organic compounds
of 4,6-diamino-2,2-dimethyl-3-[3-(2,4,5-trichlorophenoxy)propoxy]-2,3-dihydro-1,3,5-triazin-1-ium chloride methanol monosolvate
aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry, and Center for Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
*Correspondence e-mail: palangpon.kon@mahidol.ac.th
In the title methanol-solvated salt, C14H19Cl3N5O2+·Cl−·CH3OH, the triazine molecule is protonated at one of the triazine N atoms. In the crystal, the triazine cations are linked through a pair of N—H⋯N hydrogen bonds, with graph-set R22(8), forming an inversion dimer. The protonated N atom and the 2- and 4-amino groups of the triazine cation interact with the chloride anion through N—H⋯Cl hydrogen bonds, leading to the formation of a tape structure running along the b-axis direction. A short Cl⋯Cl contact [3.2937 (9) Å] is observed in the tape. The methanol molecule is linked to the chloride anion and the triazine cation, respectively, by an O—H⋯Cl hydrogen bond and a C—H⋯O interaction.
Keywords: crystal structure; triazine; antifolate drug; antimalarial; hydrogen bonding.
CCDC reference: 1414045
1. Related literature
For antifolate antimalarial drugs, see: Toyoda et al. (1997); Yuthavong (2002). For antifolate drug resistance, see: Nzila (2006); Rieckmann et al. (1996). For our previous work on the protein crystallographic analysis of dihydrofolate reductase, see: Yuvaniyama et al. (2003); Kongsaeree et al. (2005).
2. Experimental
2.1. Crystal data
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2.2. Data collection
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2.3. Refinement
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Data collection: KappaCCD Software (Nonius, 1999); cell SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2015); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: publCIF (Westrip, 2010).
Supporting information
CCDC reference: 1414045
https://doi.org/10.1107/S205698901501378X/is5407sup1.cif
contains datablocks I, New_Global_Publ_Block. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S205698901501378X/is5407Isup2.hkl
Supporting information file. DOI: https://doi.org/10.1107/S205698901501378X/is5407Isup3.cml
WR99210 was a kind gift from Dr. Bongkoch Tarnchompoo, BIOTEC, National Science and Technology Development Agency, Thailand. Single crystals of the title compound were prepared from a methanolic solution by slow evaporation at 298 K. The colorless crystals suitable for X-ray diffraction were obtained after a few days.
The N-bound H atoms were located in a difference Fourier map and were refined with restraint of N—H = 0.88 (1) Å. All other H atoms were placed in idealized positions and refined as riding atoms, with C—H = 0.93–0.97 Å and O—H = 0.82 Å, and with Uiso(H) = 1.5Ueq(O, Cmethyl) and 1.2Ueq(C) for other H atoms.
The structure of the methanol-solvated salt compound, C14H19Cl3N5O2+.Cl-.CH3OH, was determined as part of a structural study of our dihydrofolate reductase (DHFR) in complex with its antifolate inhibitors. WR99210 {systematic name: 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine} is a potent inhibitor of dihydrofolate reductase enzyme (DHFR). With a structural resemblance with cycloguanil (Cyc), a metabolite of the antimalarial drug proguanil (Toyoda et al., 1997), WR99210 has a flexible propoxy linker and a phenyl group with three chlorine atoms (Yuthavong, 2002; Nzila, 2006). Studies in animal models demonstrated a low bioavailability of WR99210, preventing its further development as an antimalarial agent (Rieckmann et al., 1996). The crystal structures of the bifunctional Plasmodium falciparum DHFR-TS and the monofunctional P. vivax DHFR have been reported in complex with WR99210, and with pyrimethamines, respectively (Yuvaniyama et al., 2003; Kongsaeree et al., 2005). The protein structures complexed with WR99210 have provided valuable insight into interdomain interactions and also opened a new dimension in the design of new drugs to fight against malaria. Herein, we report a single crystal X-ray structure of 4,6-diamino-2,2-dimethyl-3-[3-(2,4,5-trichlorophenoxy)propoxy]-2,3-dihydro-1,3,5-triazin-1-ium chloride methanol solvate, (I).
