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Kynostatin {KNI-272; systematic name: 3-[3-benzyl-2-hydroxy-9-(isoquinolin-5-yl­oxy)-6-methyl­sulfanyl­methyl-5,8-dioxo-4,7-di­aza­nonanoyl]-N-tert-butyl-1,3-thia­zolane-4-carbox­amide}, a highly selective and potent HIV protease inhibitor containing allo­phenyl­norstatin [(2S,3S)-3-amino-2-hydroxy-4-phenyl­butyric acid], has been crystallized as the hydrate, C33H41N5O6S2·0.803H2O, from aqueous hexyl­ene glycol. The observed disorder of the phenyl group in the structure is related to the mode of hydration. The backbone conformation of the mol­ecule is twisted and the overall conformation of the free inhibitor is similar to that observed in its complex with HIV protease.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270101013701/sx1119sup1.cif
Contains datablocks global, I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270101013701/sx1119Isup2.hkl
Contains datablock I

CCDC reference: 175102

Comment top

Kynostatin (KNI-272), hereinafter (I), a peptide mimic containing an allophenylnorstatin residue [Apns, (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid; Mimoto et al., 1991], was designed based on the substrate transition state concept for aspartic protease inhibition (Kiso, 1996; Kiso et al., 1999). Compound (I) showed high selectivity and potent inhibitory activity (Ki = 0.0055 nM) for HIV protease (Mimoto et al., 1992), and also displayed good pharmacokinetics and an excellent therapeutic index (Kageyama et al., 1993). Compound (I) is composed of five modules, namely 5-isoquinolyloxy acetic acid (iQoa), methylthioalanine (Mta), Apns, thioproline (Thz) and tert-butyl amine, as shown the Scheme. Crystals of (I) were grown from various alcohol solutions, and the crystal structure obtained from aqueous hexylene glycol is reported here. \sch

The molecular structure of (I) is shown in Fig.1. The phenyl group of the Apns residue is disordered, with two alternate orientations. Analysis of the electron-density map (Fig. 2) shows that rotation of the phenyl ring about the C18—C19 and C19—C20 bonds creates space for the binding of three disordered water molecules whose total site occupancy is 0.8. The water molecules are linked to each other by hydrogen bonds [Table 1; O61···O63 = 3.05 (3) and O63···O62 = 2.67 (3) Å] and interact with the peptide [O62···O32 = 2.77 (2), O61···N1 = 2.932 (12) and O62···N1 = 2.88 (2) Å]. Hydrogen bonds are also formed between the peptides; N18···O27 = 3.038 (6), N33···O26 = 2.984 (7) and O26···O12 = 2.837 (6) Å.

The peptide backbone of (I) is twisted (Fig. 2), and the conformation is different from a β-turn or extended (β-sheet) structure. The structural features of (I) seem to be similar to those of the molecule in the complex with HIV protease (Baldwin et al., 1995). Selected torsion angles are listed in Table 2, to compare the backbone structures of the two compounds. The angles involving the atoms of the Mta residue are significantly different in the free and complex structures (e.g. N13—C13—C14—S15), and the thiazolidine ring is puckered differently (N28—C28—C29—S30). In contrast, the backbone conformation of the Apns-Thz-Tbu moiety observed in the crystal of (I) is closely related to that observed in the enzyme complex. Furthermore, it is known that the range of observed solution conformations of this fragment is rather limited (Ohno et al., 1996). Thus, it is suggested that the Apns-Thz-tBu fragment has a relatively rigid conformation, which is nearly optimal for tight interactions between the Apns moiety of (I) and the catalytic centre of the HIV protease active site.

Related literature top

For related literature, see: Baldwin et al. (1995); Kageyama et al. (1993); Kiso (1996); Kiso et al. (1999); Leslie (1990); Mimoto et al. (1991, 1992); Ohno et al. (1996).

Experimental top

Compound (I) was synthesized according to the method published by Mimoto et al. (1991). Compound (I) (20 mg) was dissolved in hexylene glycol (0.3 ml), and water was added to this solution in several small portions of ?ml. The addition of water was stopped before the solution became opaque. The solution was then sealed in a vial and crystals were grown for 2–5 d at room temperature. A crystal of (I) was mounted on a nylon loop with mother liquor solution (aqueous hexylene glycol) and frozen in a nitrogen stream at 100 K.

