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Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation

Ferla, Salvatore, Gomaa, Mohamed S., Brancale, Andrea, Zhu, Jinge, Ochalek, Justin T., DeLuca, Hector F. and Simons, Claire 2014. Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation. European Journal of Medicinal Chemistry 87 , pp. 39-51. 10.1016/j.ejmech.2014.09.035

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Abstract

The synthesis of a series of imidazole styrylindoles and sulfonyl styrylindoles derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylindoles as potent inhibitors with activity greater or comparable with the standard ketoconazole. Flexible alignment and docking studies of the inhibitors in the CYP24A1 enzyme active site confirmed that complete occupation of the vitamin D access tunnel is essential to inhibitory activity, allowing exposure to multiple hydrophobic binding interactions and optimal conformation for the interaction of the imidazole nitrogen lone pair and the active site haem.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 10 September 2014
Last Modified: 01 Mar 2019 15:46
URI: http://orca-mwe.cf.ac.uk/id/eprint/65522

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