Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536807034034/bt2433sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S1600536807034034/bt2433Isup2.hkl |
CCDC reference: 657791
Key indicators
- Single-crystal X-ray study
- T = 193 K
- Mean (C-C) = 0.010 Å
- R factor = 0.125
- wR factor = 0.361
- Data-to-parameter ratio = 14.6
checkCIF/PLATON results
No syntax errors found
Alert level B RFACR01_ALERT_3_B The value of the weighted R factor is > 0.35 Weighted R factor given 0.361 PLAT031_ALERT_4_B Refined Extinction Parameter within Range ...... 1.50 Sigma PLAT084_ALERT_2_B High R2 Value .................................. 0.36
Alert level C ABSTM02_ALERT_3_C The ratio of Tmax/Tmin expected RT(exp) is > 1.10 Absorption corrections should be applied. Tmin and Tmax expected: 0.831 0.957 RT(exp) = 1.152 DIFMX01_ALERT_2_C The maximum difference density is > 0.1*ZMAX*0.75 _refine_diff_density_max given = 0.693 Test value = 0.675 DIFMX02_ALERT_1_C The maximum difference density is > 0.1*ZMAX*0.75 The relevant atom site should be identified. RFACG01_ALERT_3_C The value of the R factor is > 0.10 R factor given 0.125 PLAT026_ALERT_3_C Ratio Observed / Unique Reflections too Low .... 49 Perc. PLAT057_ALERT_3_C Correction for Absorption Required RT(exp) ... 1.19 PLAT082_ALERT_2_C High R1 Value .................................. 0.13 PLAT097_ALERT_2_C Maximum (Positive) Residual Density ............ 0.69 e/A PLAT250_ALERT_2_C Large U3/U1 Ratio for Average U(i,j) Tensor .... 2.04 PLAT340_ALERT_3_C Low Bond Precision on C-C Bonds (x 1000) Ang ... 10
Alert level G PLAT793_ALERT_1_G Check the Absolute Configuration of C1 = ... S PLAT793_ALERT_1_G Check the Absolute Configuration of C2 = ... S
0 ALERT level A = In general: serious problem 3 ALERT level B = Potentially serious problem 10 ALERT level C = Check and explain 2 ALERT level G = General alerts; check 3 ALERT type 1 CIF construction/syntax error, inconsistent or missing data 5 ALERT type 2 Indicator that the structure model may be wrong or deficient 6 ALERT type 3 Indicator that the structure quality may be low 1 ALERT type 4 Improvement, methodology, query or suggestion 0 ALERT type 5 Informative message, check
In the title compound the vicinal substituents are in a trans position with respect to each other; this is different to the structure of other related five-membered rings, as exemplified by the pyridinylimidazole SB203580 inhibitor for p38 MAPK (Wang et al., 1998; Laufer et al., 2006). For further literature, see Abu Thaher et al. (2007, and references therein).
For related literature, see: Kaminska (2005); Krasovskiy & Knochel (2004); Krasovskiy et al. (2006); Wagner & Laufer (2006).
Compound 4 was obtained by reacting 1.0 mmol of 2-(4-fluorophenyl)-1-cyclopentanone 3 to 1.05 mmol N dC l3.2LiCl (Krasovskiy et al., 2006) under dry conditions, followed by adding the prepared complex Grignard PyMgCl.LiCl, from iPrMgCl.LiCl by exchange reaction (Krasovskiy and Knochel, 2004), to the first reaction at 273 K and then at rt for 8–10 h. When the reaction was completed, saturated aqueous NH4Cl (2 ml) and water (10 ml) were added. The aqueous layer was extracted with diethyl ether (4 x 10 ml), and the combined organic extracts were dried (Na2SO4) and evaporated to dryness. The crude product was purified by flash column chromatography (n-hexane / ethyl acetate, 3:1, v/v) giving 4 (yield 58.5°) as colorless, crystalline needles. For X-ray analysis suitable crystals of compund 4 were obtained by slow evaporation at 298 K of methanol - chloroform (2:1) solution.
Hydrogen atoms attached to carbons were placed at calculated positions with C—H=0.95A% (aromatic) or 0.99–1.00 Å (sp3 C-atom). Hydrogen atom attached to O6 was located in a difference Fourier map. The isotropic displacement parameters were set to 1.2–1.5 times of the Ueq of the parent atom.
