organic compounds
The crystal structure of the title compound, C20H14Cl3N3, a potent antifungal agent discovered recently, is here reported. The elucidation of the structure may be useful to provide a better understanding of the interaction of imidazole agents with P-450-dependent enzymes involved either in ergosterol biosynthesis (in fungi) or in hormones biosynthesis (in humans).
Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536800020699/cf6026sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S1600536800020699/cf6026Isup2.hkl |
CCDC reference: 155905
Computing details top
Data collection: R3m/V (Siemens, 1989); cell refinement: R3m/V; data reduction: XDISK (Siemens, 1989); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: CAOS (Camalli & Spagna, 1994); molecular graphics: CAOS; software used to prepare material for publication: CAOS.
Figures top
Fig. 1. The molecular structure with 50% probability ellipsoids. | |
Fig. 2. The unit-cell contents viewed approximately along the a axis. |
(I) top
Crystal data top
C20H14Cl3N3 | F(000) = 824 |
Mr = 402.71 | Dx = 1.428 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71069 Å |
a = 6.887 (1) Å | Cell parameters from 38 reflections |
b = 18.847 (3) Å | θ = 4.3–18.3° |
c = 14.947 (3) Å | µ = 0.50 mm−1 |
β = 105.08 (1)° | T = 293 K |
V = 1873.2 (5) Å3 | Prism, brown |
Z = 4 | 0.4 × 0.2 × 0.15 mm |
Data collection top
Siemens P3 four-circle diffractometer | 2474 reflections with F > 6σ(F) |
Radiation source: X-ray tube | Rint = 0.028 |
Graphite monochromator | θmax = 45.1°, θmin = 1.8° |
θ/2θ scans | h = 0→13 |
Absorption correction: empirical (using intensity measurements) ψ scan (North et al., 1968) | k = 0→37 |
Tmin = 0.82, Tmax = 0.93 | l = −29→28 |
17474 measured reflections | 3 standard reflections every 97 reflections |
15414 independent reflections | intensity decay: none |
Refinement top
Refinement on F | 235 parameters |
Least-squares matrix: Full | H-atom parameters constrained |
R[F2 > 2σ(F2)] = 0.041 | w = 1/(0.0009 + 0.0108F + 0.0032F2) |
wR(F2) = 0.056 | (Δ/σ)max < 0.001 |
S = 0.90 | Δρmax = 0.42 e Å−3 |
2474 reflections | Δρmin = −0.35 e Å−3 |
Crystal data top
C20H14Cl3N3 | V = 1873.2 (5) Å3 |
Mr = 402.71 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 6.887 (1) Å | µ = 0.50 mm−1 |
b = 18.847 (3) Å | T = 293 K |
c = 14.947 (3) Å | 0.4 × 0.2 × 0.15 mm |
β = 105.08 (1)° |
Data collection top
Siemens P3 four-circle diffractometer | 2474 reflections with F > 6σ(F) |
Absorption correction: empirical (using intensity measurements) ψ scan (North et al., 1968) | Rint = 0.028 |
Tmin = 0.82, Tmax = 0.93 | 3 standard reflections every 97 reflections |
17474 measured reflections | intensity decay: none |
15414 independent reflections |
Refinement top
R[F2 > 2σ(F2)] = 0.041 | 235 parameters |
wR(F2) = 0.056 | H-atom parameters constrained |
S = 0.90 | Δρmax = 0.42 e Å−3 |
