1-{[4-(4-Chloro­phenyl)-1H-pyrrol-3-yl](2,4-di­chloro­phenyl)­methyl}-1H-imidazole (RDS 416)

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).

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.041
• wR factor = 0.056
• Data-to-parameter ratio = 10.5

checkCIF results

No syntax errors found



ADDSYM reports no extra symmetry

General Notes



ABSTM_02  When printed, the submitted absorption T values will be replaced
          by the scaled T values. Since the ratio of scaled T's is
          identical to the ratio of reported T values, the scaling does
          not imply a change to the absorption corrections used in the
          study.
          Ratio of Tmax expected/reported      0.928
          Tmax scaled      0.928 Tmin scaled      0.817

---

S1. Comment

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-450_DM) 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-450_DM 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-450_DM 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].

S2. Experimental

The title compound was synthesized previously by Artico et al. (1995).

S3. Refinement

The H atoms were placed in calculated positions (N—H and C—H = 0.96 Å).

Computing details

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

	Fig. 1. The molecular structure with 50% probability ellipsoids.
	Fig. 2. The unit-cell contents viewed approximately along the a axis.

(I)

Crystal data

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) Å^3	Prism, brown
Z = 4	0.4 × 0.2 × 0.15 mm

Data collection

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

Refinement on F	235 parameters
Least-squares matrix: Full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.041	w = 1/(0.0009 + 0.0108F + 0.0032F^2)
wR(F^2) = 0.056	(Δ/σ)max < 0.001
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 (Ų)

	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 (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
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)

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)