Spirooxindoles as novel 3D-fragment scaffolds: Synthesis and screening against CYP121 from M. tuberculosis.
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.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Holly J
HJ
Davis
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Madeline E
ME
Kavanagh
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Tudor
T
Balan
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Chris
C
Abell
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom. Electronic address: agc40@cam.ac.uk.
Anthony G
AG
Coyne
D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D000078183:Oxindoles; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D000078183:Oxindoles; D013141:Spiro Compounds; C464825:cytochrome P-450 CYP121; C022960:2-oxindole; D003577:Cytochrome P-450 Enzyme System
CYP121; Fragment-based drug discovery; Tuberculosis