2474 reflections | Δρmin = −0.35 e Å−3 |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
x | y | z | Uiso*/Ueq | ||
Cl(1) | −0.1548 (1) | 0.41838 (4) | 0.5942 (1) | 0.0630 (2) | |
Cl(2) | 0.0770 (1) | 0.41048 (5) | 0.28003 (5) | 0.0699 (3) | |
Cl(3) | −0.2278 (2) | 0.2986 (1) | 1.0404 (1) | 0.0864 (4) | |
N(1) | 0.4550 (3) | 0.5339 (1) | 0.7813 (2) | 0.048 (1) | |
N(2) | 0.3964 (3) | 0.2991 (1) | 0.7222 (1) | 0.040 (1) | |
N(3) | 0.6569 (6) | 0.2303 (2) | 0.7667 (2) | 0.080 (1) | |
C(1) | 0.4328 (4) | 0.4808 (1) | 0.7177 (2) | 0.043 (1) | |
C(2) | 0.3277 (3) | 0.4262 (1) | 0.7449 (1) | 0.038 (1) | |
C(3) | 0.2808 (4) | 0.4480 (1) | 0.8284 (2) | 0.041 (1) | |
C(4) | 0.3623 (4) | 0.5150 (1) | 0.8481 (2) | 0.050 (1) | |
C(5) | 0.2563 (3) | 0.3591 (1) | 0.6922 (2) | 0.038 (1) | |
C(6) | 0.3384 (5) | 0.2301 (1) | 0.7125 (2) | 0.056 (1) | |
C(7) | 0.4936 (4) | 0.1873 (1) | 0.7396 (2) | 0.050 (1) | |
C(8) | 0.6000 (4) | 0.3001 (1) | 0.7561 (2) | 0.052 (1) | |
C(9) | 0.2131 (3) | 0.3699 (1) | 0.5880 (1) | 0.036 (1) | |
C(10) | 0.0293 (3) | 0.3973 (1) | 0.5378 (2) | 0.041 (1) | |
C(11) | −0.0156 (4) | 0.4091 (1) | 0.4434 (2) | 0.048 (1) | |
C(12) | 0.1322 (4) | 0.3938 (1) | 0.3984 (2) | 0.048 (1) | |
C(13) | 0.3164 (4) | 0.3665 (1) | 0.4440 (2) | 0.047 (1) | |
C(14) | 0.3547 (4) | 0.3543 (1) | 0.5390 (2) | 0.043 (1) | |
C(15) | 0.1556 (4) | 0.4107 (1) | 0.8796 (2) | 0.043 (1) | |
C(16) | −0.0105 (4) | 0.4437 (1) | 0.8981 (2) | 0.052 (1) | |
C(17) | −0.1310 (5) | 0.4099 (1) | 0.9465 (2) | 0.056 (1) | |
C(18) | −0.0833 (5) | 0.3413 (1) | 0.9776 (2) | 0.054 (1) | |
C(19) | 0.0747 (5) | 0.3059 (2) | 0.9579 (2) | 0.062 (1) | |
C(20) | 0.1953 (5) | 0.3404 (1) | 0.9093 (2) | 0.059 (1) | |
H(1) | 0.5250 | 0.5777 | 0.7796 | 0.048* | |
H(2) | 0.4819 | 0.4814 | 0.6632 | 0.043* | |
H(3) | 0.3547 | 0.5436 | 0.9002 | 0.050* | |
H(4) | 0.1324 | 0.3470 | 0.7066 | 0.038* | |
H(5) | 0.2019 | 0.2145 | 0.6889 | 0.056* | |
H(6) | 0.4919 | 0.1364 | 0.7402 | 0.050* | |
H(7) | 0.6855 | 0.3411 | 0.7697 | 0.052* | |
H(8) | −0.1444 | 0.4272 | 0.4101 | 0.048* | |
H(9) | 0.4160 | 0.3561 | 0.4113 | 0.047* | |
H(10) | 0.4820 | 0.3347 | 0.5717 | 0.043* | |
H(11) | −0.0426 | 0.4914 | 0.8768 | 0.052* | |
H(12) | −0.2452 | 0.4337 | 0.9582 | 0.056* | |
H(13) | 0.1022 | 0.2576 | 0.9773 | 0.063* | |
H(14) | 0.3066 | 0.3156 | 0.8962 | 0.059* |
Atomic displacement parameters (Å2) top
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl(1) | 0.0507 (3) | 0.0591 (4) | 0.0869 (5) | 0.0108 (3) | 0.0316 (3) | 0.0025 (3) |
Cl(2) | 0.0931 (6) | 0.0647 (4) | 0.0482 (3) | 0.0124 (4) | 0.0117 (3) | 0.0095 (3) |
Cl(3) | 0.1038 (7) | 0.0820 (6) | 0.0901 (6) | −0.0104 (5) | 0.0554 (5) | 0.0184 (5) |
N(1) | 0.060 (1) | 0.0269 (7) | 0.060 (1) | −0.0071 (7) | 0.0194 (9) | −0.0038 (7) |
N(2) | 0.057 (1) | 0.0228 (6) | 0.0423 (8) | 0.0037 (7) | 0.0150 (8) | 0.0018 (6) |
