Investigation of the effect of the N-oxidation process on the inter­action of selected pyridine compounds with biomacromolecules: structural, spectral, theoretical and docking studies

Hakimi, M.; Sadeghi, F.; Feizi, N.; Moeini, K.; Kučeráková, M.; Dušek, M.

doi:10.1107/S2053229619006375

Investigation of the effect of the N-oxidation process on the interaction of selected pyridine compounds with biomacromolecules: structural, spectral, theoretical and docking studies

M. Hakimi, F. Sadeghi, N. Feizi, K. Moeini, M. Kučeráková and M. Dušek

Two new N-oxide compounds, namely glycinium 2-carboxy-1-(λ¹-oxidaneyl)-1λ⁴-pyridine-6-carboxylate–glycine–water (1/1/1), C₂H₆NO₂⁺·C₇H₄NO₅⁻·C₂H₅NO₂·H₂O or [(2,6-HpydcO)(HGLY)(GLY)(H₂O)], 1, and methyl 6-carboxy-1-(λ¹-oxidaneyl)-1λ⁴-pyridine-2-carboxylate, C₈H₇NO₅ or 2,6-HMepydcO, 2, were prepared and identified by elemental analysis, FT–IR, Raman spectroscopy and single-crystal X-ray diffraction. The X-ray analysis of 1 revealed an ionic compound containing a 2,6-HpydcO⁻ anion, a glycinium cation, a neutral glycine molecule and a water molecule. Compound 2 is a neutral compound with two independent units in its crystal structure. In addition to the hydrogen bonds, the crystal network is stabilized by π–π stacking interactions of the types pyridine–carboxylate and carboxylate–carboxylate. The thermodynamic stability and charge-distribution patterns for isolated molecules of 2,6-H₂pydcO and 2,6-HMepydcO, and their two similar derivatives, pyridine-2,6-dicarboxylic acid (2,6-H₂pydc) and dimethyl 1-(λ¹-oxidaneyl)-1λ⁴-pyridine-2,6-dicarboxylate (2,6-Me₂pydcO), were studied by density functional theory (DFT) and natural bond orbital (NBO) analysis, respectively. The ability of these compounds and their analogues to interact with nine selected biomacromolecules (BRAF kinase, CatB, DNA gyrase, HDAC7, rHA, RNR, TrxR, TS and Top II) was investigated using docking calculations.

Keywords: pyridine dicarboxylate; N-oxide; DFT calculations; docking studies; crystal structure; X-ray analysis.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229619006375/jx3030sup1.cif Contains datablocks global, 1, 1_1, 1_2, 1_3
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229619006375/jx30301sup2.hkl Contains datablock 1
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229619006375/jx30302sup3.hkl Contains datablock 2

CCDC references: 1878768; 1878767

Computing details top

For both structures, data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SUPERFLIP (Palatinus & Chapuis, 2007); program(s) used to refine structure: JANA2006 (Petříček et al., 2014); molecular graphics: DIAMOND (Brandenburg & Putz, 2005); software used to prepare material for publication: JANA2006 (Petříček et al., 2014).

Glycinium 2-carboxy-1-(λ¹-oxidaneyl)-1λ⁴-pyridine-6-carboxylate–glycine–water (1/1/1) (1) top

Crystal data top

C₂H₆NO₂⁺·C₇H₄NO₅⁻·C₂H₅NO₂·H₂O	F(000) = 736
M_r = 351.2	D_x = 1.594 Mg m⁻³
Orthorhombic, Pca2₁	Cu Kα radiation, λ = 1.54184 Å
Hall symbol: P 2c -2ac	Cell parameters from 6609 reflections
a = 10.9307 (3) Å	θ = 4.2–74.2°
b = 10.4069 (4) Å	µ = 1.25 mm⁻¹
c = 12.8686 (4) Å	T = 95 K
V = 1463.86 (8) Å³	Polygonal shape, colourless
Z = 4	0.49 × 0.06 × 0.03 × 0.06 (radius) mm