In the title compound, the WR99210 molecule is protonated at one of the nitrogen atoms of the triazine moiety. This is evident from the increase in the internal angle at protonated N1 [C1—N1—C3 = 122.30 (16) Å] compared with that of the unprotanated atoms N3 [C2—N3—C1 = 116.03 (16) Å] and N5 [C2—N5—C3 = 117.77 (15) Å]. The triazine ring adopts the conformation described as an intermediate between a flatten screw-boat and a half-chair with C3 atom. The angle between the geminal flagpole and bowsprit methyl groups is 112.31 (18)°. In addition, the propoxy linker between the triazine and the trichlorophenyl group allowed free rotations of sp3-hybridized C6, C7 and C8 atoms (Fig. 1).
In the crystal, the triazine moiety is centrosymmetrically paired through N—H···N hydrogen bonds involving the 2-amino group and the N3 atom of the triazine, leading to a hydrogen-bonding pattern with a graph-set R22(8) (Fig. 2). The pairs further interact with the chloride anion through N—H···Cl hydrogen bonds. The chloride anion connects 2-amino and 4-amino groups on either side of the paired triazine, forming an eight-membered hydrogen bonded ring motif with a graph-set R32(8). The protonated N1 and 2-amino groups of the cationic triazine also interacted with two chloride anions to form a ring motif with a graph-set R42(12). In addition, we found a graph-set R32(15) ring motif through an O—H···Cl hydrogen bond between the methanol molecule and the chloride anion as well as a C—H···O hydrogen bond between the benzene ring (C14) and the methanol molecule (Table 1).
For antifolate antimalarial drugs, see: Toyoda et al. (1997); Yuthavong (2002). For antifolate drug resistance, see: Nzila (2006); Rieckmann et al. (1996). For our previous work on the protein crystallographic analysis of dihydrofolate reductase, see: Yuvaniyama et al. (2003); Kongsaeree et al. (2005).
Data collection: KappaCCD Software (Nonius, 1999); cell
SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2015); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: publCIF (Westrip, 2010).Fig. 1. View of the molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level. | |
Fig. 2. Hydrogen bonding interactions, showing molecules linked through N—H···N, N—H···Cl and O—H···Cl (dashed lines), and C—H···O (dotted line) hydrogen bonds. |
C14H19Cl3N5O2+·Cl−·CH4O | Z = 2 |
Mr = 463.18 | F(000) = 480 |
Triclinic, P1 | Dx = 1.443 Mg m−3 |
