Structural and docking studies of potent e­thio­namide boosters

Tuberculosis remains the second only to HIV as the leading cause of death by infectious disease worldwide, and was responsible for 1.4 million deaths globally in 2011. One of the essential drugs of the second-line antitubercular regimen is the prodrug e­thio­namide, introduced in the 1960s. Ethio­namide is primarily used in cases of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB due to severe adverse side effects. As a prodrug, e­thio­namide is bioactivated by EthA, a mono-oxygenase whose activity is repressed by EthR, a member of the TetR family of regulators. Previous studies have established that inhibition of EthR improves e­thio­n­amide potency. We report here the crystal structures of three EthR inhibitors at 0.8 Å resolution (3-oxo-3-{4-[3-(thio­phen-2-yl)-1,2,4-oxa­diazol-5-yl]piperidin-1-yl}propane­nitrile (BDM31343), 4,4,4-tri­fluoro-1-{4-[3-(6-meth­oxy-1,3-benzo­thia­zol-2-yl)-1,2,4-oxa­diazol-5-yl]piperidin-1-yl}butanone (BDM41325) and 5,5,5-tri­fluoro-1-{4-[3-(4-methane­sulfonyl­phen­yl)-1,2,4-oxa­di­azol-5-yl]piperidin-1-yl}pentanone (BDM41907)), and the docking studies undertaken to investigate possible binding modes. The results revealed two distinct orientations of the three compounds in the binding channel, a direct consequence of the promiscuous nature of the largely lipophilic binding site.

Computing details

For all compounds, data collection: SMART (Bruker, 2001); cell refinement: SMART (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

(313ii_0m) 3-Oxo-3-{4-[3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}propanenitrile

Crystal data

C14H14N4O2S	F(000) = 632
Mr = 302.35	Dx = 1.434 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.54188 Å
a = 6.834 (2) Å	Cell parameters from 9903 reflections
b = 16.923 (3) Å	θ = 3.7–66.5°
c = 12.531 (2) Å	µ = 2.15 mm^−1
β = 104.882 (5)°	T = 100 K
V = 1400.6 (5) Å^3	Plate, clear light colourless
Z = 4	0.8 × 0.4 × 0.3 mm

Data collection

Bruker MicroStar diffractometer	2429 independent reflections
Radiation source: rotating anode	2413 reflections with I > 2σ(I)
HELIOS mirror system monochromator	Rint = 0.032
φ and ω scans	θmax = 66.6°, θmin = 4.5°
Absorption correction: multi-scan (SADABS; Bruker, 2008)	h = −8→8
Tmin = 0.574, Tmax = 0.753	k = −19→20
23371 measured reflections	l = −14→14

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.032	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.100	H-atom parameters constrained
S = 1.18	w = 1/[σ^2(Fo^2) + (0.049P)^2 + 0.8611P] where P = (Fo^2 + 2Fc^2)/3
2429 reflections	(Δ/σ)max < 0.001
190 parameters	Δρmax = 0.29 e Å^−3
0 restraints	Δρmin = −0.39 e Å^−3

Special details

Experimental. Absorption correction: SADABS-2008/1 (Bruker,2008) was used for absorption correction. R(int) was 0.1041 before and 0.0470 after correction. The Ratio of minimum to maximum transmission is 0.762353878852. The λ/2 correction factor is Not present

