Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation
Poirier, Marion; Pujol-Giménez, Jonai; Manatschal, Cristina; Bühlmann, Sven; Embaby, Ahmed; Javor, Sacha; Hediger, Matthias A.; Reymond, Jean-Louis; RSC Medicinal Chemistry  (2020) –; doi:10.1039/D0MD00085J

data_7240594
_publ_section_title
;
 Pyrazolyl-pyrimidones inhibit the function of human solute carrier
 protein SLC11A2 (hDMT1) by metal chelation
;
_journal_name_full               'RSC Medicinal Chemistry'
_journal_paper_doi               10.1039/D0MD00085J
_journal_year                    2020
_chemical_absolute_configuration unk
_chemical_formula_moiety         'Cl, C10 H13 N4 O2, H2 O'
_chemical_formula_sum            'C10 H15 Cl N4 O3'
_chemical_formula_weight         274.71
_chemical_name_systematic
6-ethyl-4-hydroxy-2-(3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyrimidin-1-ium
_space_group_crystal_system      monoclinic
_space_group_IT_number           4
_space_group_name_Hall           'P 2yb'
_space_group_name_H-M_alt        'P 1 21 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2020-01-07
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_audit_update_record
;
2020-01-10 deposited with the CCDC.	2020-05-07 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90.8062(4)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   8.66205(5)
_cell_length_b                   14.39226(6)
_cell_length_c                   9.94738(4)
_cell_measurement_reflns_used    36763
_cell_measurement_temperature    173.01(10)
_cell_measurement_theta_max      77.0270
_cell_measurement_theta_min      4.4440
_cell_volume                     1239.982(10)
_computing_cell_refinement       'CrysAlisPro 1.171.40.45a (Rigaku OD, 2019)'
_computing_data_collection       'CrysAlisPro 1.171.40.45a (Rigaku OD, 2019)'
_computing_data_reduction        'CrysAlisPro 1.171.40.45a (Rigaku OD, 2019)'
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL (Sheldrick, 2015)'
_computing_structure_solution    'ShelXT (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      173.01(10)
_diffrn_detector                 'CCD plate'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.992
_diffrn_measurement_details
;
List of Runs (angles in degrees, time in seconds):

  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames
  1  \w    -31.00  54.00   0.50    0.20    --  -18.75  45.00 -30.00  170
  2  \w      8.00  35.00   0.50    0.20    --   38.00  93.00  57.22   54
  3  \w      4.00  35.00   0.50    0.20    --   34.00  93.00 117.01   62
  4  \w     27.00 122.00   0.50    0.20    --   50.00  78.00 140.63  190
  5  \w     81.00 167.00   0.50    0.40    --   94.00  49.00  97.72  172
  6  \w    104.00 171.00   0.50    0.40    --  107.11 109.00 124.00  134
  7  \w     91.00 171.00   0.50    0.40    --  107.11  61.00 120.00  160
  8  \w     91.00 171.00   0.50    0.40    --  107.11  61.00 -30.00  160
  9  \w     91.00 171.00   0.50    0.40    --  107.11  61.00  30.00  160
 10  \w     95.00 171.00   0.50    0.40    --  107.11  45.00   0.00  152
 11  \w     91.00 171.00   0.50    0.40    --  107.11  61.00 150.00  160
 12  \w     95.00 171.00   0.50    0.40    --  107.11 125.00  30.00  152
 13  \w     91.00 171.00   0.50    0.40    --  107.11  61.00 -60.00  160
 14  \w     90.00 171.00   0.50    0.40    --  107.11  63.00-140.79  162
 15  \w     91.00 171.00   0.50    0.40    --  107.11  61.00 -90.00  160
 16  \w     85.00 171.00   0.50    0.40    --  107.11  77.00  90.00  172
 17  \w     85.00 171.00   0.50    0.40    --  107.11  77.00 -60.00  172
 18  \w     85.00 171.00   0.50    0.40    --  107.11  77.00-180.00  172
 19  \w     85.00 171.00   0.50    0.40    --  107.11  77.00   0.00  172
 20  \w     85.00 171.00   0.50    0.40    --  107.11  77.00  30.00  172
 21  \w     85.00 171.00   0.50    0.40    --  107.11  77.00 120.00  172
