Spirooxindoles as novel 3D-fragment scaffolds: Synthesis and screening against CYP121 from M. tuberculosis.
Accepted version
Peer-reviewed
Repository URI
Repository DOI
Change log
Authors
Davis, Holly J
Kavanagh, Madeline E
Balan, Tudor
Abell, Chris https://orcid.org/0000-0001-9174-1987
Coyne, Anthony G
Abstract
The search for new scaffolds to complement current HTS and fragment libraries is an active area of research. The development of novel strategies to synthesise compounds with 3D character in order to expand the diversity of a fragment library was explored. A range of substituted bicyclo[2,2,1]spirooxindoles were synthesised using a Diels-Alder [4+2] cycloaddition reaction. Both diastereoisomers were isolated from the reactions and these 3D fragment scaffolds were screened against the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis. A number of hits were identified to bind to CYP121 and were shown to exhibit Type I binding interactions with the heme group.
Description
Keywords
CYP121, Fragment-based drug discovery, Tuberculosis, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Indoles, Molecular Structure, Mycobacterium tuberculosis, Oxindoles, Spiro Compounds, Structure-Activity Relationship
Journal Title
Bioorg Med Chem Lett
Conference Name
Journal ISSN
0960-894X
1464-3405
1464-3405
Volume Title
26
Publisher
Elsevier BV
Publisher DOI
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/I019669/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
AGC was supported by the BBSRC for funding (BB/I019669/1). A. G.C. and T.B. would like to acknowledge BP for funding of a summer studentship through the Department of Chemistry, University of Cambridge. M.E.K. was supported by a Commonwealth (University of Cambridge) Scholarship awarded in conjunction with the Cambridge Commonwealth Trust and Cambridge Overseas Trust.