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
S1	0.27479 (6)	0.31144 (3)	0.22476 (4)	0.02569 (16)
O2	−0.00277 (17)	0.43766 (7)	−0.09192 (9)	0.0205 (3)
O1	−1.08755 (18)	0.47624 (7)	−0.37582 (10)	0.0229 (3)
N2	0.1140 (2)	0.39798 (9)	0.00272 (11)	0.0212 (3)
N1	−0.7480 (2)	0.45847 (9)	−0.34241 (11)	0.0200 (3)
N3	−0.2216 (2)	0.38676 (8)	−0.00780 (11)	0.0191 (3)
C9	−0.1072 (3)	0.28747 (10)	0.19892 (13)	0.0206 (4)
H9	−0.2501	0.2882	0.1705	0.025*
C12	−0.9412 (3)	0.44142 (10)	−0.39353 (13)	0.0190 (4)
C7	−0.0240 (3)	0.36966 (9)	0.04803 (13)	0.0184 (4)
C6	−0.1987 (2)	0.42765 (9)	−0.09150 (13)	0.0175 (3)
N4	−1.3506 (2)	0.32975 (10)	−0.54264 (13)	0.0290 (4)
C2	−0.5429 (2)	0.48936 (10)	−0.15440 (13)	0.0195 (4)
H2A	−0.6010	0.4458	−0.1195	0.023*
H2B	−0.5046	0.5326	−0.0998	0.023*
C3	−0.3544 (2)	0.45975 (10)	−0.18700 (13)	0.0183 (4)
H3	−0.2939	0.5051	−0.2185	0.022*
C1	−0.7011 (3)	0.51922 (10)	−0.25546 (14)	0.0204 (4)
H1A	−0.8262	0.5336	−0.2340	0.024*
H1B	−0.6497	0.5673	−0.2843	0.024*
C13	−0.9730 (3)	0.37381 (10)	−0.47758 (14)	0.0213 (4)
H13A	−0.9268	0.3907	−0.5427	0.026*
H13B	−0.8905	0.3277	−0.4441	0.026*
C5	−0.5705 (3)	0.42900 (11)	−0.37528 (14)	0.0218 (4)
H5A	−0.5090	0.4726	−0.4082	0.026*
H5B	−0.6127	0.3872	−0.4319	0.026*
C8	0.0269 (3)	0.32454 (10)	0.14981 (14)	0.0198 (4)
C14	−1.1862 (3)	0.35065 (10)	−0.51288 (14)	0.0225 (4)
C10	−0.0041 (3)	0.24788 (10)	0.29772 (15)	0.0244 (4)
H10	−0.0717	0.2190	0.3426	0.029*
C4	−0.4153 (2)	0.39576 (10)	−0.27644 (14)	0.0198 (4)
H4A	−0.2944	0.3778	−0.2993	0.024*
H4B	−0.4732	0.3497	−0.2465	0.024*
C11	0.1995 (3)	0.25555 (10)	0.32126 (15)	0.0261 (4)
H11	0.2903	0.2326	0.3840	0.031*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0201 (3)	0.0275 (3)	0.0269 (3)	0.00036 (16)	0.00133 (19)	0.00533 (16)
O2	0.0163 (6)	0.0250 (6)	0.0194 (6)	−0.0010 (5)	0.0033 (5)	0.0018 (5)
O1	0.0176 (6)	0.0261 (6)	0.0251 (6)	0.0022 (5)	0.0058 (5)	0.0013 (5)
N2	0.0188 (7)	0.0241 (7)	0.0186 (7)	0.0020 (6)	0.0012 (6)	0.0033 (6)
N1	0.0161 (7)	0.0258 (8)	0.0178 (7)	0.0013 (6)	0.0038 (6)	−0.0028 (6)
N3	0.0182 (7)	0.0193 (7)	0.0194 (7)	−0.0001 (5)	0.0042 (6)	−0.0006 (5)
C9	0.0246 (9)	0.0169 (8)	0.0191 (8)	0.0004 (7)	0.0035 (7)	0.0003 (6)
C12	0.0194 (9)	0.0203 (8)	0.0174 (8)	−0.0004 (6)	0.0050 (7)	0.0043 (6)
C7	0.0196 (8)	0.0164 (8)	0.0190 (8)	−0.0008 (6)	0.0044 (7)	−0.0033 (6)
C6	0.0166 (8)	0.0169 (8)	0.0193 (8)	−0.0008 (6)	0.0049 (6)	−0.0034 (6)
N4	0.0241 (9)	0.0354 (9)	0.0252 (8)	−0.0023 (7)	0.0023 (7)	−0.0004 (7)
C2	0.0184 (8)	0.0216 (8)	0.0184 (8)	−0.0003 (6)	0.0046 (7)	−0.0013 (6)
C3	0.0179 (8)	0.0188 (8)	0.0182 (8)	−0.0012 (6)	0.0045 (7)	0.0011 (6)
C1	0.0203 (9)	0.0204 (8)	0.0199 (8)	0.0005 (6)	0.0041 (7)	−0.0030 (6)
C13	0.0192 (9)	0.0226 (9)	0.0208 (9)	−0.0002 (7)	0.0029 (7)	0.0012 (7)
C5	0.0173 (8)	0.0297 (9)	0.0190 (8)	0.0004 (7)	0.0056 (7)	−0.0038 (7)
C8	0.0201 (9)	0.0171 (8)	0.0212 (8)	0.0016 (6)	0.0035 (7)	−0.0017 (6)
C14	0.0242 (10)	0.0238 (9)	0.0190 (8)	0.0006 (7)	0.0048 (7)	0.0007 (7)
C10	0.0306 (10)	0.0202 (8)	0.0219 (9)	−0.0025 (7)	0.0060 (7)	0.0000 (7)
C4	0.0169 (8)	0.0227 (9)	0.0204 (8)	−0.0004 (6)	0.0059 (7)	−0.0016 (6)
C11	0.0309 (10)	0.0217 (9)	0.0223 (9)	0.0027 (7)	0.0006 (7)	0.0038 (7)

Geometric parameters (Å, º)