 22  \w     64.00 154.00   0.50    0.40    --   82.00  66.00 113.84  180
 23  \w     71.00 159.00   0.50    0.40    --   86.00  57.00  85.17  176
 24  \w     68.00 159.00   0.50    0.40    --   86.00  67.00-106.51  182
 25  \w     66.00 159.00   0.50    0.40    --   86.00  72.00-166.24  186
 26  \w     71.00 159.00   0.50    0.40    --   86.00  57.00-125.37  176
 27  \w     64.00 159.00   0.50    0.40    --   86.00  76.00   2.34  190
 28  \w     74.00 162.00   0.50    0.40    --   90.00  61.00 -58.80  176
 29  \w     57.00 146.00   0.50    0.20    --   74.00  64.00-176.65  178
 30  \w     59.00 151.00   0.50    0.40    --   78.00  69.00 -52.42  184
 31  \w     62.00 154.00   0.50    0.40    --   82.00  72.00 -88.07  184
 32  \w     60.00 154.00   0.50    0.40    --   82.00  76.00 -70.45  188
 33  \w     61.00 154.00   0.50    0.40    --   82.00  73.00  52.23  186
 34  \w     48.00 143.00   0.50    0.20    --   70.00  75.00 100.33  190
 35  \w     51.00 143.00   0.50    0.20    --   70.00  68.00  74.46  184
 36  \w     48.00 143.00   0.50    0.20    --   70.00  75.00 175.91  190
 37  \w     36.00 131.00   0.50    0.20    --   58.00  77.00  74.11  190
 38  \w     53.00 146.00   0.50    0.20    --   74.00  74.00 -61.20  186
 39  \w     40.00 135.00   0.50    0.20    --   62.00  77.00 147.26  190
 40  \w     40.00 135.00   0.50    0.20    --   62.00  75.00  27.42  190
 41  \w     40.00 135.00   0.50    0.20    --   62.00  75.00 -62.85  190
 42  \w     44.00 139.00   0.50    0.20    --   66.00  76.00  46.67  190
 43  \w     44.00 139.00   0.50    0.20    --   66.00  76.00 123.93  190
 44  \w     44.00 139.00   0.50    0.20    --   66.00  75.00 172.98  190
 45  \w     44.00 139.00   0.50    0.20    --   66.00  75.00   1.82  190
 46  \w     47.00 143.00   0.50    0.20    --   70.00  78.00-105.75  192
 47  \w     39.00 135.00   0.50    0.20    --   62.00  79.00-140.31  192
 48  \w     43.00 139.00   0.50    0.20    --   66.00  78.00-108.91  192
 49  \w     34.00 131.00   0.50    0.20    --   58.00  80.00 -32.51  194
 50  \w     42.00 139.00   0.50    0.20    --   66.00  80.00 -25.55  194
 51  \w     35.00  68.00   0.50    0.40    --  107.11 -61.00   0.00   66
 52  \w     35.00 108.00   0.50    0.40    --  107.11-109.00  28.00  146
 53  \w     35.00  96.00   0.50    0.20    --   47.70-125.00 -60.00  122
 54  \w     35.00 112.00   0.50    0.40    --  107.11-125.00 -30.00  154
 55  \w     35.00 112.00   0.50    0.40    --  107.11-125.00-120.00  154
 56  \w     35.00 112.00   0.50    0.40    --  107.11-125.00 -90.00  154
 57  \w     35.00 106.00   0.50    0.40    --  107.11 -94.00 -30.00  142
 58  \w     23.00  87.00   0.50    0.20    --   47.70-109.00  28.00  128
 59  \w     35.00 106.00   0.50    0.40    --  107.11 -94.00 120.00  142
 60  \w     35.00 106.00   0.50    0.40    --  107.11 -94.00  90.00  142
 61  \w     35.00 102.00   0.50    0.40    --  107.11 -77.00 120.00  134
 62  \w     35.00  68.00   0.50    0.40    --  107.11 -61.00  30.00   66
 63  \w     35.00  68.00   0.50    0.40    --  107.11 -61.00  60.00   66
 64  \w     35.00  68.00   0.50    0.40    --  107.11 -61.00 150.00   66
 65  \w     -1.00  82.00   0.50    0.20    --   47.70 -99.00   0.00  166
 66  \w     17.00  43.00   0.50    0.20    --   42.00  83.00  15.12   52
 67  \w     10.00  43.00   0.50    0.20    --   38.00  90.00 -66.64   66
 68  \w     28.00 122.00   0.50    0.20    --   50.00  77.00-139.68  188
 69  \w     31.00 126.00   0.50    0.20    --   54.00  79.00-130.72  190
 70  \w     30.00 126.00   0.50    0.20    --   54.00  80.00 111.97  192
 71  \w     27.00 122.00   0.50    0.20    --   50.00  79.00 179.41  190
 72  \w     -5.00  29.00   0.50    0.20    --   26.00  96.00 -33.82   68
 73  \w    -57.00   0.00   0.50    0.20    --  -18.75 109.00 124.00  114
 74  \w    -90.00  -3.00   0.50    0.20    --  -18.75 -57.00-150.00  174
 75  \w    -90.00  -2.00   0.50    0.20    --  -18.75 -61.00  30.00  176