Refinement top

Intensity data were collected by the oscillation method using synchrotron radiation (SPring-8/BL24XU—A). A total of 60 images covered 180° rotation on the ϕ axis. Image data were processed using MOSFLM (Leslie, 1990) (Query year - 1999 given in tables above) and the CCP4 program suite (Collaborative Computational Project, Number 4, 1994). The high background regions were observed at approximately 3.0 Å resolution and these regions were excluded from the processing. A total of 15444 reflections were observed from the image data, and these were averaged to 6157 reflections by the CCP4 program suite, with Rmerge = 0.092. The H atoms of the peptide were placed in calculated positions and constrained during the refinement, with C—H = ?Å and Uiso(H) = ?Ueq(C). Please provide details of constraints used. Please also provide CIF-format details of the bond distances and angles involving H atoms. The H atoms of the water molecules were positioned by considering the hydrogen-bonding networks and were fixed during the refinement. Constraints? The absolute stereochemistry is known from the known chirality of the starting materials in the synthesis, but it could not be determined from the present data.

Computing details top

Data collection: PROCESS (Rigaku, 1996); cell refinement: MOSFLM (Leslie, 1999); data reduction: MOSFLM; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 1998); software used to prepare material for publication: PARST (Nardelli, 1983).

Figures top
[Figure 1] Fig. 1. The molecular view of (I) with displacement ellipsoids drawn at the 30% probability level. Thin and dotted lines show the two disordered structures of the Apns residue and the water molecules.
[Figure 2] Fig. 2. The electron-density map of (I) (Swiss-PdbViewer; Guex & Peitsch, 1997), showing the disordered state of (I) and the water molecules. Contours show the boundaries of 1.0 and 2.5 σ. Three water molecules (O61, O62 and O63) bind when the phenyl ring swings into an alternate conformation designated by the primed atoms.
3-[3-benzyl-2-hydroxy-9-(isoquinolin-5-yloxy)-6-methylsulfanylmethyl-5,8-dioxo- 4,7-diazanonanoyl]-N-tert-butyl-1,3-thiazolane-4-carboxamide top
Crystal data top
C33H41N5O6S2·0.803H2OZ = 2
Mr = 682.33F(000) = 724
Monoclinic, P21Dx = 1.281 Mg m3
a = 10.7631 (4) ÅSynchrotron radiation, λ = 0.83600 Å
b = 13.1751 (4) ŵ = 0.20 mm1
c = 12.5623 (5) ÅT = 100 K
β = 96.887 (2)°Plate, colourless
V = 1768.54 (11) Å30.25 × 0.10 × 0.02 mm
Data collection top
Rigaku RAXIS-IV image-plate detector
diffractometer
3321 reflections with I > 2σ(I)
Radiation source: double monochromated beamRint = 0.070
Diamond monochromatorθmax = 31.5°, θmin = 8.1°
Detector resolution: 10 pixels mm-1h = 1313
oscillation scansk = 1616
5965 measured reflectionsl = 015
3571 independent reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.067H-atom parameters constrained
wR(F2) = 0.191 w = 1/[σ2(Fo2) + (0.1047P)2 + 2.2778P]
where P = (Fo2 + 2Fc2)/3
S = 0.99(Δ/σ)max = 0.020
3571 reflectionsΔρmax = 0.81 e Å3
504 parametersΔρmin = 0.61 e Å3
1 restraintExtinction correction: SHELXL97 (Sheldrick, 1997), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.30 (3)
Crystal data top
C33H41N5O6S2·0.803H2OV = 1768.54 (11) Å3
Mr = 682.33Z = 2
Monoclinic, P21Synchrotron radiation, λ = 0.83600 Å
a = 10.7631 (4) ŵ = 0.20 mm1
b = 13.1751 (4) ÅT = 100 K
c = 12.5623 (5) Å0.25 × 0.10 × 0.02 mm
β = 96.887 (2)°
Data collection top
Rigaku RAXIS-IV image-plate detector
diffractometer
3321 reflections with I > 2σ(I)
5965 measured reflectionsRint = 0.070
3571 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0671 restraint
wR(F2) = 0.191H-atom parameters constrained
S = 0.99Δρmax = 0.81 e Å3
3571 reflectionsΔρmin = 0.61 e Å3
504 parameters
Special details top