N(3) | 0.102 (2) | 0.057 (2) | 0.078 (2) | 0.024 (2) | 0.018 (2) | 0.006 (1) |
C(1) | 0.053 (1) | 0.0249 (7) | 0.054 (1) | −0.0010 (8) | 0.018 (1) | −0.0010 (7) |
C(2) | 0.046 (1) | 0.0245 (7) | 0.045 (1) | 0.0025 (7) | 0.0159 (8) | 0.0006 (6) |
C(3) | 0.054 (1) | 0.0263 (8) | 0.045 (1) | 0.0020 (8) | 0.0175 (9) | −0.0002 (7) |
C(4) | 0.065 (2) | 0.0293 (9) | 0.056 (1) | −0.0013 (9) | 0.017 (1) | −0.0075 (9) |
C(5) | 0.045 (1) | 0.0246 (7) | 0.048 (1) | −0.0004 (7) | 0.0165 (9) | −0.0008 (7) |
C(6) | 0.078 (2) | 0.0233 (8) | 0.068 (2) | −0.0045 (9) | 0.023 (1) | 0.0015 (9) |
C(7) | 0.067 (2) | 0.0199 (7) | 0.063 (1) | 0.0077 (9) | 0.015 (1) | 0.0057 (8) |
C(8) | 0.058 (1) | 0.036 (1) | 0.059 (1) | 0.0057 (9) | 0.009 (1) | 0.0005 (9) |
C(9) | 0.039 (1) | 0.0235 (6) | 0.045 (1) | −0.0020 (7) | 0.0115 (8) | −0.0020 (7) |
C(10) | 0.041 (1) | 0.0280 (8) | 0.055 (1) | 0.0000 (7) | 0.0158 (9) | −0.0016 (8) |
C(11) | 0.046 (1) | 0.038 (1) | 0.057 (1) | 0.0029 (9) | 0.006 (1) | 0.0023 (9) |
C(12) | 0.064 (1) | 0.0336 (9) | 0.044 (1) | −0.0011 (9) | 0.009 (1) | 0.0010 (8) |
C(13) | 0.051 (1) | 0.043 (1) | 0.049 (1) | 0.0021 (9) | 0.017 (1) | −0.0011 (9) |
C(14) | 0.042 (1) | 0.039 (1) | 0.048 (1) | 0.0020 (8) | 0.0125 (9) | 0.0015 (8) |
C(15) | 0.059 (1) | 0.0318 (8) | 0.0400 (9) | 0.0029 (9) | 0.0156 (9) | −0.0005 (7) |
C(16) | 0.067 (2) | 0.0336 (9) | 0.060 (1) | 0.005 (1) | 0.026 (1) | 0.0028 (9) |
C(17) | 0.065 (2) | 0.048 (1) | 0.061 (1) | 0.005 (1) | 0.029 (1) | −0.000 (1) |
C(18) | 0.071 (2) | 0.050 (1) | 0.048 (1) | −0.006 (1) | 0.026 (1) | 0.005 (1) |
C(19) | 0.084 (2) | 0.043 (1) | 0.066 (2) | 0.011 (1) | 0.032 (1) | 0.019 (1) |
C(20) | 0.079 (2) | 0.040 (1) | 0.066 (2) | 0.015 (1) | 0.035 (1) | 0.014 (1) |
Geometric parameters (Å, º) top
Cl(1)—C(10) | 1.742 (2) | C(7)—H(6) | 0.960 |
Cl(2)—C(12) | 1.739 (3) | C(8)—H(7) | 0.960 |
Cl(3)—C(18) | 1.734 (3) | C(9)—C(10) | 1.392 (4) |
N(1)—C(1) | 1.360 (3) | C(9)—C(14) | 1.395 (3) |
N(1)—C(4) | 1.364 (3) | C(10)—C(11) | 1.381 (4) |
N(1)—H(1) | 0.960 | C(11)—C(12) | 1.388 (3) |
N(2)—C(5) | 1.479 (3) | C(11)—H(8) | 0.960 |
N(2)—C(6) | 1.357 (3) | C(12)—C(13) | 1.375 (4) |
N(2)—C(8) | 1.362 (4) | C(13)—C(14) | 1.395 (4) |
N(3)—C(7) | 1.360 (5) | C(13)—H(9) | 0.960 |
N(3)—C(8) | 1.370 (4) | C(14)—H(10) | 0.960 |
C(1)—C(2) | 1.379 (3) | C(15)—C(16) | 1.391 (4) |
C(1)—H(2) | 0.960 | C(15)—C(20) | 1.402 (4) |
C(2)—C(3) | 1.429 (3) | C(16)—C(17) | 1.389 (4) |
C(2)—C(5) | 1.503 (3) | C(16)—H(11) | 0.960 |
C(3)—C(4) | 1.382 (3) | C(17)—C(18) | 1.383 (4) |
C(3)—C(15) | 1.472 (3) | C(17)—H(12) | 0.960 |
C(4)—H(3) | 0.960 | C(18)—C(19) | 1.373 (4) |
C(5)—C(9) | 1.522 (3) | C(19)—C(20) | 1.397 (4) |
C(5)—H(4) | 0.960 | C(19)—H(13) | 0.960 |
C(6)—C(7) | 1.316 (4) | C(20)—H(14) | 0.960 |
C(6)—H(5) | 0.960 | ||
C(4)—N(1)—C(1) | 109.3 (2) | C(10)—C(9)—C(14) | 117.2 (2) |
H(1)—N(1)—C(1) | 125.4 | C(10)—C(9)—C(5) | 120.7 (2) |