Compound 4 was prepared in the course of our study on cyclopentene derivatives bearing the typical vicinal 4-pyridyl and 4-fluorophenyl pharmacophores of MAP Kinase inhibitors. Pyridinylimidazoles are described in the literature as inhibitors for p38 MAP Kinase (Wagner et al., 2006; Kaminska, 2005). The prototypical pyridinylimidazole SB 203580 is one of the best studied p38 inhibitors reported until now. Figure 1 shows the most important interactions between the ATP binding sites of p38 kinase and the imidazole inhibitor SB203580 (Wang et al., 1998; Laufer et al., 2006). The 4-fluorophenyl ring of SB203580 occupies a hydrophobic back pocket gaining selectivity. Vicinal to this interaction site, 4-pyridinyl moiety forms a hydrogen bond from the backbone NH group of Met 109 of p38 MAP Kinase (Fig. 1).
Meanwhile, the importance of a further hydrogen bond between N3 of the imidazole core and Lys53 of p38 MAP Kinase, as shown in figure 1, is not yet clear and the speculation about its significance is not settled. Based on this concept, replacement of imidazole core by a cyclopentene ring would require the preparation of 2-fluorophenyl-1-pyridinyl cyclopentanol 4 as a key compound for such comparative bioassay study. Going from the data obtained from the X-ray structure of compound 4 (Figs. 2 and 3), it is impossible for the vicinal 4-fluorophenyl and 4-pyridinyl groups (due to their location in trans position to each other) to exert their expected functions with p38 MAPK as described above in case of SB203580 inhibitor (Fig. 1).
So, the loss of the biological activity of compound 4 can not be attributed just to the absence of the nitrogen atoms in the cyclopentane core itself. Accordingly, and based on this result, we plan to prepare cyclopentene derivatives which have vicinal 4-fluorophenyl and 4-pyridinyl groups in cis orientation in order to get more accurate and comparable information about the extent of the importance of the hydrogen bond between N3 of the imidazole core and Lys 53 of P38 MAP Kinase in terms of its biological activity.
In the title compound the vicinal substituents are in a trans position with respect to each other; this is different to the structure of other related five-membered rings, as exemplified by the pyridinylimidazole SB203580 inhibitor for p38 MAPK (Wang et al., 1998; Laufer et al., 2006). For further literature, see Abu Thaher et al. (2007, and references therein).
For related literature, see: Kaminska (2005); Krasovskiy & Knochel (2004); Krasovskiy et al. (2006); Wagner & Laufer (2006).
Data collection: CAD-4 Software (Enraf–Nonius, 1989); cell refinement: CAD-4 Software; data reduction: CORINC (Dräger & Gattow, 1971); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97.
C16H16FNO | F(000) = 544 |
Mr = 257.30 | Dx = 1.278 Mg m−3 |
Monoclinic, P21/c | Cu Kα radiation, λ = 1.54178 Å |
Hall symbol: -P 2ybc | Cell parameters from 25 reflections |