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 (Å2) top
xyzUiso*/UeqOcc. (<1)
N10.7262 (5)0.3745 (4)0.4204 (4)0.0433 (12)
C20.6760 (5)0.3165 (5)0.4949 (5)0.0427 (13)
H20.72250.26190.52500.051*
C30.5610 (5)0.3344 (4)0.5277 (4)0.0341 (11)
H30.53230.29370.58010.041*
C40.3666 (5)0.4408 (4)0.5086 (4)0.0298 (11)
C50.2969 (5)0.5156 (5)0.4545 (5)0.0364 (12)
H50.21790.53130.47280.044*
C60.3453 (5)0.5698 (5)0.3699 (4)0.0368 (12)
H60.29630.61890.33180.044*
C70.4615 (5)0.5502 (4)0.3448 (4)0.0338 (11)
H70.49360.58810.29190.041*
C80.6561 (5)0.4491 (4)0.3766 (5)0.0360 (12)
H80.69000.48970.32690.043*
C90.4863 (4)0.4148 (4)0.4815 (4)0.0275 (10)
C100.5346 (5)0.4723 (4)0.3988 (4)0.0300 (10)
O110.3287 (3)0.3871 (3)0.5943 (3)0.0337 (8)
C110.2272 (5)0.4309 (4)0.6415 (4)0.0364 (12)
H110.23790.50400.64560.044*
H120.14940.41690.59650.044*
C120.2195 (5)0.3894 (4)0.7526 (4)0.0316 (11)
O120.1507 (4)0.4322 (3)0.8100 (3)0.0391 (10)
N130.2886 (4)0.3067 (3)0.7833 (3)0.0296 (9)
H130.32630.27530.73640.041*
C130.3017 (5)0.2686 (4)0.8933 (4)0.0289 (10)
H140.24670.30700.93540.040*
C140.4376 (5)0.2791 (5)0.9445 (5)0.0365 (12)
H150.44380.25471.01780.044*
H160.49010.23610.90590.044*
S150.49746 (15)0.40805 (12)0.94521 (14)0.0483 (5)
C160.4082 (8)0.4681 (6)1.0394 (6)0.0612 (19)
H170.43220.53811.04740.067*
H180.32070.46371.01370.067*
H190.42390.43451.10750.067*
C170.2626 (5)0.1574 (4)0.8884 (4)0.0317 (11)
O170.3245 (4)0.0945 (3)0.8440 (4)0.0428 (10)
N180.1570 (4)0.1348 (3)0.9310 (4)0.0308 (9)
H200.12750.17710.97370.037*
C180.0913 (5)0.0378 (4)0.9046 (5)0.0339 (11)
H210.13720.00830.84940.041*
C190.0320 (13)0.0643 (11)0.8453 (12)0.035 (3)0.491 (12)
H220.07930.00230.82960.042*0.491 (12)
H230.07780.10560.89130.042*0.491 (12)
C200.0243 (13)0.1215 (15)0.7403 (12)0.037 (3)0.491 (12)
C210.0496 (17)0.224 (2)0.7378 (16)0.042 (4)0.491 (12)
H240.07630.25660.79640.051*0.491 (12)
C220.0330 (15)0.2769 (14)0.6416 (15)0.060 (5)0.491 (12)
H250.05120.34590.63650.072*0.491 (12)
C230.0096 (12)0.2280 (16)0.5562 (11)0.058 (5)0.491 (12)
H260.02300.26450.49530.070*0.491 (12)
C240.0316 (12)0.1286 (15)0.5605 (11)0.054 (4)0.491 (12)
H270.05810.09580.50160.064*0.491 (12)
C250.0150 (4)0.0725 (4)0.6539 (4)0.047 (3)0.491 (12)
H280.03070.00310.65660.056*0.491 (12)
C260.1111 (4)0.0390 (4)0.9963 (4)0.0304 (11)
H290.20130.04751.01660.036*
O260.0571 (4)0.0052 (4)1.0870 (4)0.0531 (14)
H300.00050.03451.09770.053*
C270.0557 (5)0.1417 (4)0.9576 (4)0.0285 (10)
O270.0411 (3)0.1727 (3)0.9914 (3)0.0361 (9)
N280.1099 (4)0.1918 (3)0.8825 (4)0.0281 (9)
C280.0501 (4)0.2847 (3)0.8367 (4)0.0280 (10)
H310.03860.33290.89410.039*
C290.1391 (5)0.3298 (4)0.7624 (5)0.0393 (13)
H320.12970.40290.75740.047*
H330.12300.30100.69100.047*
S300.29496 (13)0.29578 (11)0.82504 (14)0.0430 (5)
C310.2325 (5)0.1706 (4)0.8481 (5)0.0357 (12)
H340.22420.13050.78280.043*
H350.28590.13470.90340.043*