H(1)—N(1)—C(4) | 125.3 | Cl(1)—C(10)—C(11) | 117.4 (2) |
C(5)—N(2)—C(8) | 129.0 (2) | C(9)—C(10)—C(11) | 122.7 (2) |
C(6)—N(2)—C(8) | 107.5 (2) | C(9)—C(10)—Cl(1) | 119.8 (2) |
C(6)—N(2)—C(5) | 123.4 (2) | C(12)—C(11)—C(10) | 117.7 (3) |
C(8)—N(3)—C(7) | 110.4 (3) | H(8)—C(11)—C(10) | 121.1 |
N(1)—C(1)—C(2) | 108.4 (2) | H(8)—C(11)—C(12) | 121.2 |
H(2)—C(1)—C(2) | 125.8 | C(11)—C(12)—C(13) | 122.4 (2) |
H(2)—C(1)—N(1) | 125.8 | Cl(2)—C(12)—C(13) | 120.1 (2) |
C(3)—C(2)—C(1) | 107.3 (2) | Cl(2)—C(12)—C(11) | 117.5 (2) |
C(5)—C(2)—C(1) | 126.8 (2) | C(14)—C(13)—H(9) | 120.9 |
C(5)—C(2)—C(3) | 125.6 (2) | C(12)—C(13)—H(9) | 121.0 |
C(15)—C(3)—C(4) | 125.9 (2) | C(12)—C(13)—C(14) | 118.1 (2) |
C(2)—C(3)—C(4) | 106.1 (2) | C(9)—C(14)—C(13) | 121.8 (2) |
C(2)—C(3)—C(15) | 127.8 (2) | H(10)—C(14)—C(13) | 119.1 |
C(3)—C(4)—N(1) | 108.9 (2) | H(10)—C(14)—C(9) | 119.0 |
H(3)—C(4)—N(1) | 125.6 | C(16)—C(15)—C(3) | 120.9 (2) |
H(3)—C(4)—C(3) | 125.5 | C(20)—C(15)—C(3) | 121.6 (2) |
H(4)—C(5)—C(2) | 105.8 | C(20)—C(15)—C(16) | 117.5 (2) |
C(9)—C(5)—C(2) | 111.9 (2) | C(17)—C(16)—C(15) | 122.2 (2) |
C(9)—C(5)—H(4) | 108.2 | H(11)—C(16)—C(15) | 118.9 |
N(2)—C(5)—C(2) | 112.7 (2) | H(11)—C(16)—C(17) | 119.0 |
N(2)—C(5)—H(4) | 107.3 | H(12)—C(17)—C(18) | 120.6 |
N(2)—C(5)—C(9) | 110.6 (2) | C(16)—C(17)—C(18) | 118.7 (3) |
N(2)—C(6)—C(7) | 111.2 (3) | C(16)—C(17)—H(12) | 120.6 |
H(5)—C(6)—C(7) | 124.4 | Cl(3)—C(18)—C(19) | 119.3 (2) |
H(5)—C(6)—N(2) | 124.4 | C(17)—C(18)—C(19) | 121.0 (3) |
H(6)—C(7)—N(3) | 127.2 | C(17)—C(18)—Cl(3) | 119.8 (2) |
C(6)—C(7)—N(3) | 105.6 (2) | C(18)—C(19)—H(13) | 120.1 |
C(6)—C(7)—H(6) | 127.2 | C(20)—C(19)—H(13) | 120.1 |
N(3)—C(8)—N(2) | 105.3 (3) | C(20)—C(19)—C(18) | 119.8 (3) |
H(7)—C(8)—N(2) | 127.3 | C(15)—C(20)—H(14) | 119.6 |
H(7)—C(8)—N(3) | 127.4 | C(19)—C(20)—H(14) | 119.7 |
C(5)—C(9)—C(14) | 122.1 (2) | C(19)—C(20)—C(15) | 120.7 (3) |
Experimental details
Crystal data | |
Chemical formula | C20H14Cl3N3 |
Mr | 402.71 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 293 |
a, b, c (Å) | 6.887 (1), 18.847 (3), 14.947 (3) |
β (°) | 105.08 (1) |
V (Å3) | 1873.2 (5) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.50 |
Crystal size (mm) | 0.4 × 0.2 × 0.15 |
Data collection | |
Diffractometer | Siemens P3 four-circle diffractometer |
Absorption correction | Empirical (using intensity measurements) ψ scan (North et al., 1968) |
Tmin, Tmax | 0.82, 0.93 |
No. of measured, independent and observed [F > 6σ(F)] reflections | 17474, 15414, 2474 |
Rint | 0.028 |
(sin θ/λ)max (Å−1) | 0.997 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.041, 0.056, 0.90 |
No. of reflections | 2474 |
No. of parameters | 235 |
No. of restraints | ? |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.42, −0.35 |
Computer programs: R3m/V (Siemens, 1989), R3m/V, XDISK (Siemens, 1989), SIR97 (Altomare et al., 1999), CAOS (Camalli & Spagna, 1994), CAOS.
