Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of ( E )- N -(2-(1 H -imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

Abstract

CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC 0.11-0.35μM) compared with the standard ketoconazole. Molecular modelling using our CYP24A1 homology model showed the inhibitors to fill the hydrophobic binding site, forming key transition metal interaction between the imidazole nitrogen and the haem Fe and multiple interactions with the active site amino acid residues.

Analysis of the binding sites of vitamin D 1α-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: Homology modelling, molecular dynamics simulations and identification of key binding requirements

“…However, increased levels of CYP24A1 have been observed in a number of human cancers including breast 8 , colon 9 , prostate 10 and skin cancers 11 , directly correlating with a reduction in circulating calcitriol. To enhance circulating levels of the biologically active form of vitamin D, CYP24A1 inhibitors have been developed [12][13][14][15][16][17][18][19] and, although potent inhibitors with IC50 values in the nanomolar range have been described, one of the biggest challenges has been designing inhibitors selective for CYP24A1 over CYP27B1. A few azole inhibitors with good selectivity have been described, notably (R)-VID400 12 which is ~ 40-fold more selective for CYP24A1 compared with CYP27B1 and the SDZ compounds, SDZ-88357 12 and SDZ-285082 13 , which are ~ 166-fold and 47-fold respectively more selective for CYP27B1 over CYP24A1 (Fig.…”

Synthesis and Experimental Structure of a Multifunctional Catechol‐Azomethinebenzoic Acid, DFT/DMol3 Calculations, and Molecular Docking with Hsp90

“…The scoring function of the docking protocol is considered to be successful if the best-docked conformation of a ligand resembles the bound native co-crystallized ligand demonstrat-ing RMSD value of � 2.0 Å. [42,[58][59][60] In the binding pocket, G shows multiple hydrophobic … hydrophobic interactions with Asn40, Asp43, Ala44, Ile85, Gly86, Met87, Asp91, Asn95, Leu96, Gly125, Val126, Phe128, Tyr129, Thr174, and Ile176 and hydrophilic interactions with Lys47 and Arg101 (Figure 7, right).…”

“…[64] In summary, 1 should show reasonable to good absorption and permeability. [61][62][63] logS was calculated to À 2.99 which lies in the center of the logS distribution of traded drugs [58] indicating that 1 should allow oral application although it has low water solubility. Finally, compound 1 showed no violations of Lipinski's rule and complied with all parameters.…”