a = 11.7228 (8) Å | θ = 20–25.7° |
b = 13.6606 (8) Å | µ = 0.73 mm−1 |
c = 8.6194 (11) Å | T = 193 K |
β = 104.366 (10)° | Plate, colourless |
V = 1337.2 (2) Å3 | 0.30 × 0.30 × 0.06 mm |
Z = 4 |
Enraf–Nonius CAD-4 diffractometer | Rint = 0.050 |
Radiation source: rotating anode | θmax = 70.3°, θmin = 3.9° |
Graphite monochromator | h = −14→13 |
ω/2θ scans | k = 0→16 |
2701 measured reflections | l = 0→10 |
2523 independent reflections | 3 standard reflections every 60 min |
1235 reflections with I > 2σ(I) | intensity decay: 5% |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.126 | H-atom parameters constrained |
wR(F2) = 0.361 |
[1 + -exp(-4.00(sinθ/λ)2)]/[σ2(Fo2) + (0.08P)2 + sinθ/λ],
where P = 0.33333Fo2 + 0.66667Fc2 |
S = 1.28 | (Δ/σ)max < 0.001 |
2523 reflections | Δρmax = 0.69 e Å−3 |
173 parameters | Δρmin = −0.67 e Å−3 |
0 restraints | Extinction correction: SHELXL97, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.006 (4) |
C16H16FNO | V = 1337.2 (2) Å3 |
Mr = 257.30 | Z = 4 |
Monoclinic, P21/c | Cu Kα radiation |
a = 11.7228 (8) Å | µ = 0.73 mm−1 |
b = 13.6606 (8) Å | T = 193 K |
c = 8.6194 (11) Å | 0.30 × 0.30 × 0.06 mm |
β = 104.366 (10)° |
Enraf–Nonius CAD-4 diffractometer | Rint = 0.050 |
2701 measured reflections | 3 standard reflections every 60 min |
2523 independent reflections | intensity decay: 5% |
1235 reflections with I > 2σ(I) |
R[F2 > 2σ(F2)] = 0.126 | 0 restraints |
wR(F2) = 0.361 | H-atom parameters constrained |
S = 1.28 | Δρmax = 0.69 e Å−3 |
2523 reflections | Δρmin = −0.67 e Å−3 |
173 parameters |
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | ||
C1 | 0.1840 (6) | 0.4649 (4) | 0.8347 (8) | 0.0455 (17) | |
C2 | 0.3152 (6) | 0.4837 (4) | 0.8462 (8) | 0.0469 (17) | |
H2 | 0.3433 | 0.5334 | 0.9323 | 0.056* | |
C3 | 0.3736 (7) | 0.3850 (5) | 0.9078 (10) | 0.060 (2) | |
H3A | 0.3741 | 0.3405 | 0.8173 | 0.072* | |
H3B | 0.4556 | 0.3951 | 0.9709 | 0.072* | |
C4 | 0.2981 (8) | 0.3433 (5) | 1.0124 (11) | 0.064 (2) | |
H4A | 0.3429 | 0.3428 | 1.1260 | 0.077* | |
H4B | 0.2747 | 0.2752 | 0.9798 | 0.077* | |
C5 | 0.1886 (7) | 0.4085 (4) | 0.9909 (9) | 0.0553 (19) | |
H5A | 0.1966 | 0.4540 | 1.0824 | 0.066* | |
H5B | 0.1168 | 0.3684 | 0.9812 | 0.066* | |
O6 | 0.1394 (4) | 0.4049 (3) | 0.6997 (5) | 0.0528 (13) | |
H6 | 0.1084 | 0.3547 | 0.7282 | 0.079* | |
C7 | 0.1137 (6) | 0.5605 (4) | 0.8200 (9) | 0.0463 (17) | |
C8 | 0.0127 (6) | 0.5733 (5) | 0.6989 (10) | 0.0525 (18) | |
H8 | −0.0170 | 0.5217 | 0.6263 | 0.063* | |
C9 | −0.0443 (8) | 0.6628 (5) | 0.6854 (10) | 0.061 (2) | |
H9 | −0.1124 | 0.6709 | 0.5997 | 0.074* | |
N10 | −0.0107 (6) | 0.7380 (4) | 0.7833 (9) | 0.0617 (18) | |
C11 | 0.0856 (7) | 0.7239 (5) | 0.9014 (11) | 0.061 (2) | |
H11 | 0.1128 | 0.7764 | 0.9734 | 0.073* | |
C12 | 0.1476 (7) | 0.6374 (4) | 0.9246 (10) | 0.0550 (19) | |
H12 | 0.2141 | 0.6308 | 1.0131 | 0.066* | |