S1—C8	1.7273 (18)	C9—C10	1.425 (2)
S1—C11	1.7149 (19)	C12—C13	1.532 (2)
O2—N2	1.4170 (18)	C7—C8	1.450 (2)
O2—C6	1.351 (2)	C6—C3	1.485 (2)
O1—C12	1.229 (2)	N4—C14	1.145 (2)
N2—C7	1.310 (2)	C2—C3	1.532 (2)
N1—C12	1.343 (2)	C2—C1	1.525 (2)
N1—C1	1.472 (2)	C3—C4	1.537 (2)
N1—C5	1.465 (2)	C13—C14	1.463 (2)
N3—C7	1.383 (2)	C5—C4	1.517 (2)
N3—C6	1.299 (2)	C10—C11	1.353 (3)
C9—C8	1.379 (2)
C11—S1—C8	91.39 (9)	N3—C6—C3	129.46 (15)
C6—O2—N2	106.43 (12)	C1—C2—C3	110.63 (13)
C7—N2—O2	102.89 (13)	C6—C3—C2	112.48 (13)
C12—N1—C1	120.23 (14)	C6—C3—C4	109.49 (13)
C12—N1—C5	125.21 (14)	C2—C3—C4	109.63 (13)
C5—N1—C1	114.04 (13)	N1—C1—C2	110.88 (13)
C6—N3—C7	102.46 (14)	C14—C13—C12	111.25 (14)
C8—C9—C10	111.40 (16)	N1—C5—C4	110.62 (13)
O1—C12—N1	123.86 (16)	C9—C8—S1	111.73 (13)
O1—C12—C13	120.22 (15)	C9—C8—C7	126.54 (16)
N1—C12—C13	115.92 (14)	C7—C8—S1	121.73 (13)
N2—C7—N3	114.97 (15)	N4—C14—C13	177.06 (19)
N2—C7—C8	122.50 (16)	C11—C10—C9	113.31 (16)
N3—C7—C8	122.52 (15)	C5—C4—C3	109.62 (14)
O2—C6—C3	117.18 (14)	C10—C11—S1	112.16 (14)
N3—C6—O2	113.25 (14)

(41325) 4,4,4-Trifluoro-1-{4-[3-(6-methoxy-1,3-benzothiazol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}butanone

Crystal data

C19H19F3N4O3S	Dx = 1.538 Mg m^−3
Mr = 440.44	Cu Kα radiation, λ = 1.54188 Å
Orthorhombic, P212121	Cell parameters from 9938 reflections
a = 4.8280 (1) Å	θ = 3.3–66.3°
b = 16.1865 (5) Å	µ = 2.06 mm^−1
c = 24.3327 (7) Å	T = 100 K
V = 1901.56 (9) Å^3	Needle, clear light colourless
Z = 4	0.3 × 0.02 × 0.02 mm
F(000) = 912

Data collection

Bruker Platinum CCD diffractometer	3233 independent reflections
Radiation source: fine-focus sealed tube	3011 reflections with I > 2σ(I)
HELIOS mirrors monochromator	Rint = 0.044
φ and ω scans	θmax = 66.5°, θmin = 3.3°
Absorption correction: multi-scan (SADABS; Bruker, 2008)	h = −5→5
Tmin = 0.623, Tmax = 0.753	k = −19→19
19327 measured reflections	l = −28→28

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.030	H-atom parameters constrained
wR(F^2) = 0.079	w = 1/[σ^2(Fo^2) + (0.0502P)^2 + 0.5712P] where P = (Fo^2 + 2Fc^2)/3
S = 0.98	(Δ/σ)max = 0.001
3233 reflections	Δρmax = 0.26 e Å^−3
272 parameters	Δρmin = −0.17 e Å^−3
0 restraints	Absolute structure: Flack (1983), 1301 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.154 (17)

Special details

Experimental. Absorption correction: SADABS-2008/1 (Bruker,2008) was used for absorption correction. R(int) was 0.1211 before and 0.0639 after correction. The Ratio of minimum to maximum transmission is 0.8276. The λ/2 correction factor is 0.0015.