C320.0768 (5)0.2602 (4)0.7725 (4)0.0314 (11)
O320.0943 (4)0.1804 (3)0.7221 (3)0.0372 (9)
N330.1618 (4)0.3350 (3)0.7733 (4)0.0329 (10)
H360.13960.38880.80940.039*
C330.2910 (6)0.3319 (5)0.7165 (6)0.0452 (14)
C340.3595 (6)0.2375 (6)0.7460 (6)0.0542 (18)
H370.36180.23590.82220.054*
H380.31680.17840.72450.054*
H390.44340.23840.71010.054*
C350.3563 (8)0.4253 (8)0.7562 (12)0.105 (5)
H410.35740.42070.83230.105*
H420.44060.42860.72130.105*
H430.31190.48540.73970.105*
C360.2866 (10)0.3375 (7)0.5954 (7)0.070 (2)
H440.24530.27830.57220.070*
H450.24130.39710.57880.070*
H460.37030.34060.55920.070*
C19'0.0615 (12)0.0508 (8)0.8923 (13)0.033 (3)0.509 (12)
H23'0.08910.05280.96300.040*0.509 (12)
H22'0.10020.00750.85450.040*0.509 (12)
C20'0.1036 (10)0.1475 (8)0.8314 (10)0.039 (3)0.509 (12)
C25'0.0433 (18)0.176 (2)0.7441 (18)0.048 (5)0.509 (12)
H28'0.01760.13540.71850.058*0.509 (12)
C24'0.0816 (18)0.271 (2)0.696 (2)0.067 (5)0.509 (12)
H27'0.04320.29520.63890.081*0.509 (12)
C23'0.1733 (15)0.3274 (10)0.7337 (15)0.066 (5)0.509 (12)
H26'0.19310.38990.70160.053*0.509 (12)
C22'0.2373 (15)0.2978 (12)0.8147 (10)0.053 (4)0.509 (12)
H25'0.30320.33570.83530.064*0.509 (12)
C21'0.1993 (12)0.2081 (10)0.8649 (10)0.047 (3)0.509 (12)
H24'0.23840.18680.92320.057*0.509 (12)
O610.0038 (10)0.3377 (13)0.4640 (9)0.053 (4)0.366 (9)
H620.01100.27500.46530.058*0.366 (9)
H610.08020.36220.44340.058*0.366 (9)
O620.0318 (18)0.043 (2)0.6072 (17)0.051 (6)0.204 (5)
H630.11170.03520.60700.056*0.204 (5)
H640.00140.08140.65270.056*0.204 (5)
O630.0373 (14)0.1078 (14)0.4713 (13)0.034 (4)0.233 (6)
H650.07170.16370.48830.038*0.233 (6)
H660.01570.06580.51210.038*0.233 (6)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.033 (2)0.039 (3)0.061 (3)0.010 (2)0.020 (2)0.014 (2)
C20.033 (3)0.037 (3)0.060 (3)0.010 (3)0.013 (2)0.016 (3)
C30.030 (2)0.031 (3)0.043 (3)0.002 (2)0.013 (2)0.005 (2)
C40.034 (2)0.026 (3)0.032 (2)0.001 (2)0.0124 (19)0.001 (2)
C50.031 (2)0.036 (3)0.044 (3)0.011 (2)0.013 (2)0.005 (2)
C60.040 (3)0.033 (3)0.037 (3)0.010 (2)0.008 (2)0.010 (2)
C70.038 (3)0.031 (3)0.034 (2)0.001 (2)0.009 (2)0.002 (2)
C80.034 (3)0.031 (3)0.046 (3)0.001 (2)0.016 (2)0.000 (2)
C90.026 (2)0.023 (2)0.033 (2)0.001 (2)0.0051 (18)0.000 (2)
C100.034 (2)0.022 (2)0.035 (2)0.001 (2)0.0077 (19)0.000 (2)
O110.0347 (18)0.0295 (19)0.0401 (18)0.0083 (16)0.0174 (15)0.0056 (16)
C110.034 (2)0.034 (3)0.045 (3)0.013 (2)0.022 (2)0.011 (2)
C120.031 (2)0.026 (2)0.042 (3)0.004 (2)0.018 (2)0.004 (2)
O120.042 (2)0.0281 (19)0.053 (2)0.0109 (16)0.0280 (17)0.0083 (17)
N130.034 (2)0.027 (2)0.0289 (19)0.0050 (18)0.0088 (16)0.0026 (17)
C130.033 (2)0.022 (2)0.034 (2)0.002 (2)0.0125 (19)0.0003 (19)
C140.033 (3)0.034 (3)0.042 (3)0.001 (2)0.003 (2)0.001 (2)
S150.0432 (8)0.0378 (8)0.0632 (9)0.0111 (7)0.0034 (7)0.0015 (7)
C160.079 (5)0.043 (4)0.060 (4)0.006 (4)0.005 (4)0.013 (3)