Data collection top

Rigaku OD SuperNova Dual source diffractometer with an AtlasS2 detector	2482 independent reflections
Radiation source: X-ray tube	2432 reflections with I > 3σ(I)
Mirror monochromator	R_int = 0.020
Detector resolution: 5.2027 pixels mm^-1	θ_max = 74.5°, θ_min = 4.3°
ω scans	h = −13→12
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2018)	k = −12→12
T_min = 0.736, T_max = 1	l = −15→12
8004 measured reflections

Refinement top

Refinement on F²	H atoms treated by a mixture of independent and constrained refinement
R[F > 3σ(F)] = 0.025	Weighting scheme based on measured s.u.'s w = 1/(σ²(I) + 0.0016I²)
wR(F) = 0.080	(Δ/σ)_max = 0.004
S = 1.65	Δρ_max = 0.19 e Å⁻³
2482 reflections	Δρ_min = −0.16 e Å⁻³
230 parameters	Extinction correction: B-C type 1 Gaussian isotropic (Becker & Coppens, 1974)
3 restraints	Extinction coefficient: 1200 (200)
57 constraints	Absolute structure: 925 of Friedel pairs used in the refinement

Special details top

Refinement. The refinement was carried out against all reflections. The conventional R-factor is always based on F. The goodness of fit as well as the weighted R-factor are based on F and F² for refinement carried out on F and F², respectively. The threshold expression is used only for calculating R-factors etc. and it is not relevant to the choice of reflections for refinement.