C13 | 0.3400 (6) | 0.5238 (4) | 0.6929 (9) | 0.0465 (16) | |
C14 | 0.3684 (7) | 0.6227 (5) | 0.6829 (10) | 0.0548 (19) | |
H14 | 0.3739 | 0.6635 | 0.7737 | 0.066* | |
C15 | 0.3884 (7) | 0.6625 (5) | 0.5464 (10) | 0.061 (2) | |
H15 | 0.4086 | 0.7297 | 0.5425 | 0.073* | |
C16 | 0.3788 (7) | 0.6039 (5) | 0.4171 (10) | 0.063 (2) | |
C17 | 0.3516 (7) | 0.5067 (5) | 0.4207 (10) | 0.061 (2) | |
H17 | 0.3454 | 0.4670 | 0.3285 | 0.074* | |
C18 | 0.3332 (6) | 0.4667 (5) | 0.5597 (9) | 0.0558 (19) | |
H18 | 0.3157 | 0.3990 | 0.5632 | 0.067* | |
F19 | 0.3971 (5) | 0.6414 (3) | 0.2785 (6) | 0.0785 (16) |
U11 | U22 | U33 | U12 | U13 | U23 | |
C1 | 0.073 (4) | 0.021 (2) | 0.050 (4) | −0.004 (2) | 0.030 (4) | −0.008 (2) |
C2 | 0.057 (4) | 0.028 (2) | 0.058 (4) | 0.002 (2) | 0.018 (3) | −0.007 (3) |
C3 | 0.066 (5) | 0.038 (3) | 0.077 (5) | 0.009 (3) | 0.021 (4) | 0.003 (3) |
C4 | 0.088 (6) | 0.036 (3) | 0.069 (5) | 0.006 (3) | 0.023 (4) | 0.011 (3) |
C5 | 0.084 (5) | 0.030 (3) | 0.059 (4) | −0.006 (3) | 0.031 (4) | 0.003 (3) |
O6 | 0.082 (3) | 0.0270 (18) | 0.056 (3) | −0.010 (2) | 0.030 (3) | −0.0010 (18) |
C7 | 0.047 (4) | 0.033 (3) | 0.067 (5) | 0.000 (2) | 0.030 (4) | 0.001 (3) |
C8 | 0.048 (4) | 0.043 (3) | 0.071 (5) | 0.001 (3) | 0.022 (4) | −0.006 (3) |
C9 | 0.074 (5) | 0.054 (4) | 0.063 (5) | 0.012 (3) | 0.030 (4) | 0.003 (4) |
N10 | 0.071 (5) | 0.045 (3) | 0.077 (5) | 0.014 (3) | 0.036 (4) | 0.005 (3) |
C11 | 0.061 (5) | 0.041 (3) | 0.086 (6) | 0.009 (3) | 0.028 (5) | −0.013 (4) |
C12 | 0.068 (5) | 0.035 (3) | 0.069 (5) | 0.005 (3) | 0.029 (4) | 0.000 (3) |
C13 | 0.051 (4) | 0.030 (3) | 0.065 (4) | 0.004 (2) | 0.026 (3) | −0.002 (3) |
C14 | 0.066 (5) | 0.039 (3) | 0.065 (5) | 0.003 (3) | 0.026 (4) | −0.001 (3) |
C15 | 0.079 (5) | 0.038 (3) | 0.076 (6) | 0.004 (3) | 0.036 (4) | 0.007 (3) |
C16 | 0.075 (5) | 0.048 (4) | 0.077 (6) | 0.010 (3) | 0.040 (5) | 0.023 (4) |
C17 | 0.072 (5) | 0.056 (4) | 0.061 (5) | 0.004 (3) | 0.026 (4) | −0.012 (4) |
C18 | 0.065 (5) | 0.037 (3) | 0.073 (5) | −0.006 (3) | 0.029 (4) | −0.002 (3) |
F19 | 0.111 (4) | 0.066 (3) | 0.070 (3) | 0.008 (2) | 0.044 (3) | 0.022 (2) |
C1—O6 | 1.413 (7) | C8—H8 | 0.9500 |
C1—C7 | 1.533 (8) | C9—N10 | 1.326 (10) |
C1—C2 | 1.538 (9) | C9—H9 | 0.9500 |
C1—C5 | 1.541 (9) | N10—C11 | 1.333 (11) |
C2—C13 | 1.523 (9) | C11—C12 | 1.375 (9) |
C2—C3 | 1.545 (9) | C11—H11 | 0.9500 |
C2—H2 | 1.0000 | C12—H12 | 0.9500 |
C3—C4 | 1.522 (10) | C13—C18 | 1.374 (9) |
C3—H3A | 0.9900 | C13—C14 | 1.400 (9) |
C3—H3B | 0.9900 | C14—C15 | 1.368 (10) |
C4—C5 | 1.536 (11) | C14—H14 | 0.9500 |
C4—H4A | 0.9900 | C15—C16 | 1.354 (11) |
C4—H4B | 0.9900 | C15—H15 | 0.9500 |
C5—H5A | 0.9900 | C16—F19 | 1.365 (8) |
C5—H5B | 0.9900 | C16—C17 | 1.368 (10) |
O6—H6 | 0.8400 | C17—C18 | 1.381 (10) |
C7—C12 | 1.377 (9) | C17—H17 | 0.9500 |
C7—C8 | 1.382 (10) | C18—H18 | 0.9500 |
C8—C9 | 1.384 (10) | ||
O6—C1—C7 | 110.2 (6) | C8—C7—C1 | 120.8 (6) |