C170.037 (3)0.023 (2)0.035 (2)0.005 (2)0.007 (2)0.002 (2)
O170.053 (2)0.0247 (19)0.052 (2)0.0087 (18)0.0136 (19)0.0083 (18)
N180.037 (2)0.0164 (18)0.040 (2)0.0005 (17)0.0062 (17)0.0039 (17)
C180.036 (3)0.020 (2)0.045 (3)0.002 (2)0.002 (2)0.003 (2)
C190.031 (6)0.030 (6)0.040 (7)0.003 (5)0.008 (5)0.014 (6)
C200.023 (6)0.036 (8)0.050 (7)0.005 (6)0.003 (4)0.003 (7)
C210.030 (7)0.046 (12)0.048 (8)0.006 (11)0.004 (6)0.015 (11)
C220.038 (7)0.066 (10)0.074 (10)0.005 (7)0.002 (7)0.035 (9)
C230.037 (6)0.093 (13)0.043 (7)0.016 (7)0.003 (5)0.030 (8)
C240.031 (6)0.088 (12)0.042 (6)0.007 (7)0.006 (5)0.019 (7)
C250.034 (6)0.068 (9)0.038 (6)0.011 (6)0.004 (4)0.004 (6)
C260.028 (2)0.023 (2)0.042 (3)0.004 (2)0.017 (2)0.007 (2)
O260.061 (3)0.046 (3)0.061 (3)0.034 (2)0.044 (2)0.032 (2)
C270.030 (2)0.023 (2)0.035 (2)0.0024 (19)0.0119 (18)0.000 (2)
O270.0364 (19)0.0289 (19)0.047 (2)0.0151 (16)0.0217 (17)0.0110 (17)
N280.0277 (19)0.0175 (19)0.042 (2)0.0017 (16)0.0149 (17)0.0018 (17)
C280.030 (2)0.014 (2)0.040 (2)0.0020 (18)0.0077 (19)0.0002 (19)
C290.043 (3)0.024 (2)0.053 (3)0.003 (2)0.015 (2)0.006 (2)
S300.0321 (7)0.0322 (8)0.0660 (10)0.0076 (5)0.0113 (6)0.0108 (7)
C310.029 (2)0.028 (3)0.053 (3)0.000 (2)0.017 (2)0.006 (2)
C320.035 (3)0.020 (2)0.041 (3)0.002 (2)0.012 (2)0.004 (2)
O320.0364 (19)0.0243 (18)0.052 (2)0.0006 (16)0.0112 (17)0.0104 (17)
N330.036 (2)0.021 (2)0.041 (2)0.0022 (18)0.0002 (18)0.0033 (18)
C330.039 (3)0.032 (3)0.061 (4)0.007 (2)0.010 (3)0.014 (3)
C340.040 (3)0.065 (5)0.061 (4)0.011 (3)0.018 (3)0.023 (4)
C350.051 (4)0.072 (6)0.178 (11)0.024 (4)0.043 (6)0.078 (7)
C360.090 (6)0.047 (4)0.065 (4)0.014 (4)0.030 (4)0.019 (4)
C19'0.037 (6)0.012 (5)0.049 (8)0.005 (4)0.005 (5)0.001 (5)
C20'0.035 (5)0.024 (5)0.057 (7)0.008 (4)0.001 (5)0.009 (5)
C25'0.029 (8)0.033 (11)0.080 (12)0.001 (11)0.007 (7)0.002 (13)
C24'0.043 (9)0.084 (15)0.072 (12)0.034 (11)0.004 (9)0.004 (12)
C23'0.060 (9)0.022 (6)0.106 (12)0.002 (6)0.033 (9)0.013 (7)
C22'0.064 (8)0.049 (8)0.042 (6)0.002 (7)0.010 (6)0.005 (6)
C21'0.052 (7)0.034 (6)0.050 (6)0.007 (6)0.016 (5)0.011 (6)
O610.026 (5)0.091 (11)0.045 (6)0.004 (6)0.015 (5)0.007 (7)
O620.025 (9)0.084 (18)0.048 (11)0.003 (11)0.017 (8)0.003 (12)
O630.027 (7)0.043 (10)0.035 (8)0.001 (7)0.011 (6)0.015 (7)
Geometric parameters (Å, º) top
N1—C81.318 (8)O61—O62i1.82 (3)
N1—C21.369 (8)O62—O61ii1.82 (3)
C2—C31.371 (7)C2—H20.930 (6)
C3—C91.412 (7)C3—H30.930 (5)
C4—C51.369 (8)C5—H50.930 (6)
C4—O111.389 (6)C6—H60.930 (6)
C4—C91.414 (7)C7—H70.930 (5)
C5—C61.429 (8)C8—H80.929 (6)
C6—C71.351 (7)C11—H110.971 (5)
C7—C101.416 (8)C11—H120.970 (5)
C8—C101.403 (7)N13—H130.860 (4)
C9—C101.432 (7)C13—H140.980 (6)
O11—C111.426 (6)C14—H150.970 (6)
C11—C121.511 (7)C14—H160.970 (6)
C12—O121.230 (6)C16—H170.960 (8)
C12—N131.348 (7)C16—H180.960 (8)
N13—C131.462 (7)C16—H190.960 (8)
C13—C171.524 (7)N18—H200.860 (5)