The program used for refinement, Jana2006, uses the weighting scheme based on the experimental expectations, see _refine_ls_weighting_details, that does not force S to be one. Therefore the values of S are usually larger than the ones from the SHELX program.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.20407 (12)	0.10762 (10)	0.01347 (11)	0.0197 (3)
O2	0.77050 (10)	0.37972 (10)	0.13865 (10)	0.0137 (3)
O3	0.40294 (10)	−0.12662 (10)	−0.07686 (10)	0.0148 (3)
O4	0.02520 (9)	0.21107 (10)	0.17074 (10)	0.0152 (3)
O5	0.35303 (11)	−0.50934 (11)	−0.07973 (11)	0.0187 (3)
O6	−0.17205 (9)	0.15411 (10)	0.16340 (10)	0.0154 (3)
O7	0.33622 (11)	0.32755 (13)	0.24976 (11)	0.0233 (4)
O8	0.59044 (10)	0.30478 (10)	0.19672 (10)	0.0158 (3)
O9	0.48123 (10)	−0.34364 (11)	−0.06606 (10)	0.0165 (3)
O10	0.26647 (11)	0.10554 (10)	−0.15284 (10)	0.0163 (3)
N1	0.28764 (10)	−0.17250 (12)	−0.08201 (11)	0.0108 (3)
N2	0.10677 (11)	−0.02976 (12)	0.18420 (11)	0.0127 (3)
N3	0.68827 (11)	0.61109 (11)	0.08930 (11)	0.0131 (4)
C1	0.37227 (15)	−0.39423 (15)	−0.07919 (13)	0.0136 (4)
C2	0.22655 (12)	0.05559 (14)	−0.07094 (14)	0.0123 (4)
C3	0.19476 (13)	−0.08761 (14)	−0.07802 (13)	0.0110 (4)
C4	−0.05550 (13)	0.13130 (14)	0.16902 (13)	0.0113 (4)
C5	0.65682 (14)	0.39050 (13)	0.15903 (12)	0.0113 (4)
C6	0.26737 (13)	−0.30155 (14)	−0.08985 (12)	0.0109 (4)
C7	0.07547 (14)	−0.13133 (14)	−0.08257 (13)	0.0132 (4)
C8	0.05009 (14)	−0.26118 (15)	−0.09625 (12)	0.0143 (4)
C9	0.59873 (13)	0.51869 (14)	0.13372 (13)	0.0138 (4)
C10	−0.02688 (12)	−0.01116 (13)	0.17693 (13)	0.0113 (4)
C11	0.14828 (16)	−0.34626 (14)	−0.09984 (12)	0.0146 (4)
H1	0.304 (2)	0.2570 (18)	0.286 (2)	0.0279*
H2	0.4208 (12)	0.316 (2)	0.245 (2)	0.0279*
H1o9	0.463 (2)	−0.2560 (13)	−0.069 (2)	0.0198*
H1n3	0.650488	0.681111	0.07101	0.0158*
H2n3	0.743505	0.629239	0.13571	0.0158*
H3n3	0.723226	0.577016	0.035172	0.0158*
H1n2	0.123128	−0.111542	0.186117	0.0152*
H2n2	0.141987	0.004565	0.130303	0.0152*
H3n2	0.133944	0.006733	0.240478	0.0152*
H1c7	0.009245	−0.071258	−0.076184	0.0159*
H1c8	−0.032565	−0.291212	−0.103019	0.0172*
H1c9	0.53288	0.506055	0.085428	0.0165*
H2c9	0.563273	0.55449	0.195522	0.0165*
H1c10	−0.065464	−0.046048	0.237715	0.0135*
H2c10	−0.057381	−0.054555	0.116404	0.0135*
H1c11	0.133539	−0.436444	−0.109288	0.0175*
H1o6	−0.1919 (19)	0.2412 (13)	0.1577 (19)	0.0185*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0297 (6)	0.0130 (5)	0.0163 (6)	−0.0019 (4)	0.0065 (5)	−0.0021 (5)
O2	0.0095 (5)	0.0124 (5)	0.0192 (6)	0.0018 (4)	0.0016 (4)	0.0023 (4)
O3	0.0098 (5)	0.0135 (5)	0.0212 (6)	−0.0029 (4)	−0.0011 (5)	0.0010 (5)
O4	0.0129 (5)	0.0106 (5)	0.0221 (6)	−0.0019 (4)	0.0025 (4)	0.0004 (5)
O5	0.0212 (5)	0.0129 (5)	0.0219 (6)	0.0033 (4)	0.0030 (5)	0.0008 (5)
O6	0.0105 (5)	0.0113 (5)	0.0244 (6)	0.0019 (4)	−0.0007 (4)	0.0016 (4)
O7	0.0176 (5)	0.0245 (6)	0.0276 (7)	0.0009 (5)	−0.0028 (5)	0.0086 (5)
O8	0.0152 (5)	0.0116 (4)	0.0208 (6)	0.0008 (4)	0.0023 (4)	0.0019 (4)
O9	0.0142 (5)	0.0151 (5)	0.0200 (6)	0.0036 (4)	−0.0014 (4)	0.0014 (4)
O10	0.0213 (5)	0.0112 (5)	0.0164 (6)	−0.0003 (4)	0.0043 (5)	0.0019 (4)
N1	0.0101 (6)	0.0115 (6)	0.0107 (6)	−0.0010 (4)	0.0005 (5)	0.0004 (5)
N2	0.0153 (6)	0.0093 (5)	0.0134 (6)	0.0021 (4)	0.0003 (5)	0.0004 (5)
N3	0.0126 (6)	0.0103 (6)	0.0165 (7)	0.0021 (5)	−0.0002 (5)	0.0010 (5)
C1	0.0159 (6)	0.0147 (7)	0.0103 (7)	0.0035 (5)	0.0023 (6)	0.0025 (6)
C2	0.0134 (6)	0.0093 (6)	0.0143 (7)	0.0014 (5)	0.0008 (6)	0.0004 (6)
C3	0.0116 (6)	0.0108 (6)	0.0105 (7)	−0.0012 (5)	0.0012 (5)	0.0019 (6)
C4	0.0119 (6)	0.0113 (6)	0.0108 (7)	0.0013 (5)	0.0010 (6)	0.0013 (5)
C5	0.0128 (6)	0.0113 (7)	0.0099 (7)	0.0012 (5)	−0.0014 (5)	−0.0011 (6)
C6	0.0105 (6)	0.0105 (7)	0.0117 (8)	0.0000 (5)	0.0008 (5)	0.0004 (6)
C7	0.0149 (7)	0.0130 (7)	0.0118 (7)	0.0010 (5)	−0.0002 (6)	−0.0004 (6)
C8	0.0131 (6)	0.0152 (7)	0.0147 (8)	−0.0024 (6)	−0.0004 (5)	0.0023 (6)
C9	0.0107 (6)	0.0111 (7)	0.0195 (8)	0.0009 (5)	0.0020 (6)	0.0029 (6)
C10	0.0086 (7)	0.0099 (6)	0.0153 (7)	−0.0001 (5)	0.0017 (6)	0.0001 (6)
C11	0.0215 (8)	0.0101 (7)	0.0121 (8)	−0.0016 (6)	−0.0009 (6)	0.0019 (5)