a = 8.5930 (4) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 9.3510 (3) Å | Cell parameters from 2724 reflections |
c = 14.6970 (7) Å | θ = 2.9–23.3° |
α = 75.422 (3)° | µ = 0.58 mm−1 |
β = 78.2260 (19)° | T = 298 K |
γ = 70.194 (3)° | Rod, colourless |
V = 1066.13 (8) Å3 | 0.32 × 0.20 × 0.18 mm |
Nonius KappaCCD diffractometer | 2681 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.017 |
Detector resolution: 9 pixels mm-1 | θmax = 23.3°, θmin = 3.1° |
CCD scans | h = −9→9 |
5032 measured reflections | k = −10→9 |
2935 independent reflections | l = −16→16 |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.034 | Hydrogen site location: mixed |
wR(F2) = 0.087 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.06 | w = 1/[σ2(Fo2) + (0.0351P)2 + 0.5001P] where P = (Fo2 + 2Fc2)/3 |
2935 reflections | (Δ/σ)max = 0.001 |
268 parameters | Δρmax = 0.26 e Å−3 |
6 restraints | Δρmin = −0.26 e Å−3 |
C14H19Cl3N5O2+·Cl−·CH4O | γ = 70.194 (3)° |
Mr = 463.18 | V = 1066.13 (8) Å3 |
Triclinic, P1 | Z = 2 |
a = 8.5930 (4) Å | Mo Kα radiation |
b = 9.3510 (3) Å | µ = 0.58 mm−1 |
c = 14.6970 (7) Å | T = 298 K |
α = 75.422 (3)° | 0.32 × 0.20 × 0.18 mm |
β = 78.2260 (19)° |
Nonius KappaCCD diffractometer | 2681 reflections with I > 2σ(I) |
5032 measured reflections | Rint = 0.017 |
2935 independent reflections | θmax = 23.3° |
R[F2 > 2σ(F2)] = 0.034 | 6 restraints |
wR(F2) = 0.087 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.06 | Δρmax = 0.26 e Å−3 |
2935 reflections | Δρmin = −0.26 e Å−3 |
268 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 | ||
Cl1 | −0.26674 (7) | −0.09037 (6) | 0.98859 (4) | 0.05048 (18) | |
Cl2 | −0.50317 (9) | 0.36361 (7) | 1.18779 (4) | 0.0669 (2) | |
Cl3 | −0.27290 (9) | 0.54749 (7) | 1.04479 (5) | 0.0658 (2) | |
Cl4 | 0.17598 (7) | 0.43814 (6) | 0.40327 (4) | 0.05568 (19) | |
O1 | 0.36692 (15) | 0.10928 (15) | 0.69350 (9) | 0.0364 (3) | |
O2 | −0.07327 (17) | 0.09663 (16) | 0.86849 (10) | 0.0423 (3) | |
O3 | 0.0138 (3) | 0.4448 (3) | 0.22657 (17) | 0.0928 (7) | |
H3 | 0.0601 | 0.4417 | 0.2709 | 0.139* | |
N1 | 0.6726 (2) | 0.30658 (19) | 0.58733 (12) | 0.0404 (4) | |
N2 | 0.9243 (2) | 0.2208 (2) | 0.49858 (14) | 0.0459 (4) | |
N3 | 0.77155 (19) | 0.05192 (18) | 0.56004 (11) | 0.0369 (4) | |
N4 | 0.5995 (2) | −0.1015 (2) | 0.61841 (14) | 0.0491 (5) | |
N5 | 0.49520 (18) | 0.15639 (17) | 0.62848 (11) | 0.0327 (4) | |
C1 | 0.7877 (2) | 0.1939 (2) | 0.54981 (13) | 0.0338 (4) | |
C2 | 0.6256 (2) | 0.0339 (2) | 0.60370 (13) | 0.0334 (4) | |
