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Journal of Enzyme Inhibition and Medicinal Chemistry Volume 24, 2009 - Issue 2
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Research Article

Design and synthesis of substituted imidazole and triazole N-phenylbenzo[d]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26

Stephane PautusMedicinal Chemistry, Welsh School of Pharmacy, Cardiff University, Cardiff, UK
,
Ahmed S. AboraiaMedicinal Chemistry, Welsh School of Pharmacy, Cardiff University, Cardiff, UK
,
Claire E. BassettMedicinal Chemistry, Welsh School of Pharmacy, Cardiff University, Cardiff, UK
,
Andrea BrancaleMedicinal Chemistry, Welsh School of Pharmacy, Cardiff University, Cardiff, UK
,
Michael P. CooganSchool of Chemistry, Cardiff University, Cardiff, UK
&
Claire SimonsMedicinal Chemistry, Welsh School of Pharmacy, Cardiff University, Cardiff, UKCorrespondence[email protected]
Pages 487-498 | Received 04 Mar 2008, Accepted 15 May 2008, Published online: 20 Oct 2008

Figures & data

Table I.  Structure and therapeutic application of retinoic acid isomers used clinically.

Figure 1.  Structure and key binding interactions of designed N -phenylbenzo[d]oxazolamines.

Figure 1.  Structure and key binding interactions of designed N -phenylbenzo[d]oxazolamines.

Figure 2.  Disconnective strategy toward substituted N-phenylbenzo[d]oxazolamines.

Figure 2.  Disconnective strategy toward substituted N-phenylbenzo[d]oxazolamines.

Figure 3.  Diagram showing both enantiomers R and S of 4-{[4-(benzoxazol-2-ylamino)phenyl]imidazol-1-yl-methyl}benzoic acid docked at the active site region of the CYP26A1 model. Hydrogen bonding interactions are shown as green lines and co-ordination with the transition metal is indicated with a purple line. Colour coding of the atoms: grey = C, red = O, blue = N, brown = Fe and yellow = S. Amino-acid residues identified are involved in hydrophobic interactions.

Figure 3.  Diagram showing both enantiomers R and S of 4-{[4-(benzoxazol-2-ylamino)phenyl]imidazol-1-yl-methyl}benzoic acid docked at the active site region of the CYP26A1 model. Hydrogen bonding interactions are shown as green lines and co-ordination with the transition metal is indicated with a purple line. Colour coding of the atoms: grey = C, red = O, blue = N, brown = Fe and yellow = S. Amino-acid residues identified are involved in hydrophobic interactions.

Scheme 1.  Reagents and Conditions: (i) NaBH4, MeOH, 1 h, rt, 60% (ii) H2, Pd/C, EtOH, 1 h, 48% (iii) CSCl2, CH2Cl2, H2O, 18 h, 0°C, 60–89% (iv) (a) 2-aminophenol, EtOH, o/n, rt, then (b) HgO, S, reflux, 2 h, 35–61% (v) 1,1'-carbonyldiimidazole, imidazole, CH3CN, reflux 2-12 h, 50–90% (vi) 2 M aq. NaOH, MeOH, reflux, 30 min, 62%.

Scheme 1.  Reagents and Conditions: (i) NaBH4, MeOH, 1 h, rt, 60% (ii) H2, Pd/C, EtOH, 1 h, 48% (iii) CSCl2, CH2Cl2, H2O, 18 h, 0°C, 60–89% (iv) (a) 2-aminophenol, EtOH, o/n, rt, then (b) HgO, S, reflux, 2 h, 35–61% (v) 1,1'-carbonyldiimidazole, imidazole, CH3CN, reflux 2-12 h, 50–90% (vi) 2 M aq. NaOH, MeOH, reflux, 30 min, 62%.

Scheme 2.  Reagents and Conditions (i) (a) 2-aminophenol, EtOH, o/n, rt, then (b) HgO, S, reflux, 2 h, 46% (ii) HBr, AcOH, reflux 6 h then o/n rt, 77% (iii) NaBH4, MeOH, 1–12 h, rt, 42–91% (iv) 1,1′-carbonyldiimidazole, imidazole, CH3CN, reflux 2–12 h, 38–74%.

Scheme 2.  Reagents and Conditions (i) (a) 2-aminophenol, EtOH, o/n, rt, then (b) HgO, S, reflux, 2 h, 46% (ii) HBr, AcOH, reflux 6 h then o/n rt, 77% (iii) NaBH4, MeOH, 1–12 h, rt, 42–91% (iv) 1,1′-carbonyldiimidazole, imidazole, CH3CN, reflux 2–12 h, 38–74%.

Scheme 3.  Reagents and Conditions (i) 1H-1,2,4-triazole, SOCl2, K2CO3, CH3CN, 72 h, rt,11 35%, 12 12% (ii) 1H-tetrazole, SOCl2, K2CO3, CH3CN, 72 h, rt, 32%.

Scheme 3.  Reagents and Conditions (i) 1H-1,2,4-triazole, SOCl2, K2CO3, CH3CN, 72 h, rt,11 35%, 12 12% (ii) 1H-tetrazole, SOCl2, K2CO3, CH3CN, 72 h, rt, 32%.

Table II.  IC50 data for the novel imidazole N-phenylbenzo[d]oxazolamines (5).

Table III.  IC50 data for the novel triazole and tetrazole derivatives compared with imidazoleA

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