Cytochromes P-450 are a superfamily of enzymes which catalyzes the oxidation of a large number of biological substrates (Ortiz de Montellano, 1986). In particular, cytochrome P-450-dependent lanosterol 14α-demethylase (P-450DM) catalyzes in fungi the first step of the lanosterol conversion to ergosterol, by removal the 14α-methyl group from lanosterol (Vanden Bossche, 1988). Azole antifungals are known to inhibit fungal P-450DM leading to accumulation of 14α-methylated sterols which cause inhibition of fungi growth by changing the membrane permeability (Adams & Metcalf, 1990; Yeagle et al., 1977, and references cited therein). In fact, the antimycotic derivatives bind to P-450DM by coordination of the ring N atom to the sixth coordination position of the Fe atom of the enzymatic protoporphyrin system (Hitchcock et al., 1990).
Starting from 1960, a number of potent antifungal azole derivatives, such as bifonazole, miconazole, econazole, ketoconazole and fluconazole (Fromtling, 1986; D'Arcy & Scott, 1987; Kerridge, 1988; Koltin, 1990) were synthesized and are now used in clinical practice against topical or systemic fungal infections. More recent biological studies showed some P-450-dependent enzymes to be inhibited by azole derivatives, thus opening new frontiers in the research on azole drugs. Aromatase (Banting et al., 1989) and C17,20-lyase (Njar & Brodie, 1999) are crucial targets for inhibition of mammalian or prostatic cancer, respectively. Unfortunately, aromatase, C17,20-lyase and 14α-demethylase stuctures have not been completely elucidated to date and theoretical approaches have been made in recent years to better understand the interaction of azole derivatives with P-450-dependent enzymes (Tafi et al., 1996; Ji et al., 2000). Our ten-year interest in antifungal drugs led us to discover several classes of azole derivatives endowed with interesting antimicotic activities (Artico et al., 1993, 1995; Di Santo et al., 1993, 1994, 1997; Massa Di Santo, Retico et al., 1992; Massa, Di Santo, Artico, Costi, Di Filippo et al., 1992, Massa, Di Santo, Costi, Simonetti et al., 1993 Massa, Di Santo, Costi, Mai et al., 1993;; Tafi et al., 1996). In particular, we reported about the high anti-Candida potency of a new class of imidazole derivatives, namely 3-aryl-4-[α-(1H-imidazol-1-yl)arylmethyl]pyrroles, which were highly effective, either in vitro or in vivo, against Candida albicans at doses lower than that of bifonazole used as reference drug (Artico et al., 1995). One of the most potent compounds was 3-(4-chlorophenyl)-4-[α-(1H-imidazol-1-yl)(2,4-dichlorophenyl)methylpyrrole (RDS 416), (I), which showed comparable topical efficacy to that of bifonazole in in vivo inhibition of cutaneous candidiasis (C. albicans A170) in white male rabbits. The aim of this work is to elucidate the spatial disposition of RDS 416, for a better understanding of its interaction with 14α-lanosterol demethylase.
The crystal structure of (I) consists of one molecule in the asymmetric unit. The geometry of the four rings is in good agreement with the accepted values. The three angles around C5 involving non-H substitutents are wider than the theoretical tetrahedral value of 109.5°, but the three angles involving the H atom are smaller; this tetrahedral deformation is explained in terms of the bulkiness of the non-H substituents together with the small volume of the H atom. The dihedral angle between the pyrrol ring plane and its attached Cl–phenyl group [52.9 (1)°] shows absence of mesomeric effect. The only short intermolecular distance observed is N1···C7i of 2.940 (3) Å [symmetry code: (i) 1 - x, 1/2 + y, 3/2 - z].