Geometric parameters (Å, º) top

O1—C2	1.238 (2)	N3—H1n3	0.87
O2—C5	1.2749 (18)	N3—H2n3	0.87
O4—C4	1.2116 (18)	N3—H3n3	0.87
O5—C1	1.2164 (19)	C1—C6	1.505 (2)
O6—C4	1.2979 (18)	C2—C3	1.533 (2)
O6—H1o6	0.935 (14)	C3—C7	1.382 (2)
O7—H1	0.93 (2)	C4—C10	1.519 (2)
O7—H2	0.934 (13)	C5—C9	1.513 (2)
O8—C5	1.2481 (18)	C6—C11	1.388 (2)
O9—C1	1.3131 (19)	C7—C8	1.391 (2)
O9—H1o9	0.935 (14)	C7—H1c7	0.96
O10—C2	1.254 (2)	C8—C11	1.392 (2)
N1—C3	1.3467 (19)	C8—H1c8	0.96
N1—C6	1.3649 (19)	C9—H1c9	0.96
N2—C10	1.4767 (18)	C9—H2c9	0.96
N2—H1n2	0.87	C10—H1c10	0.96
N2—H2n2	0.87	C10—H2c10	0.96
N2—H3n2	0.87	C11—H1c11	0.96
N3—C9	1.4864 (19)

C4—O6—H1o6	114.2 (12)	O2—C5—O8	125.71 (13)
H1—O7—H2	108 (2)	O2—C5—C9	116.25 (12)
C1—O9—H1o9	101.0 (13)	O8—C5—C9	118.03 (13)
C3—N1—C6	121.73 (12)	N1—C6—C1	120.02 (13)
C10—N2—H1n2	109.47	N1—C6—C11	119.26 (13)
C10—N2—H2n2	109.47	C1—C6—C11	120.54 (13)
C10—N2—H3n2	109.47	C3—C7—C8	120.89 (14)
H1n2—N2—H2n2	109.47	C3—C7—H1c7	119.56
H1n2—N2—H3n2	109.47	C8—C7—H1c7	119.56
H2n2—N2—H3n2	109.47	C7—C8—C11	117.94 (14)
C9—N3—H1n3	109.47	C7—C8—H1c8	121.03
C9—N3—H2n3	109.47	C11—C8—H1c8	121.03
C9—N3—H3n3	109.47	N3—C9—C5	112.14 (12)
H1n3—N3—H2n3	109.47	N3—C9—H1c9	109.47
H1n3—N3—H3n3	109.47	N3—C9—H2c9	109.47
H2n3—N3—H3n3	109.47	C5—C9—H1c9	109.47
O5—C1—O9	123.53 (15)	C5—C9—H2c9	109.47
O5—C1—C6	119.94 (14)	H1c9—C9—H2c9	106.66
O9—C1—C6	116.49 (13)	N2—C10—C4	109.63 (11)
O1—C2—O10	128.70 (14)	N2—C10—H1c10	109.47
O1—C2—C3	115.61 (14)	N2—C10—H2c10	109.47
O10—C2—C3	115.59 (14)	C4—C10—H1c10	109.47
N1—C3—C2	117.98 (12)	C4—C10—H2c10	109.47
N1—C3—C7	119.58 (13)	H1c10—C10—H2c10	109.31
C2—C3—C7	122.44 (13)	C6—C11—C8	120.44 (14)
O4—C4—O6	126.18 (14)	C6—C11—H1c11	119.78
O4—C4—C10	121.18 (13)	C8—C11—H1c11	119.78
O6—C4—C10	112.61 (12)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O7—H1···O10ⁱ	0.93 (2)	1.93 (2)	2.8582 (17)	175 (2)
O7—H2···O8	0.934 (13)	1.958 (15)	2.8712 (16)	165 (3)
O9—H1o9···O3	0.935 (14)	1.500 (15)	2.4192 (15)	167 (2)
O9—H1o9···N1	0.935 (14)	2.11 (2)	2.7735 (16)	127.0 (16)
N3—H1n3···O1ⁱⁱ	0.87	2.39	3.0905 (16)	137.48
N3—H1n3···O4ⁱⁱ	0.87	2.19	2.7750 (16)	124.63
N3—H2n3···O7ⁱⁱ	0.87	1.84	2.6994 (19)	169.48
N3—H3n3···O5ⁱⁱⁱ	0.87	2.17	3.0160 (18)	165.09
N2—H1n2···O6ⁱⁱⁱ	0.87	2.30	2.7553 (16)	112.63
N2—H1n2···O8^iv	0.87	2.05	2.8721 (16)	157.98
N2—H2n2···O1	0.87	1.97	2.8289 (19)	170.28
N2—H3n2···O10ⁱ	0.87	2.03	2.8810 (18)	165.11
C7—H1c7···O3^iv	0.96	2.36	3.2815 (19)	159.62
C8—H1c8···O5^v	0.96	2.44	3.2231 (19)	138.39
O6—H1o6···O2^vi	0.935 (14)	1.519 (14)	2.4512 (15)	175 (2)
O6—H1o6···C5^vi	0.935 (14)	2.269 (18)	3.0910 (17)	146.3 (17)