C13—C141.531 (7)C18—H210.979 (6)
C14—S151.817 (6)C19—H220.970 (14)
S15—C161.794 (8)C19—H230.970 (15)
C17—O171.238 (7)C21—H240.93 (2)
C17—N181.347 (7)C22—H250.930 (18)
N18—C181.478 (7)C23—H260.929 (16)
C18—C191.484 (13)C24—H270.931 (16)
C18—C261.529 (7)C25—H280.930 (5)
C18—C19'1.642 (14)C26—H290.980 (4)
C19—C201.53 (2)O26—H300.756 (5)
C20—C251.372 (17)C28—H310.980 (5)
C20—C211.37 (3)C29—H320.970 (5)
C21—C221.43 (3)C29—H330.970 (6)
C22—C231.38 (3)C31—H340.971 (6)
C23—C241.33 (3)C31—H350.970 (6)
C24—C251.416 (14)N33—H360.860 (4)
C26—O261.412 (6)C34—H370.961 (8)
C26—C271.535 (7)C34—H380.959 (8)
C27—O271.240 (6)C34—H390.960 (6)
C27—N281.341 (6)C35—H410.959 (15)
N28—C311.465 (6)C35—H420.960 (9)
N28—C281.468 (6)C35—H430.960 (11)
C28—C321.535 (7)C36—H440.960 (10)
C28—C291.535 (7)C36—H450.960 (10)
C29—S301.822 (6)C36—H460.960 (10)
S30—C311.817 (6)C19'—H23'0.970 (17)
C32—O321.230 (7)C19'—H22'0.970 (12)
C32—N331.346 (7)C25'—H28'0.93 (2)
N33—C331.485 (7)C24'—H27'0.93 (3)
C33—C341.514 (10)C23'—H26'0.930 (14)
C33—C361.530 (12)C22'—H25'0.929 (16)
C33—C351.531 (10)C21'—H24'0.931 (13)
C19'—C20'1.528 (18)O61—H620.830 (17)
C20'—C25'1.39 (3)O61—H610.892 (12)
C20'—C21'1.406 (18)O62—H630.87 (2)
C25'—C24'1.43 (3)O62—H640.87 (2)
C24'—C23'1.36 (3)O63—H650.863 (18)
C23'—C22'1.35 (2)O63—H660.771 (17)
C22'—C21'1.38 (2)
C8—N1—C2116.7 (5)O11—C11—H12109.4 (5)
N1—C2—C3123.6 (5)C12—C11—H11109.2 (5)
C2—C3—C9119.7 (5)C12—C11—H12109.3 (5)
C5—C4—O11123.8 (4)H11—C11—H12107.9 (5)
C5—C4—C9121.0 (4)C12—N13—H13118.8 (5)
O11—C4—C9115.1 (4)C13—N13—H13118.8 (4)
C4—C5—C6120.1 (5)N13—C13—H14109.7 (4)
C7—C6—C5120.6 (5)C14—C13—H14109.6 (5)
C6—C7—C10120.2 (5)C17—C13—H14109.7 (5)
N1—C8—C10125.4 (5)C13—C14—H15108.8 (5)
C3—C9—C4125.0 (5)C13—C14—H16108.8 (5)
C3—C9—C10117.1 (4)S15—C14—H15108.7 (5)
C4—C9—C10117.9 (5)S15—C14—H16108.7 (5)
C8—C10—C7122.7 (5)H15—C14—H16107.6 (6)
C8—C10—C9117.2 (5)S15—C16—H17109.5 (6)
C7—C10—C9120.1 (4)S15—C16—H18109.4 (7)
C4—O11—C11115.3 (4)S15—C16—H19109.5 (6)
O11—C11—C12111.5 (4)H17—C16—H18109.5 (8)
O12—C12—N13123.6 (5)H17—C16—H19109.5 (8)
O12—C12—C11118.5 (5)H18—C16—H19109.4 (8)
N13—C12—C11117.8 (4)C17—N18—H20119.8 (5)
C12—N13—C13122.3 (4)C18—N18—H20119.8 (4)
N13—C13—C17107.3 (4)N18—C18—H21103.5 (5)
N13—C13—C14110.2 (4)C19—C18—H21103.6 (7)
C17—C13—C14110.4 (4)C26—C18—H21103.6 (5)
C13—C14—S15114.0 (4)C18—C19—H22108.7 (12)
C16—S15—C14101.4 (3)C18—C19—H23108.7 (12)
O17—C17—N18123.8 (5)C20—C19—H22108.7 (13)
O17—C17—C13120.1 (5)C20—C19—H23108.7 (13)
N18—C17—C13116.0 (4)H22—C19—H23107.6 (14)
C17—N18—C18120.4 (4)C20—C21—H24121 (2)
N18—C18—C19106.5 (7)C22—C21—H24121.9 (19)
N18—C18—C26112.6 (4)C21—C22—H25119.3 (19)
C19—C18—C26124.7 (8)C23—C22—H25119.4 (18)
N18—C18—C19'112.2 (5)C22—C23—H26119.9 (14)
C19—C18—C19'26.2 (5)C24—C23—H26119.9 (18)
C26—C18—C19'100.8 (7)C23—C24—H27119.7 (17)
C18—C19—C20114.2 (12)C25—C24—H27119.8 (12)