C3 | 0.5346 (2) | 0.2785 (2) | 0.65866 (14) | 0.0356 (4) | |
C4 | 0.5862 (3) | 0.2234 (3) | 0.75760 (15) | 0.0501 (5) | |
H4C | 0.4938 | 0.2043 | 0.8026 | 0.060* | |
H4D | 0.6195 | 0.3015 | 0.7732 | 0.060* | |
H4E | 0.6779 | 0.1294 | 0.7596 | 0.060* | |
C5 | 0.3872 (3) | 0.4247 (2) | 0.65107 (18) | 0.0509 (6) | |
H5A | 0.2982 | 0.4096 | 0.7001 | 0.061* | |
H5B | 0.3498 | 0.4478 | 0.5903 | 0.061* | |
H5C | 0.4200 | 0.5094 | 0.6580 | 0.061* | |
C6 | 0.2207 (2) | 0.1419 (3) | 0.64724 (14) | 0.0422 (5) | |
H6A | 0.2490 | 0.0902 | 0.5939 | 0.051* | |
H6B | 0.1740 | 0.2525 | 0.6248 | 0.051* | |
C7 | 0.0993 (2) | 0.0797 (3) | 0.72291 (15) | 0.0421 (5) | |
H7A | 0.0103 | 0.0749 | 0.6935 | 0.051* | |
H7B | 0.1564 | −0.0249 | 0.7532 | 0.051* | |
C8 | 0.0247 (3) | 0.1781 (2) | 0.79714 (14) | 0.0418 (5) | |
H8A | 0.1119 | 0.1912 | 0.8241 | 0.050* | |
H8B | −0.0448 | 0.2796 | 0.7698 | 0.050* | |
C9 | −0.1674 (2) | 0.1672 (2) | 0.94055 (13) | 0.0348 (4) | |
C10 | −0.2683 (2) | 0.0871 (2) | 1.00452 (13) | 0.0349 (4) | |
C11 | −0.3698 (3) | 0.1481 (2) | 1.07983 (14) | 0.0405 (5) | |
H11 | −0.4368 | 0.0939 | 1.1217 | 0.049* | |
C12 | −0.3719 (3) | 0.2895 (2) | 1.09306 (14) | 0.0419 (5) | |
C13 | −0.2726 (3) | 0.3696 (2) | 1.02998 (14) | 0.0418 (5) | |
C14 | −0.1711 (3) | 0.3094 (2) | 0.95396 (14) | 0.0407 (5) | |
H14 | −0.1053 | 0.3647 | 0.9118 | 0.049* | |
C15 | 0.0334 (5) | 0.2948 (4) | 0.2183 (3) | 0.1067 (12) | |
H15A | −0.0107 | 0.2981 | 0.1625 | 0.160* | |
H15B | −0.0254 | 0.2456 | 0.2732 | 0.160* | |
H15C | 0.1498 | 0.2369 | 0.2133 | 0.160* | |
H1 | 0.700 (3) | 0.3881 (18) | 0.5866 (17) | 0.053 (7)* | |
H2A | 0.944 (3) | 0.3083 (16) | 0.4926 (16) | 0.045 (6)* | |
H2B | 1.002 (2) | 0.144 (2) | 0.4770 (16) | 0.052 (7)* | |
H4A | 0.680 (2) | −0.181 (2) | 0.6007 (17) | 0.057 (7)* | |
H4B | 0.507 (2) | −0.108 (3) | 0.6546 (16) | 0.067 (8)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.0612 (4) | 0.0386 (3) | 0.0568 (3) | −0.0254 (3) | 0.0059 (3) | −0.0153 (2) |
Cl2 | 0.0924 (5) | 0.0554 (4) | 0.0519 (4) | −0.0290 (3) | 0.0215 (3) | −0.0243 (3) |
Cl3 | 0.0963 (5) | 0.0422 (3) | 0.0678 (4) | −0.0344 (3) | 0.0018 (3) | −0.0180 (3) |
Cl4 | 0.0613 (4) | 0.0410 (3) | 0.0719 (4) | −0.0260 (3) | 0.0097 (3) | −0.0241 (3) |
O1 | 0.0292 (7) | 0.0467 (8) | 0.0340 (7) | −0.0173 (6) | 0.0032 (5) | −0.0070 (6) |
O2 | 0.0422 (8) | 0.0407 (8) | 0.0426 (8) | −0.0178 (6) | 0.0095 (6) | −0.0107 (6) |
O3 | 0.1093 (18) | 0.0790 (15) | 0.0964 (17) | −0.0336 (13) | −0.0224 (13) | −0.0144 (12) |