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
S1	1.19629 (12)	0.92060 (3)	0.647631 (19)	0.02465 (13)
F3	0.8214 (3)	0.19896 (8)	0.67661 (5)	0.0390 (3)
O3	1.9539 (4)	0.99316 (9)	0.79415 (5)	0.0284 (4)
F2	0.8442 (3)	0.09400 (7)	0.62270 (5)	0.0391 (4)
N2	0.7857 (4)	0.82130 (10)	0.57801 (7)	0.0262 (4)
F1	0.4530 (3)	0.15353 (8)	0.63769 (6)	0.0410 (3)
O2	0.6128 (3)	0.76181 (8)	0.55254 (6)	0.0267 (4)
C7	0.9437 (5)	0.77629 (12)	0.61012 (8)	0.0236 (5)
N4	1.3036 (4)	0.77044 (10)	0.67989 (6)	0.0238 (4)
N3	0.8918 (4)	0.69274 (11)	0.60831 (7)	0.0256 (4)
C15	0.6852 (5)	0.36244 (13)	0.53876 (8)	0.0276 (5)
C8	1.1502 (4)	0.81311 (12)	0.64614 (8)	0.0232 (4)
C4	0.7155 (5)	0.57204 (13)	0.50735 (8)	0.0263 (5)
H4A	0.7252	0.6097	0.4754	0.032*
H4B	0.9066	0.5622	0.5205	0.032*
C9	1.4708 (5)	0.82302 (12)	0.71030 (8)	0.0236 (5)
O1	0.8435 (4)	0.34067 (10)	0.50226 (7)	0.0438 (5)
C14	1.4429 (5)	0.90749 (12)	0.69876 (7)	0.0228 (5)
C3	0.5450 (5)	0.61274 (12)	0.55323 (8)	0.0256 (5)
H3	0.3607	0.6292	0.5380	0.031*
C12	1.7825 (5)	0.94164 (12)	0.76535 (8)	0.0241 (5)
C18	0.7249 (5)	0.16813 (12)	0.62883 (9)	0.0283 (5)
C13	1.5949 (5)	0.96794 (12)	0.72594 (8)	0.0245 (5)
H13	1.5713	1.0249	0.7178	0.029*
N1	0.5511 (4)	0.43555 (10)	0.53718 (7)	0.0278 (4)
C6	0.6894 (5)	0.68803 (12)	0.57337 (8)	0.0234 (4)
C10	1.6607 (5)	0.79825 (12)	0.75088 (8)	0.0268 (5)
H10	1.6838	0.7414	0.7594	0.032*
C5	0.5865 (6)	0.49045 (13)	0.48978 (8)	0.0301 (5)
H5A	0.4041	0.5009	0.4725	0.036*
H5B	0.7069	0.4634	0.4622	0.036*
C2	0.4992 (5)	0.55156 (12)	0.60076 (8)	0.0278 (5)
H2A	0.6779	0.5411	0.6194	0.033*
H2B	0.3712	0.5764	0.6279	0.033*
C17	0.7773 (5)	0.22405 (12)	0.58143 (8)	0.0278 (5)
H17A	0.7122	0.1971	0.5472	0.033*
H17B	0.9790	0.2336	0.5779	0.033*
C11	1.8113 (5)	0.85692 (12)	0.77786 (8)	0.0265 (5)
H11	1.9380	0.8404	0.8056	0.032*
C1	0.3794 (5)	0.46993 (13)	0.58073 (9)	0.0288 (5)
H1A	0.3696	0.4304	0.6117	0.035*
H1B	0.1891	0.4789	0.5668	0.035*
C16	0.6304 (5)	0.30683 (12)	0.58818 (8)	0.0268 (5)
H16A	0.6970	0.3344	0.6220	0.032*
H16B	0.4287	0.2975	0.5920	0.032*
C19	1.9780 (6)	1.07649 (13)	0.77480 (9)	0.0328 (5)
H19A	2.0253	1.0762	0.7356	0.049*
H19B	2.1238	1.1050	0.7954	0.049*
H19C	1.8015	1.1053	0.7801	0.049*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0283 (3)	0.0242 (2)	0.0215 (2)	0.0040 (2)	−0.0006 (2)	0.00219 (19)
F3	0.0562 (10)	0.0341 (7)	0.0268 (6)	0.0072 (7)	−0.0083 (7)	−0.0009 (5)
O3	0.0359 (10)	0.0277 (7)	0.0215 (7)	−0.0002 (7)	−0.0019 (7)	−0.0003 (6)
F2	0.0534 (10)	0.0264 (6)	0.0374 (7)	0.0080 (6)	0.0074 (7)	0.0018 (5)
N2	0.0264 (10)	0.0279 (8)	0.0244 (8)	−0.0001 (8)	0.0006 (8)	0.0025 (7)
F1	0.0345 (8)	0.0386 (7)	0.0498 (8)	−0.0039 (6)	0.0061 (7)	0.0102 (6)
O2	0.0275 (9)	0.0263 (7)	0.0263 (7)	0.0021 (6)	−0.0028 (6)	0.0025 (6)
C7	0.0242 (12)	0.0275 (10)	0.0190 (9)	0.0009 (9)	0.0065 (9)	0.0019 (8)
N4	0.0236 (10)	0.0260 (8)	0.0217 (8)	0.0028 (8)	0.0019 (8)	0.0017 (7)
N3	0.0266 (11)	0.0275 (9)	0.0227 (8)	0.0017 (8)	0.0001 (8)	0.0026 (7)
C15	0.0301 (12)	0.0275 (10)	0.0251 (10)	−0.0021 (10)	−0.0032 (10)	−0.0017 (8)
C8	0.0231 (12)	0.0269 (10)	0.0196 (9)	0.0020 (9)	0.0061 (9)	0.0017 (8)
C4	0.0298 (12)	0.0309 (10)	0.0182 (9)	−0.0002 (10)	0.0008 (9)	0.0049 (8)
C9	0.0238 (12)	0.0269 (10)	0.0202 (10)	0.0028 (9)	0.0046 (9)	0.0008 (8)
O1	0.0566 (13)	0.0367 (8)	0.0381 (9)	0.0099 (9)	0.0197 (10)	0.0062 (7)
C14	0.0235 (12)	0.0288 (10)	0.0161 (9)	0.0044 (9)	0.0059 (9)	0.0021 (8)
C3	0.0230 (12)	0.0272 (10)	0.0266 (10)	0.0038 (9)	−0.0002 (10)	0.0035 (9)
C12	0.0264 (12)	0.0296 (10)	0.0162 (9)	0.0005 (9)	0.0059 (9)	−0.0022 (8)
C18	0.0328 (14)	0.0235 (9)	0.0288 (10)	0.0020 (10)	−0.0012 (10)	−0.0025 (8)
C13	0.0296 (12)	0.0232 (10)	0.0208 (10)	0.0043 (9)	0.0046 (9)	0.0007 (8)
N1	0.0344 (12)	0.0265 (9)	0.0225 (8)	−0.0002 (8)	−0.0014 (8)	0.0034 (7)
C6	0.0232 (11)	0.0264 (9)	0.0205 (9)	0.0047 (9)	0.0060 (9)	0.0027 (8)
C10	0.0316 (13)	0.0255 (10)	0.0233 (10)	0.0053 (9)	0.0040 (10)	0.0043 (8)
C5	0.0403 (14)	0.0304 (11)	0.0196 (10)	0.0002 (10)	−0.0027 (10)	0.0046 (9)
C2	0.0302 (14)	0.0283 (11)	0.0250 (10)	0.0047 (10)	0.0071 (10)	0.0036 (8)
C17	0.0290 (13)	0.0266 (10)	0.0278 (10)	−0.0004 (9)	0.0017 (10)	−0.0008 (8)
C11	0.0276 (12)	0.0315 (10)	0.0205 (9)	0.0017 (10)	0.0027 (10)	0.0031 (8)
C1	0.0291 (13)	0.0288 (10)	0.0286 (11)	0.0007 (10)	0.0011 (10)	0.0076 (9)
C16	0.0263 (13)	0.0269 (10)	0.0273 (10)	0.0020 (9)	0.0012 (9)	0.0040 (8)
C19	0.0454 (16)	0.0278 (11)	0.0252 (10)	−0.0020 (11)	−0.0023 (11)	−0.0008 (9)