C25—C20—C21121.5 (16)C20—C25—H28120.4 (9)
C25—C20—C19120.3 (15)C24—C25—H28120.2 (9)
C21—C20—C19118.1 (15)C18—C26—H29108.4 (4)
C20—C21—C22117 (2)O26—C26—H29108.5 (4)
C23—C22—C21121.0 (19)C27—C26—H29108.5 (4)
C24—C23—C22120.3 (13)C26—O26—H30114.1 (5)
C23—C24—C25120.5 (14)N28—C28—H31109.9 (4)
C20—C25—C24119.4 (12)C29—C28—H31109.9 (4)
O26—C26—C18111.4 (5)C32—C28—H31109.9 (4)
O26—C26—C27110.6 (4)C28—C29—H32110.8 (5)
C18—C26—C27109.3 (4)C28—C29—H33110.8 (5)
O27—C27—N28122.2 (5)S30—C29—H32110.8 (4)
O27—C27—C26119.5 (4)S30—C29—H33110.9 (5)
N28—C27—C26118.2 (4)H32—C29—H33108.8 (5)
C27—N28—C31126.7 (4)N28—C31—H34111.0 (5)
C27—N28—C28118.7 (4)N28—C31—H35111.1 (5)
C31—N28—C28114.3 (4)S30—C31—H34110.9 (4)
N28—C28—C32110.6 (4)S30—C31—H35111.0 (4)
N28—C28—C29106.6 (4)H34—C31—H35109.1 (6)
C32—C28—C29110.1 (4)C32—N33—H36117.5 (4)
C28—C29—S30104.6 (4)C33—N33—H36117.4 (5)
C31—S30—C2987.3 (3)C33—C34—H37109.5 (7)
N28—C31—S30103.7 (4)C33—C34—H38109.5 (7)
O32—C32—N33124.6 (5)C33—C34—H39109.5 (6)
O32—C32—C28121.4 (5)H37—C34—H38109.5 (7)
N33—C32—C28113.9 (4)H37—C34—H39109.5 (7)
C32—N33—C33125.1 (5)H38—C34—H39109.5 (7)
N33—C33—C34111.1 (6)C33—C35—H41109.6 (10)
N33—C33—C36109.7 (6)C33—C35—H42109.5 (8)
C34—C33—C36110.9 (6)C33—C35—H43109.4 (9)
N33—C33—C35105.2 (5)H41—C35—H42109.5 (12)
C34—C33—C35109.0 (7)H41—C35—H43109.5 (12)
C36—C33—C35110.8 (8)H42—C35—H43109.4 (9)
C20'—C19'—C18111.6 (10)C33—C36—H44109.5 (8)
C25'—C20'—C21'120.9 (16)C33—C36—H45109.4 (8)
C25'—C20'—C19'118.6 (16)C33—C36—H46109.5 (8)
C21'—C20'—C19'120.5 (12)H44—C36—H45109.4 (9)
C20'—C25'—C24'115 (2)H44—C36—H46109.4 (10)
C23'—C24'—C25'121 (2)H45—C36—H46109.5 (10)
C22'—C23'—C24'123.9 (18)C20'—C19'—H23'109.3 (12)
C23'—C22'—C21'116.2 (14)C20'—C19'—H22'109.3 (9)
C22'—C21'—C20'122.4 (14)H23'—C19'—H22'108.0 (13)
N1—C2—H2118.2 (6)C20'—C25'—H28'122.1 (19)
C3—C2—H2118.2 (6)C24'—C25'—H28'122 (2)
C2—C3—H3120.1 (5)C25'—C24'—H27'120 (2)
C9—C3—H3120.2 (5)C23'—C24'—H27'119 (2)
C4—C5—H5120.0 (6)C24'—C23'—H26'118.0 (16)
C6—C5—H5119.9 (6)C22'—C23'—H26'118.1 (15)
C5—C6—H6119.7 (6)C23'—C22'—H25'121.9 (15)
C7—C6—H6119.8 (6)C21'—C22'—H25'121.9 (15)
C6—C7—H7119.8 (5)C20'—C21'—H24'118.7 (12)
C10—C7—H7119.9 (5)C22'—C21'—H24'118.8 (13)
N1—C8—H8117.3 (6)H62—O61—H61106.3 (15)
C10—C8—H8117.3 (5)H63—O62—H64124 (2)
O11—C11—H11109.4 (5)H65—O63—H66124 (2)
Symmetry codes: (i) x, y1/2, z+1; (ii) x, y+1/2, z+1.
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O26—H30···O270.762.2692.669 (6)114
O62—H64···O320.871.9162.77 (2)166
O61—H62···O630.832.2233.05 (3)178
O63—H66···O620.771.8972.67 (3)177
N18—H20···O27iii0.862.253.038 (6)152
N33—H36···O26iv0.862.142.984 (7)169
O26—H30···O12iv0.762.1452.837 (6)153
O61—H61···N1v0.892.0752.932 (12)161
O62—H63···N1vi0.872.1732.88 (2)139
Symmetry codes: (iii) x, y1/2, z+2; (iv) x, y+1/2, z+2; (v) x1, y, z; (vi) x+1, y+1/2, z+1.