N1 | 0.0407 (9) | 0.0317 (9) | 0.0515 (10) | −0.0178 (8) | 0.0047 (8) | −0.0123 (8) |
N2 | 0.0406 (10) | 0.0400 (11) | 0.0577 (11) | −0.0220 (9) | 0.0091 (8) | −0.0093 (9) |
N3 | 0.0341 (9) | 0.0332 (9) | 0.0432 (9) | −0.0151 (7) | 0.0078 (7) | −0.0109 (7) |
N4 | 0.0443 (11) | 0.0340 (10) | 0.0682 (13) | −0.0196 (9) | 0.0168 (9) | −0.0172 (9) |
N5 | 0.0283 (8) | 0.0344 (9) | 0.0365 (8) | −0.0138 (7) | 0.0058 (6) | −0.0111 (7) |
C1 | 0.0334 (10) | 0.0335 (11) | 0.0346 (10) | −0.0140 (9) | 0.0008 (8) | −0.0060 (8) |
C2 | 0.0354 (10) | 0.0323 (10) | 0.0335 (10) | −0.0135 (8) | 0.0018 (8) | −0.0086 (8) |
C3 | 0.0337 (10) | 0.0342 (10) | 0.0408 (11) | −0.0117 (8) | 0.0014 (8) | −0.0138 (8) |
C4 | 0.0487 (13) | 0.0593 (14) | 0.0474 (13) | −0.0177 (11) | −0.0071 (10) | −0.0173 (11) |
C5 | 0.0450 (12) | 0.0382 (12) | 0.0661 (15) | −0.0051 (10) | −0.0028 (11) | −0.0183 (10) |
C6 | 0.0342 (11) | 0.0594 (13) | 0.0372 (11) | −0.0190 (10) | −0.0018 (8) | −0.0124 (9) |
C7 | 0.0345 (11) | 0.0544 (13) | 0.0433 (11) | −0.0211 (9) | −0.0007 (9) | −0.0130 (10) |
C8 | 0.0373 (11) | 0.0454 (12) | 0.0425 (11) | −0.0194 (9) | 0.0047 (9) | −0.0068 (9) |
C9 | 0.0326 (10) | 0.0356 (11) | 0.0358 (10) | −0.0116 (8) | −0.0022 (8) | −0.0065 (8) |
C10 | 0.0379 (11) | 0.0301 (10) | 0.0379 (11) | −0.0124 (8) | −0.0048 (8) | −0.0061 (8) |
C11 | 0.0458 (12) | 0.0398 (12) | 0.0368 (11) | −0.0210 (9) | 0.0022 (9) | −0.0039 (9) |
C12 | 0.0503 (12) | 0.0394 (12) | 0.0356 (11) | −0.0151 (10) | −0.0002 (9) | −0.0091 (9) |
C13 | 0.0526 (12) | 0.0325 (11) | 0.0431 (12) | −0.0162 (9) | −0.0068 (10) | −0.0073 (9) |
C14 | 0.0428 (11) | 0.0379 (11) | 0.0425 (11) | −0.0202 (9) | −0.0007 (9) | −0.0030 (9) |
C15 | 0.152 (4) | 0.064 (2) | 0.120 (3) | −0.035 (2) | −0.050 (3) | −0.0171 (19) |
Cl1—C10 | 1.7290 (19) | C4—H4D | 0.9600 |
Cl2—C12 | 1.734 (2) | C4—H4E | 0.9600 |
Cl3—C13 | 1.730 (2) | C5—H5A | 0.9600 |
O1—N5 | 1.4177 (19) | C5—H5B | 0.9600 |
O1—C6 | 1.455 (2) | C5—H5C | 0.9600 |
O2—C9 | 1.361 (2) | C6—C7 | 1.509 (3) |
O2—C8 | 1.436 (2) | C6—H6A | 0.9700 |
O3—C15 | 1.389 (4) | C6—H6B | 0.9700 |
O3—H3 | 0.8200 | C7—C8 | 1.506 (3) |
N1—C1 | 1.325 (3) | C7—H7A | 0.9700 |
N1—C3 | 1.462 (2) | C7—H7B | 0.9700 |
N1—H1 | 0.866 (10) | C8—H8A | 0.9700 |
N2—C1 | 1.324 (2) | C8—H8B | 0.9700 |
N2—H2A | 0.868 (10) | C9—C14 | 1.382 (3) |
N2—H2B | 0.874 (10) | C9—C10 | 1.396 (3) |
N3—C2 | 1.332 (2) | C10—C11 | 1.377 (3) |
