Spirooxindoles as novel 3D-fragment scaffolds: Synthesis and screening against CYP121 from $\textit{M. tuberculosis}$

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Davis, Holly J ; Kavanagh, Madeline ; Balan, Tudor ; Abell, Christopher ; Coyne, Anthony George (2016)

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 $\textit{Mycobacterium tuberculosis}$. A number of hits were identified to bind to CYP121 and were shown to exhibit Type I binding interactions with the heme group. 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. This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.bmcl.2016.05.073
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