Experimental details

Crystal data
Chemical formulaC33H41N5O6S2·0.803H2O
Mr682.33
Crystal system, space groupMonoclinic, P21
Temperature (K)100
a, b, c (Å)10.7631 (4), 13.1751 (4), 12.5623 (5)
β (°) 96.887 (2)
V3)1768.54 (11)
Z2
Radiation typeSynchrotron, λ = 0.83600 Å
µ (mm1)0.20
Crystal size (mm)0.25 × 0.10 × 0.02
Data collection
DiffractometerRigaku RAXIS-IV image-plate detector
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
5965, 3571, 3321
Rint0.070
(sin θ/λ)max1)0.624
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.067, 0.191, 0.99
No. of reflections3571
No. of parameters504
No. of restraints1
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.81, 0.61

Computer programs: PROCESS (Rigaku, 1996), MOSFLM (Leslie, 1999), MOSFLM, SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), PLATON (Spek, 1998), PARST (Nardelli, 1983).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O26—H30···O270.762.2692.669 (6)114
O62—H64···O320.871.9162.77 (2)166
O61—H62···O630.832.2233.05 (3)178
O63—H66···O620.771.8972.67 (3)177
N18—H20···O27i0.862.2523.038 (6)152
N33—H36···O26ii0.862.1352.984 (7)169
O26—H30···O12ii0.762.1452.837 (6)153
O61—H61···N1iii0.892.0752.932 (12)161
O62—H63···N1iv0.872.1732.88 (2)139
Symmetry codes: (i) x, y1/2, z+2; (ii) x, y+1/2, z+2; (iii) x1, y, z; (iv) x+1, y+1/2, z+1.
Selected torsion angles for (I) in this crystal and in the complex with HIV protease (°) top
Torsion angleThis crystalComplex
O11-C11-C12-N1312.4 (6)39.4
C11-C12-N13-C13-171.4 (4)168.8
C12-N13-C13-C17-125.3 (5)-120.1
N13-C13-C14-S15-57.3 (5)-161.4
N13-C13-C17-N18112.7 (5)71.8
C13-C17-N18-C18-162.8 (4)-175.9
C17-N18-C18-C26-104.8 (6)-108.2
N18-C18-C19-C20*-61.0 (12)-54.1
N18-C18-C19'-C20'*-41.7 (11)-54.1
C18-C19-C20-C21105.2 (17)98.9
C18-C19-C20-C25-70.5 (17)-81.2
C18-C19'-C20'-C21'139.1 (11)98.9
C18-C19'-C20'-C25'-39.2 (17)-81.2
N18-C18-C26-O26-65.1 (6)-74.9
N18-C18-C26-C27172.3 (4)165.1
C18-C26-C27-N28-66.8 (6)-88.4
O26-C26-C27-O27-14.2 (7)-32.5
C26-C27-N28-C28173.7 (4)169.1
C27-N28-C28-C32-65.8 (6)-64.7
N28-C28-C29-S30-32.3 (4)23.6
N28-C28-C32-N33148.8 (4)145.6
C28-C32-N33-C33179.0 (5)-169.6
C32-N33-C33-C3453.4 (8)54.5
*The phenyl group is disordered on two sites.
 

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