N3—C1 | 1.349 (2) | C11—C12 | 1.378 (3) |
N4—C2 | 1.317 (3) | C11—H11 | 0.9300 |
N4—H4A | 0.883 (10) | C12—C13 | 1.381 (3) |
N4—H4B | 0.873 (10) | C13—C14 | 1.383 (3) |
N5—C2 | 1.369 (2) | C14—H14 | 0.9300 |
N5—C3 | 1.481 (2) | C15—H15A | 0.9600 |
C3—C5 | 1.514 (3) | C15—H15B | 0.9600 |
C3—C4 | 1.519 (3) | C15—H15C | 0.9600 |
C4—H4C | 0.9600 | ||
N5—O1—C6 | 110.75 (13) | O1—C6—H6A | 110.8 |
C9—O2—C8 | 118.27 (15) | C7—C6—H6A | 110.8 |
C15—O3—H3 | 109.5 | O1—C6—H6B | 110.8 |
C1—N1—C3 | 122.30 (16) | C7—C6—H6B | 110.8 |
C1—N1—H1 | 117.3 (16) | H6A—C6—H6B | 108.9 |
C3—N1—H1 | 116.2 (16) | C8—C7—C6 | 112.46 (17) |
C1—N2—H2A | 121.4 (15) | C8—C7—H7A | 109.1 |
C1—N2—H2B | 118.5 (16) | C6—C7—H7A | 109.1 |
H2A—N2—H2B | 120 (2) | C8—C7—H7B | 109.1 |
C2—N3—C1 | 116.03 (16) | C6—C7—H7B | 109.1 |
C2—N4—H4A | 119.9 (16) | H7A—C7—H7B | 107.8 |
C2—N4—H4B | 114.9 (18) | O2—C8—C7 | 105.97 (16) |
H4A—N4—H4B | 124 (2) | O2—C8—H8A | 110.5 |
C2—N5—O1 | 112.83 (14) | C7—C8—H8A | 110.5 |
C2—N5—C3 | 117.77 (15) | O2—C8—H8B | 110.5 |
O1—N5—C3 | 110.56 (13) | C7—C8—H8B | 110.5 |
N2—C1—N1 | 119.24 (17) | H8A—C8—H8B | 108.7 |
N2—C1—N3 | 117.74 (17) | O2—C9—C14 | 125.37 (17) |
N1—C1—N3 | 123.01 (16) | O2—C9—C10 | 115.84 (17) |
N4—C2—N3 | 120.33 (17) | C14—C9—C10 | 118.79 (18) |
N4—C2—N5 | 118.00 (17) | C11—C10—C9 | 120.85 (18) |
N3—C2—N5 | 121.51 (16) | C11—C10—Cl1 | 119.59 (14) |
N1—C3—N5 | 103.00 (14) | C9—C10—Cl1 | 119.56 (15) |
N1—C3—C5 | 108.81 (16) | C10—C11—C12 | 120.00 (18) |
N5—C3—C5 | 109.49 (16) | C10—C11—H11 | 120.0 |
N1—C3—C4 | 111.45 (16) | C12—C11—H11 | 120.0 |
N5—C3—C4 | 111.35 (16) | C11—C12—C13 | 119.49 (18) |
C5—C3—C4 | 112.31 (18) | C11—C12—Cl2 | 118.64 (15) |
C3—C4—H4C | 109.5 | C13—C12—Cl2 | 121.85 (16) |
C3—C4—H4D | 109.5 | C12—C13—C14 | 120.82 (18) |
H4C—C4—H4D | 109.5 | C12—C13—Cl3 | 120.49 (16) |
C3—C4—H4E | 109.5 | C14—C13—Cl3 | 118.68 (15) |
H4C—C4—H4E | 109.5 | C9—C14—C13 | 120.05 (18) |
H4D—C4—H4E | 109.5 | C9—C14—H14 | 120.0 |
C3—C5—H5A | 109.5 | C13—C14—H14 | 120.0 |
C3—C5—H5B | 109.5 | O3—C15—H15A | 109.5 |
H5A—C5—H5B | 109.5 | O3—C15—H15B | 109.5 |
C3—C5—H5C | 109.5 | H15A—C15—H15B | 109.5 |
H5A—C5—H5C | 109.5 | O3—C15—H15C | 109.5 |
H5B—C5—H5C | 109.5 | H15A—C15—H15C | 109.5 |
O1—C6—C7 | 104.82 (15) | H15B—C15—H15C | 109.5 |
C6—O1—N5—C2 | −107.86 (18) | O1—C6—C7—C8 | 72.4 (2) |
C6—O1—N5—C3 | 117.90 (17) | C9—O2—C8—C7 | −174.20 (16) |
C3—N1—C1—N2 | −168.24 (18) | C6—C7—C8—O2 | −174.17 (16) |
C3—N1—C1—N3 | 12.8 (3) | C8—O2—C9—C14 | −3.3 (3) |