Geometric parameters (Å, º)

S1—C8	1.754 (2)	C15—C16	1.525 (3)
S1—C14	1.735 (2)	C4—C3	1.535 (3)
F3—C18	1.348 (2)	C4—C5	1.522 (3)
O3—C12	1.368 (3)	C9—C14	1.402 (3)
O3—C19	1.433 (3)	C9—C10	1.406 (3)
F2—C18	1.339 (2)	C14—C13	1.391 (3)
N2—O2	1.417 (2)	C3—C6	1.487 (3)
N2—C7	1.313 (3)	C3—C2	1.539 (3)
F1—C18	1.351 (3)	C12—C13	1.386 (3)
O2—C6	1.349 (2)	C12—C11	1.412 (3)
C7—N3	1.376 (3)	C18—C17	1.488 (3)
C7—C8	1.455 (3)	N1—C5	1.466 (3)
N4—C8	1.303 (3)	N1—C1	1.456 (3)
N4—C9	1.387 (3)	C10—C11	1.364 (3)
N3—C6	1.298 (3)	C2—C1	1.522 (3)
C15—O1	1.224 (3)	C17—C16	1.525 (3)
C15—N1	1.350 (3)
C14—S1—C8	88.88 (10)	C2—C3—C4	110.34 (16)
C12—O3—C19	117.03 (17)	O3—C12—C13	124.23 (18)
C7—N2—O2	103.04 (15)	O3—C12—C11	114.98 (19)
C6—O2—N2	106.01 (15)	C13—C12—C11	120.8 (2)
N2—C7—N3	114.9 (2)	F3—C18—F1	105.25 (18)
N2—C7—C8	121.97 (18)	F3—C18—C17	112.62 (18)
N3—C7—C8	123.13 (18)	F2—C18—F3	106.20 (18)
C8—N4—C9	109.98 (17)	F2—C18—F1	106.20 (18)
C6—N3—C7	102.47 (17)	F2—C18—C17	112.68 (18)
O1—C15—N1	122.10 (19)	F1—C18—C17	113.27 (19)
O1—C15—C16	120.71 (19)	C12—C13—C14	117.25 (18)
N1—C15—C16	117.19 (19)	C15—N1—C5	119.87 (19)
C7—C8—S1	120.36 (15)	C15—N1—C1	125.97 (17)
N4—C8—S1	116.13 (16)	C1—N1—C5	114.05 (17)
N4—C8—C7	123.48 (18)	O2—C6—C3	118.25 (18)
C5—C4—C3	110.94 (19)	N3—C6—O2	113.61 (19)
N4—C9—C14	115.81 (18)	N3—C6—C3	128.10 (19)
N4—C9—C10	125.41 (18)	C11—C10—C9	119.14 (19)
C14—C9—C10	118.79 (19)	N1—C5—C4	110.66 (17)
C9—C14—S1	109.20 (16)	C1—C2—C3	111.88 (17)
C13—C14—S1	128.11 (16)	C18—C17—C16	111.84 (18)
C13—C14—C9	122.69 (19)	C10—C11—C12	121.3 (2)
C6—C3—C4	109.88 (18)	N1—C1—C2	110.41 (18)
C6—C3—C2	110.32 (17)	C17—C16—C15	110.67 (18)