O6—C1—C2 | 108.0 (5) | C7—C8—C9 | 118.7 (7) |
C7—C1—C2 | 111.8 (4) | C7—C8—H8 | 120.6 |
O6—C1—C5 | 110.8 (4) | C9—C8—H8 | 120.6 |
C7—C1—C5 | 113.6 (5) | N10—C9—C8 | 124.7 (9) |
C2—C1—C5 | 102.1 (6) | N10—C9—H9 | 117.6 |
C13—C2—C1 | 114.0 (6) | C8—C9—H9 | 117.6 |
C13—C2—C3 | 116.6 (5) | C9—N10—C11 | 115.8 (6) |
C1—C2—C3 | 103.1 (5) | N10—C11—C12 | 123.5 (7) |
C13—C2—H2 | 107.5 | N10—C11—H11 | 118.2 |
C1—C2—H2 | 107.5 | C12—C11—H11 | 118.2 |
C3—C2—H2 | 107.5 | C11—C12—C7 | 120.2 (8) |
C4—C3—C2 | 104.9 (6) | C11—C12—H12 | 119.9 |
C4—C3—H3A | 110.8 | C7—C12—H12 | 119.9 |
C2—C3—H3A | 110.8 | C18—C13—C14 | 117.5 (6) |
C4—C3—H3B | 110.8 | C18—C13—C2 | 122.5 (5) |
C2—C3—H3B | 110.8 | C14—C13—C2 | 120.0 (6) |
H3A—C3—H3B | 108.8 | C15—C14—C13 | 122.1 (7) |
C3—C4—C5 | 107.6 (6) | C15—C14—H14 | 119.0 |
C3—C4—H4A | 110.2 | C13—C14—H14 | 119.0 |
C5—C4—H4A | 110.2 | C16—C15—C14 | 118.4 (6) |
C3—C4—H4B | 110.2 | C16—C15—H15 | 120.8 |
C5—C4—H4B | 110.2 | C14—C15—H15 | 120.8 |
H4A—C4—H4B | 108.5 | C15—C16—F19 | 120.0 (6) |
C4—C5—C1 | 104.0 (5) | C15—C16—C17 | 121.8 (7) |
C4—C5—H5A | 110.9 | F19—C16—C17 | 118.2 (7) |
C1—C5—H5A | 110.9 | C16—C17—C18 | 119.4 (7) |
C4—C5—H5B | 110.9 | C16—C17—H17 | 120.3 |
C1—C5—H5B | 110.9 | C18—C17—H17 | 120.3 |
H5A—C5—H5B | 109.0 | C13—C18—C17 | 120.8 (6) |
C1—O6—H6 | 109.3 | C13—C18—H18 | 119.6 |
C12—C7—C8 | 116.9 (6) | C17—C18—H18 | 119.6 |
C12—C7—C1 | 122.3 (7) | ||
O6—C1—C2—C13 | 53.2 (6) | C7—C8—C9—N10 | −1.7 (11) |
C7—C1—C2—C13 | −68.2 (7) | C8—C9—N10—C11 | 0.4 (11) |
C5—C1—C2—C13 | 170.0 (5) | C9—N10—C11—C12 | −0.6 (11) |
O6—C1—C2—C3 | −74.2 (6) | N10—C11—C12—C7 | 2.2 (11) |
C7—C1—C2—C3 | 164.4 (6) | C8—C7—C12—C11 | −3.3 (9) |
C5—C1—C2—C3 | 42.6 (6) | C1—C7—C12—C11 | 176.3 (6) |
C13—C2—C3—C4 | −157.3 (6) | C1—C2—C13—C18 | −73.7 (7) |
C1—C2—C3—C4 | −31.6 (7) | C3—C2—C13—C18 | 46.4 (9) |
C2—C3—C4—C5 | 8.3 (9) | C1—C2—C13—C14 | 104.9 (7) |
C3—C4—C5—C1 | 18.1 (8) | C3—C2—C13—C14 | −135.0 (7) |
O6—C1—C5—C4 | 77.5 (7) | C18—C13—C14—C15 | 0.3 (11) |
C7—C1—C5—C4 | −157.8 (6) | C2—C13—C14—C15 | −178.3 (7) |
C2—C1—C5—C4 | −37.3 (6) | C13—C14—C15—C16 | 0.8 (12) |
O6—C1—C7—C12 | −171.5 (5) | C14—C15—C16—F19 | 179.4 (7) |
C2—C1—C7—C12 | −51.4 (8) | C14—C15—C16—C17 | −1.0 (12) |
C5—C1—C7—C12 | 63.5 (8) | C15—C16—C17—C18 | 0.0 (12) |
O6—C1—C7—C8 | 8.0 (7) | F19—C16—C17—C18 | 179.7 (7) |
C2—C1—C7—C8 | 128.2 (6) | C14—C13—C18—C17 | −1.3 (11) |
C5—C1—C7—C8 | −116.9 (7) | C2—C13—C18—C17 | 177.3 (7) |
C12—C7—C8—C9 | 3.0 (9) | C16—C17—C18—C13 | 1.1 (11) |
C1—C7—C8—C9 | −176.6 (6) |
D—H···A | D—H | H···A | D···A | D—H···A |
O6—H6···N10i | 0.84 | 1.95 | 2.758 (7) | 161 |
Symmetry code: (i) −x, y−1/2, −z+3/2. |
Experimental details
Crystal data | |
Chemical formula | C16H16FNO |
Mr | 257.30 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 193 |
a, b, c (Å) | 11.7228 (8), 13.6606 (8), 8.6194 (11) |
β (°) | 104.366 (10) |
V (Å3) | 1337.2 (2) |