C2—N3—C1—N2 | −173.42 (18) | C8—O2—C9—C10 | 176.05 (17) |
C2—N3—C1—N1 | 5.6 (3) | O2—C9—C10—C11 | −179.53 (18) |
C1—N3—C2—N4 | −178.78 (19) | C14—C9—C10—C11 | −0.1 (3) |
C1—N3—C2—N5 | 5.9 (3) | O2—C9—C10—Cl1 | 0.1 (2) |
O1—N5—C2—N4 | 19.0 (2) | C14—C9—C10—Cl1 | 179.54 (15) |
C3—N5—C2—N4 | 149.69 (18) | C9—C10—C11—C12 | −0.3 (3) |
O1—N5—C2—N3 | −165.59 (16) | Cl1—C10—C11—C12 | −179.98 (16) |
C3—N5—C2—N3 | −34.9 (3) | C10—C11—C12—C13 | 0.5 (3) |
C1—N1—C3—N5 | −35.7 (2) | C10—C11—C12—Cl2 | 179.18 (16) |
C1—N1—C3—C5 | −151.85 (19) | C11—C12—C13—C14 | −0.1 (3) |
C1—N1—C3—C4 | 83.8 (2) | Cl2—C12—C13—C14 | −178.82 (17) |
C2—N5—C3—N1 | 45.5 (2) | C11—C12—C13—Cl3 | 179.94 (17) |
O1—N5—C3—N1 | 177.24 (14) | Cl2—C12—C13—Cl3 | 1.3 (3) |
C2—N5—C3—C5 | 161.15 (17) | O2—C9—C14—C13 | 179.80 (18) |
O1—N5—C3—C5 | −67.12 (19) | C10—C9—C14—C13 | 0.4 (3) |
C2—N5—C3—C4 | −74.1 (2) | C12—C13—C14—C9 | −0.3 (3) |
O1—N5—C3—C4 | 57.68 (19) | Cl3—C13—C14—C9 | 179.62 (16) |
N5—O1—C6—C7 | 177.50 (15) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···Cl4i | 0.87 (1) | 2.27 (1) | 3.1236 (17) | 167 (2) |
N2—H2A···Cl4ii | 0.87 (1) | 2.64 (2) | 3.3285 (17) | 137 (2) |
N2—H2B···N3iii | 0.87 (1) | 2.26 (1) | 3.122 (2) | 170 (2) |
N4—H4A···Cl4iv | 0.88 (1) | 2.31 (1) | 3.1419 (19) | 158 (2) |
O3—H3···Cl4 | 0.82 | 2.35 | 3.166 (2) | 176 |
C14—H14···O3v | 0.93 | 2.53 | 3.423 (3) | 161 |
Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) x+1, y, z; (iii) −x+2, −y, −z+1; (iv) −x+1, −y, −z+1; (v) −x, −y+1, −z+1. |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···Cl4i | 0.866 (10) | 2.274 (11) | 3.1236 (17) | 167 (2) |
N2—H2A···Cl4ii | 0.868 (10) | 2.638 (17) | 3.3285 (17) | 137.3 (18) |
N2—H2B···N3iii | 0.874 (10) | 2.258 (11) | 3.122 (2) | 170 (2) |
N4—H4A···Cl4iv | 0.883 (10) | 2.307 (13) | 3.1419 (19) | 158 (2) |
O3—H3···Cl4 | 0.82 | 2.35 | 3.166 (2) | 176 |
C14—H14···O3v | 0.93 | 2.53 | 3.423 (3) | 161 |
Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) x+1, y, z; (iii) −x+2, −y, −z+1; (iv) −x+1, −y, −z+1; (v) −x, −y+1, −z+1. |
Acknowledgements
The authors are grateful for financial support from the Thailand Research Fund (TRF), the Thailand–Tropical Diseases Research Program (T-2), and the Wellcome Trust. A scholarship from the Thailand Graduate Institute of Science and Technology (TGIST) to PK is acknowledged. This study was conducted in a facility supported by the Center of Excellence for Innovation in Chemistry (PERCH–CIC).