(bdm41907) 5,5,5-Trifluoro-1-{4-[3-(4-methanesulfonylphenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pentanone

Crystal data

C19H22F3N3O4S	Z = 4
Mr = 445.45	F(000) = 928
Monoclinic, P21/c	Dx = 1.457 Mg m^−3
a = 10.7027 (6) Å	Cu Kα radiation, λ = 1.54188 Å
b = 19.853 (2) Å	Cell parameters from 6971 reflections
c = 9.873 (2) Å	θ = 4.3–67.5°
β = 104.568 (2)°	µ = 1.96 mm^−1
V = 2030.4 (5) Å^3	T = 100 K

Data collection

Bruker APEXII CCD diffractometer	3493 independent reflections
Radiation source: fine-focus sealed tube	2888 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.041
φ and ω scans	θmax = 66.2°, θmin = 4.3°
Absorption correction: multi-scan (SADABS; Bruker, 2008)	h = −12→11
Tmin = 0.500, Tmax = 0.753	k = −23→23
14675 measured reflections	l = −10→11

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.039	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.127	H-atom parameters constrained
S = 0.99	w = 1/[σ^2(Fo^2) + (0.1P)^2] where P = (Fo^2 + 2Fc^2)/3
3493 reflections	(Δ/σ)max = 0.001
272 parameters	Δρmax = 0.40 e Å^−3
0 restraints	Δρmin = −0.33 e Å^−3

Special details

Experimental. SADABS-2008/1 (Bruker,2008) was used for absorption correction. R(int) was 0.1368 before and 0.0514 after correction. The Ratio of minimum to maximum transmission is 0.6643. The λ/2 correction factor is 0.0015.