Z | 4 |
Radiation type | Cu Kα |
µ (mm−1) | 0.73 |
Crystal size (mm) | 0.30 × 0.30 × 0.06 |
Data collection | |
Diffractometer | Enraf–Nonius CAD-4 |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 2701, 2523, 1235 |
Rint | 0.050 |
(sin θ/λ)max (Å−1) | 0.611 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.126, 0.361, 1.28 |
No. of reflections | 2523 |
No. of parameters | 173 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.69, −0.67 |
Computer programs: CAD-4 Software (Enraf–Nonius, 1989), CAD-4 Software, CORINC (Dräger & Gattow, 1971), SIR92 (Altomare et al., 1994), SHELXL97 (Sheldrick, 1997), PLATON (Spek, 2003), SHELXL97.
D—H···A | D—H | H···A | D···A | D—H···A |
O6—H6···N10i | 0.84 | 1.95 | 2.758 (7) | 160.5 |
Symmetry code: (i) −x, y−1/2, −z+3/2. |
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Compound 4 was prepared in the course of our study on cyclopentene derivatives bearing the typical vicinal 4-pyridyl and 4-fluorophenyl pharmacophores of MAP Kinase inhibitors. Pyridinylimidazoles are described in the literature as inhibitors for p38 MAP Kinase (Wagner et al., 2006; Kaminska, 2005). The prototypical pyridinylimidazole SB 203580 is one of the best studied p38 inhibitors reported until now. Figure 1 shows the most important interactions between the ATP binding sites of p38 kinase and the imidazole inhibitor SB203580 (Wang et al., 1998; Laufer et al., 2006). The 4-fluorophenyl ring of SB203580 occupies a hydrophobic back pocket gaining selectivity. Vicinal to this interaction site, 4-pyridinyl moiety forms a hydrogen bond from the backbone NH group of Met 109 of p38 MAP Kinase (Fig. 1).
Meanwhile, the importance of a further hydrogen bond between N3 of the imidazole core and Lys53 of p38 MAP Kinase, as shown in figure 1, is not yet clear and the speculation about its significance is not settled. Based on this concept, replacement of imidazole core by a cyclopentene ring would require the preparation of 2-fluorophenyl-1-pyridinyl cyclopentanol 4 as a key compound for such comparative bioassay study. Going from the data obtained from the X-ray structure of compound 4 (Figs. 2 and 3), it is impossible for the vicinal 4-fluorophenyl and 4-pyridinyl groups (due to their location in trans position to each other) to exert their expected functions with p38 MAPK as described above in case of SB203580 inhibitor (Fig. 1).
So, the loss of the biological activity of compound 4 can not be attributed just to the absence of the nitrogen atoms in the cyclopentane core itself. Accordingly, and based on this result, we plan to prepare cyclopentene derivatives which have vicinal 4-fluorophenyl and 4-pyridinyl groups in cis orientation in order to get more accurate and comparable information about the extent of the importance of the hydrogen bond between N3 of the imidazole core and Lys 53 of P38 MAP Kinase in terms of its biological activity.