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The structure of the methanol-solvated salt compound, C14H19Cl3N5O2+.Cl-.CH3OH, was determined as part of a structural study of our dihydrofolate reductase (DHFR) in complex with its antifolate inhibitors. WR99210 {systematic name: 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine} is a potent inhibitor of dihydrofolate reductase enzyme (DHFR). With a structural resemblance with cycloguanil (Cyc), a metabolite of the antimalarial drug proguanil (Toyoda et al., 1997), WR99210 has a flexible propoxy linker and a phenyl group with three chlorine atoms (Yuthavong, 2002; Nzila, 2006). Studies in animal models demonstrated a low bioavailability of WR99210, preventing its further development as an antimalarial agent (Rieckmann et al., 1996). The crystal structures of the bifunctional Plasmodium falciparum DHFR-TS and the monofunctional P. vivax DHFR have been reported in complex with WR99210, and with pyrimethamines, respectively (Yuvaniyama et al., 2003; Kongsaeree et al., 2005). The protein structures complexed with WR99210 have provided valuable insight into interdomain interactions and also opened a new dimension in the design of new drugs to fight against malaria. Herein, we report a single crystal X-ray structure of 4,6-diamino-2,2-dimethyl-3-[3-(2,4,5-trichlorophenoxy)propoxy]-2,3-dihydro-1,3,5-triazin-1-ium chloride methanol solvate, (I).
In the title compound, the WR99210 molecule is protonated at one of the nitrogen atoms of the triazine moiety. This is evident from the increase in the internal angle at protonated N1 [C1—N1—C3 = 122.30 (16) Å] compared with that of the unprotanated atoms N3 [C2—N3—C1 = 116.03 (16) Å] and N5 [C2—N5—C3 = 117.77 (15) Å]. The triazine ring adopts the conformation described as an intermediate between a flatten screw-boat and a half-chair with C3 atom. The angle between the geminal flagpole and bowsprit methyl groups is 112.31 (18)°. In addition, the propoxy linker between the triazine and the trichlorophenyl group allowed free rotations of sp3-hybridized C6, C7 and C8 atoms (Fig. 1).
In the crystal, the triazine moiety is centrosymmetrically paired through N—H···N hydrogen bonds involving the 2-amino group and the N3 atom of the triazine, leading to a hydrogen-bonding pattern with a graph-set R22(8) (Fig. 2). The pairs further interact with the chloride anion through N—H···Cl hydrogen bonds. The chloride anion connects 2-amino and 4-amino groups on either side of the paired triazine, forming an eight-membered hydrogen bonded ring motif with a graph-set R32(8). The protonated N1 and 2-amino groups of the cationic triazine also interacted with two chloride anions to form a ring motif with a graph-set R42(12). In addition, we found a graph-set R32(15) ring motif through an O—H···Cl hydrogen bond between the methanol molecule and the chloride anion as well as a C—H···O hydrogen bond between the benzene ring (C14) and the methanol molecule (Table 1).