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
S1	0.86771 (5)	0.01498 (2)	0.64449 (5)	0.02435 (18)
F3	−0.16300 (13)	−0.22202 (6)	1.79652 (16)	0.0451 (4)
O1	0.28587 (13)	−0.29775 (6)	1.50616 (14)	0.0267 (3)
O2	0.58542 (14)	−0.01908 (6)	1.32373 (14)	0.0281 (3)
O4	0.81625 (14)	0.07622 (7)	0.57614 (15)	0.0347 (4)
F2	−0.03447 (13)	−0.30657 (6)	1.83594 (15)	0.0458 (4)
N1	0.43127 (16)	−0.21297 (7)	1.55178 (17)	0.0224 (4)
N3	0.64913 (15)	−0.09779 (8)	1.19826 (17)	0.0231 (4)
O3	0.85658 (14)	−0.04611 (7)	0.56338 (15)	0.0332 (4)
N2	0.61281 (18)	0.01419 (8)	1.20844 (18)	0.0287 (4)
F1	−0.14104 (14)	−0.28443 (8)	1.62673 (16)	0.0547 (4)
C2	0.53663 (19)	−0.19914 (9)	1.3603 (2)	0.0228 (4)
H2A	0.4534	−0.1911	1.2912	0.027*
H2B	0.5960	−0.2209	1.3113	0.027*
C8	0.69437 (18)	−0.02217 (9)	1.0118 (2)	0.0209 (4)
C14	0.32039 (18)	−0.24270 (9)	1.56227 (19)	0.0210 (4)
C15	0.23701 (19)	−0.20635 (9)	1.6438 (2)	0.0235 (4)
H15B	0.2917	−0.1919	1.7356	0.028*
H15A	0.1992	−0.1655	1.5917	0.028*
C17	0.03241 (19)	−0.21193 (10)	1.7257 (2)	0.0264 (5)
H17B	0.0777	−0.1918	1.8165	0.032*
H17A	−0.0040	−0.1748	1.6609	0.032*
C9	0.73312 (19)	−0.07634 (9)	0.9424 (2)	0.0237 (4)
H9	0.7246	−0.1211	0.9729	0.028*
C7	0.64922 (18)	−0.03484 (9)	1.1388 (2)	0.0212 (4)
C12	0.75486 (19)	0.05500 (10)	0.8516 (2)	0.0264 (5)
H12	0.7618	0.0996	0.8197	0.032*
C10	0.78392 (19)	−0.06474 (10)	0.8290 (2)	0.0249 (4)
H10	0.8108	−0.1014	0.7814	0.030*
C11	0.79547 (18)	0.00088 (9)	0.7849 (2)	0.0222 (4)
C5	0.4840 (2)	−0.14944 (10)	1.6185 (2)	0.0246 (4)
H5B	0.5654	−0.1585	1.6899	0.030*
H5A	0.4220	−0.1292	1.6662	0.030*
C13	0.70397 (19)	0.04327 (10)	0.9655 (2)	0.0253 (4)
H13	0.6757	0.0800	1.0119	0.030*
C6	0.61042 (18)	−0.08480 (9)	1.3099 (2)	0.0210 (4)
C3	0.59392 (19)	−0.13172 (9)	1.4223 (2)	0.0216 (4)
H3	0.6812	−0.1408	1.4854	0.026*
C18	−0.0747 (2)	−0.25569 (10)	1.7461 (2)	0.0311 (5)
C4	0.50971 (19)	−0.10008 (9)	1.5104 (2)	0.0231 (4)
H4B	0.5536	−0.0597	1.5588	0.028*
H4A	0.4265	−0.0856	1.4479	0.028*
C16	0.1288 (2)	−0.25146 (10)	1.6667 (2)	0.0271 (5)
H16A	0.0834	−0.2722	1.5765	0.033*
H16B	0.1664	−0.2881	1.7322	0.033*
C1	0.51539 (19)	−0.24560 (9)	1.4755 (2)	0.0239 (4)
H1A	0.4755	−0.2882	1.4337	0.029*
H1B	0.5994	−0.2564	1.5409	0.029*
C19	1.0322 (2)	0.02749 (12)	0.7268 (2)	0.0313 (5)
H19A	1.0796	0.0367	0.6558	0.047*
H19C	1.0673	−0.0131	0.7793	0.047*
H19B	1.0413	0.0658	0.7910	0.047*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0266 (3)	0.0271 (3)	0.0192 (3)	−0.00415 (18)	0.0056 (2)	0.00358 (18)
F3	0.0423 (8)	0.0300 (7)	0.0731 (10)	0.0033 (6)	0.0335 (7)	0.0003 (6)
O1	0.0340 (8)	0.0208 (7)	0.0263 (8)	−0.0029 (6)	0.0093 (6)	−0.0023 (6)
O2	0.0426 (9)	0.0214 (7)	0.0251 (8)	0.0012 (6)	0.0174 (6)	−0.0006 (5)
O4	0.0359 (9)	0.0392 (9)	0.0293 (8)	0.0005 (6)	0.0085 (7)	0.0161 (6)
F2	0.0500 (8)	0.0285 (7)	0.0668 (10)	0.0042 (6)	0.0294 (7)	0.0142 (6)
N1	0.0283 (9)	0.0182 (8)	0.0229 (9)	−0.0021 (6)	0.0103 (7)	−0.0030 (6)
N3	0.0273 (9)	0.0215 (8)	0.0223 (9)	−0.0005 (7)	0.0095 (7)	−0.0011 (7)
O3	0.0408 (9)	0.0378 (9)	0.0237 (8)	−0.0116 (7)	0.0132 (7)	−0.0058 (6)
N2	0.0434 (11)	0.0224 (9)	0.0244 (10)	0.0013 (7)	0.0161 (8)	0.0030 (7)
F1	0.0424 (9)	0.0688 (10)	0.0542 (10)	−0.0230 (7)	0.0145 (7)	−0.0198 (8)
C2	0.0293 (11)	0.0196 (10)	0.0210 (11)	−0.0014 (8)	0.0092 (8)	−0.0036 (7)
C8	0.0216 (10)	0.0211 (10)	0.0189 (10)	−0.0016 (7)	0.0029 (8)	0.0003 (7)
C14	0.0283 (11)	0.0176 (9)	0.0160 (10)	0.0013 (7)	0.0036 (8)	0.0041 (7)
C15	0.0281 (11)	0.0216 (10)	0.0215 (11)	0.0013 (8)	0.0076 (8)	0.0025 (7)
C17	0.0284 (11)	0.0216 (10)	0.0293 (12)	0.0003 (8)	0.0078 (9)	0.0015 (8)
C9	0.0313 (11)	0.0181 (10)	0.0220 (11)	−0.0012 (8)	0.0072 (8)	0.0019 (7)
C7	0.0245 (10)	0.0193 (9)	0.0193 (10)	−0.0011 (7)	0.0044 (8)	0.0006 (7)
C12	0.0326 (11)	0.0175 (10)	0.0289 (11)	−0.0011 (8)	0.0073 (9)	0.0051 (8)
C10	0.0316 (11)	0.0207 (10)	0.0235 (11)	0.0004 (8)	0.0091 (8)	−0.0015 (8)
C11	0.0235 (10)	0.0234 (10)	0.0193 (11)	−0.0025 (8)	0.0049 (8)	0.0034 (8)
C5	0.0317 (11)	0.0217 (10)	0.0223 (11)	−0.0047 (8)	0.0104 (8)	−0.0050 (8)
C13	0.0306 (11)	0.0198 (10)	0.0255 (11)	0.0009 (8)	0.0070 (8)	−0.0014 (8)
C6	0.0231 (10)	0.0181 (9)	0.0220 (11)	−0.0014 (7)	0.0060 (8)	−0.0027 (7)
C3	0.0273 (11)	0.0199 (10)	0.0187 (10)	−0.0003 (7)	0.0078 (8)	−0.0022 (7)
C18	0.0323 (12)	0.0235 (11)	0.0405 (13)	0.0025 (9)	0.0147 (10)	−0.0023 (9)
C4	0.0274 (11)	0.0203 (9)	0.0235 (11)	−0.0036 (8)	0.0099 (8)	−0.0044 (8)
C16	0.0302 (12)	0.0235 (10)	0.0292 (12)	−0.0014 (8)	0.0103 (9)	−0.0011 (8)
C1	0.0287 (11)	0.0209 (10)	0.0237 (11)	0.0016 (8)	0.0095 (8)	−0.0036 (8)
C19	0.0266 (12)	0.0399 (12)	0.0265 (12)	−0.0056 (9)	0.0048 (9)	0.0015 (9)