Symmetry codes: (i) −x+1/2, y, z+1/2; (ii) x+1/2, −y+1, z; (iii) x+1/2, −y, z; (iv) x−1/2, −y, z; (v) x−1/2, −y−1, z; (vi) x−1, y, z.

Methyl 6-carboxy-1-(λ¹-oxidaneyl)-1λ⁴-pyridine-2-carboxylate (1_1) top

Crystal data top

C₈H₇NO₅	F(000) = 816
M_r = 197.15	D_x = 1.619 Mg m⁻³
Monoclinic, P2₁/n	Cu Kα radiation, λ = 1.54184 Å
Hall symbol: -P 2yn	Cell parameters from 901 reflections
a = 7.3758 (8) Å	θ = 7.2–71.7°
b = 11.7446 (10) Å	µ = 1.20 mm⁻¹
c = 18.9211 (17) Å	T = 95 K
β = 99.328 (8)°	Polygon shape, white
V = 1617.4 (3) Å³	0.08 × 0.03 × 0.02 mm
Z = 8

Data collection top

Rigaku OD SuperNova Dual source diffractometer with an AtlasS2 detector	4549 independent reflections
Radiation source: X-ray tube	1931 reflections with I > 3σ(I)
Mirror monochromator	R_int = 0
Detector resolution: 5.2027 pixels mm^-1	θ_max = 74.4°, θ_min = 6.1°
ω scans	h = −9→8
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2018)	k = −14→14
T_min = 0.974, T_max = 1	l = −23→23
4549 measured reflections

Refinement top

Refinement on F²	50 constraints
R[F > 3σ(F)] = 0.040	H atoms treated by a mixture of independent and constrained refinement
wR(F) = 0.062	Weighting scheme based on measured s.u.'s w = 1/(σ²(I) + 0.000016I²)
S = 1.02	(Δ/σ)_max = 0.004
4549 reflections	Δρ_max = 0.28 e Å⁻³
260 parameters	Δρ_min = −0.25 e Å⁻³
1 restraint