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.0330798000
_diffrn_orient_matrix_UB_12      -0.0242020000
_diffrn_orient_matrix_UB_13      -0.1476781000
_diffrn_orient_matrix_UB_21      -0.0472268000
_diffrn_orient_matrix_UB_22      -0.1015539000
_diffrn_orient_matrix_UB_23      0.0261567000
_diffrn_orient_matrix_UB_31      -0.1682360000
_diffrn_orient_matrix_UB_32      0.0237219000
_diffrn_orient_matrix_UB_33      -0.0386779000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0300
_diffrn_reflns_av_unetI/netI     0.0133
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.992
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -10
_diffrn_reflns_limit_k_max       18
_diffrn_reflns_limit_k_min       -17
_diffrn_reflns_limit_l_max       12
_diffrn_reflns_limit_l_min       -12
_diffrn_reflns_number            53002
_diffrn_reflns_point_group_measured_fraction_full 0.998
_diffrn_reflns_point_group_measured_fraction_max 0.972
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         76.972
_diffrn_reflns_theta_min         4.445
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    2.824
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.54013
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.40.45a (Rigaku Oxford Diffraction, 2019)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            'clear colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.472
_exptl_crystal_description       irregular
_exptl_crystal_F_000             576
_exptl_crystal_size_max          0.2
_exptl_crystal_size_mid          0.1
_exptl_crystal_size_min          0.05
_refine_diff_density_max         0.153
_refine_diff_density_min         -0.192
_refine_diff_density_rms         0.045
_refine_ls_abs_structure_details
;
 Flack x determined using 2249 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.004(3)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.069
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     350
_refine_ls_number_reflns         5090
_refine_ls_number_restraints     7
_refine_ls_restrained_S_all      1.071
_refine_ls_R_factor_all          0.0258
_refine_ls_R_factor_gt           0.0242
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0305P)^2^+0.2736P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0589
_refine_ls_wR_factor_ref         0.0604
_reflns_Friedel_coverage         0.883
_reflns_Friedel_fraction_full    0.995
_reflns_Friedel_fraction_max     0.951
_reflns_number_gt                4976
_reflns_number_total             5090
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d0md00085j3.cif
_cod_data_source_block           19JLR010_MP303A1
_cod_original_cell_volume        1239.982(9)
_cod_database_code               7240594
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         'C40 H40 N8 O8 Cl8 '
_shelx_estimated_absorpt_t_max   0.872
_shelx_estimated_absorpt_t_min   0.602
_reflns_odcompleteness_completeness 100.00
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     66.97
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups
2. Restrained distances
 O14-H14
 0.82 with sigma of 0.001
 H33B-H33A
 1.44 with sigma of 0.02
 H34B-H34A
 1.44 with sigma of 0.02
 O33-H33B
 0.95 with sigma of 0.02
 H34B-O34
 0.95 with sigma of 0.02
 H33B-H14 \\sim H14-H33A
 with sigma of 0.02
3.a Secondary CH2 refined with riding coordinates:
 C15(H15A,H15B), C31(H31A,H31B)
3.b Aromatic/amide H refined with riding coordinates:
 N27(H27), N11(H11), N4(H4), N19(H19), C25(H25), C9(H9), C2(H2), C17(H17)
3.c Idealised Me refined as rotating group:
 C32(H32A,H32B,H32C), C16(H16A,H16B,H16C), C13(H13A,H13B,H13C), C29(H29A,H29B,
 H29C)
3.d Idealised tetrahedral OH refined as rotating group:
 O30(H30)
;
_shelx_res_checksum              8732
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 1.640
_oxdiff_exptl_absorpt_empirical_full_min 0.815