Geometric parameters (Å, º)

S1—O4	1.4318 (15)	C2—C3	1.534 (2)
S1—O3	1.4416 (15)	C2—C1	1.525 (3)
S1—C11	1.771 (2)	C8—C9	1.393 (3)
S1—C19	1.761 (2)	C8—C7	1.474 (3)
F3—C18	1.351 (2)	C8—C13	1.389 (3)
O1—C14	1.239 (2)	C14—C15	1.525 (3)
O2—N2	1.409 (2)	C15—C16	1.525 (3)
O2—C6	1.346 (2)	C17—C18	1.492 (3)
F2—C18	1.342 (2)	C17—C16	1.524 (3)
N1—C14	1.353 (2)	C9—C10	1.381 (3)
N1—C5	1.468 (2)	C12—C11	1.386 (3)
N1—C1	1.462 (2)	C12—C13	1.387 (3)
N3—C7	1.381 (2)	C10—C11	1.389 (3)
N3—C6	1.298 (2)	C5—C4	1.524 (3)
N2—C7	1.307 (2)	C6—C3	1.492 (3)
F1—C18	1.340 (3)	C3—C4	1.536 (2)
O4—S1—O3	118.96 (9)	N2—C7—C8	121.69 (17)
O4—S1—C11	108.13 (9)	C11—C12—C13	119.29 (18)
O4—S1—C19	108.60 (10)	C9—C10—C11	119.66 (18)
O3—S1—C11	108.09 (9)	C12—C11—S1	120.02 (14)
O3—S1—C19	107.95 (10)	C12—C11—C10	120.97 (18)
C19—S1—C11	104.12 (10)	C10—C11—S1	118.98 (15)
C6—O2—N2	106.60 (14)	N1—C5—C4	110.81 (15)
C14—N1—C5	125.89 (16)	C12—C13—C8	120.02 (18)
C14—N1—C1	120.78 (15)	O2—C6—C3	117.79 (16)
C1—N1—C5	113.24 (15)	N3—C6—O2	113.13 (16)
C6—N3—C7	102.47 (15)	N3—C6—C3	129.06 (16)
C7—N2—O2	103.07 (15)	C2—C3—C4	110.49 (15)
C1—C2—C3	110.51 (15)	C6—C3—C2	111.02 (15)
C9—C8—C7	119.23 (17)	C6—C3—C4	111.20 (15)
C13—C8—C9	120.28 (18)	F3—C18—C17	113.21 (17)
C13—C8—C7	120.43 (17)	F2—C18—F3	105.46 (17)
O1—C14—N1	121.30 (17)	F2—C18—C17	113.43 (17)
O1—C14—C15	120.34 (17)	F1—C18—F3	105.67 (18)
N1—C14—C15	118.36 (16)	F1—C18—F2	105.77 (17)
C16—C15—C14	111.54 (16)	F1—C18—C17	112.61 (18)
C18—C17—C16	111.65 (16)	C5—C4—C3	111.64 (15)
C10—C9—C8	119.76 (18)	C17—C16—C15	111.51 (16)
N3—C7—C8	123.47 (16)	N1—C1—C2	110.04 (15)
N2—C7—N3	114.73 (17)