/2014
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