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.3114 (3)	0.27930 (16)	0.00008 (11)	0.0207 (8)
O2	−0.1809 (3)	0.3197 (2)	−0.21714 (13)	0.0283 (9)
O3	0.6339 (3)	0.88713 (18)	0.20312 (12)	0.0231 (8)
O4	0.7857 (3)	0.75471 (19)	0.27406 (11)	0.0263 (8)
O5	0.4132 (3)	0.82622 (16)	0.10106 (12)	0.0219 (8)
O6	0.3106 (3)	0.10620 (17)	0.05051 (12)	0.0244 (8)
O7	−0.2756 (3)	0.1632 (2)	−0.27922 (13)	0.0355 (9)
O8	0.1663 (3)	0.57316 (18)	−0.02712 (11)	0.0235 (8)
O9	0.2014 (3)	0.76235 (18)	−0.01753 (12)	0.0308 (9)
O10	0.0292 (3)	0.30052 (15)	−0.10587 (13)	0.0258 (9)
N1	0.4579 (4)	0.71601 (18)	0.11373 (14)	0.0144 (9)
N2	0.0331 (4)	0.18752 (19)	−0.11308 (15)	0.0188 (9)
C1	0.6324 (4)	0.5774 (3)	0.18552 (16)	0.0201 (11)
C2	0.5499 (4)	0.4914 (3)	0.14217 (17)	0.0214 (11)
C3	0.1381 (4)	0.0062 (2)	−0.06910 (17)	0.0208 (12)
C4	0.5855 (4)	0.6893 (2)	0.17203 (17)	0.0162 (10)
C5	0.2615 (5)	0.1820 (3)	−0.00161 (17)	0.0196 (11)
C6	0.6762 (5)	0.7804 (3)	0.22125 (19)	0.0222 (12)
C7	0.1396 (4)	0.1230 (2)	−0.06249 (17)	0.0154 (11)
C8	−0.0705 (4)	0.1367 (3)	−0.17122 (17)	0.0180 (11)
C9	−0.1869 (5)	0.2091 (3)	−0.2282 (2)	0.0273 (13)
C10	0.2393 (5)	0.6685 (3)	0.00369 (17)	0.0194 (11)
C11	0.3755 (4)	0.6352 (2)	0.06885 (17)	0.0139 (10)
C12	0.0316 (4)	0.5923 (2)	−0.09234 (16)	0.0266 (11)
C13	0.4194 (4)	0.5222 (2)	0.08253 (17)	0.0170 (11)
C14	−0.0712 (5)	0.0213 (2)	−0.17781 (17)	0.0222 (11)
C15	0.0325 (4)	−0.0469 (2)	−0.12710 (16)	0.0231 (12)
C16	0.4371 (5)	0.1496 (2)	0.11261 (18)	0.0280 (12)
H1c1	0.724337	0.558646	0.225807	0.0241*
H1c2	0.580451	0.413055	0.15238	0.0257*
H1c3	0.211264	−0.0391	−0.033002	0.025*
H1c12	−0.0154	0.520353	−0.111294	0.0319*
H2c12	−0.067626	0.637985	−0.080982	0.0319*
H3c12	0.089978	0.63088	−0.127326	0.0319*
H1c13	0.360522	0.464209	0.051132	0.0204*
H1c14	−0.14532	−0.013414	−0.218513	0.0267*
H1c15	0.031586	−0.128257	−0.131876	0.0277*
H1c16	0.481036	0.087424	0.143648	0.0336*
H2c16	0.539129	0.186608	0.096573	0.0336*
H3c16	0.373758	0.20315	0.138208	0.0336*
H1o3	0.540 (3)	0.884 (2)	0.1651 (14)	0.0277*
H1o2	−0.093 (4)	0.341 (3)	−0.1795 (15)	0.034*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0254 (14)	0.0121 (12)	0.0242 (13)	−0.0018 (10)	0.0027 (10)	−0.0017 (9)
O2	0.0272 (16)	0.0325 (15)	0.0247 (14)	0.0106 (13)	0.0026 (11)	0.0076 (11)
O3	0.0187 (15)	0.0212 (13)	0.0268 (14)	−0.0056 (11)	−0.0037 (11)	−0.0040 (10)
O4	0.0236 (13)	0.0290 (14)	0.0229 (13)	0.0008 (12)	−0.0065 (10)	−0.0007 (11)
O5	0.0272 (15)	0.0098 (11)	0.0262 (14)	−0.0009 (10)	−0.0026 (11)	−0.0035 (9)
O6	0.0305 (15)	0.0216 (13)	0.0183 (12)	−0.0041 (11)	−0.0041 (10)	0.0020 (9)
O7	0.0264 (16)	0.0546 (17)	0.0219 (14)	−0.0045 (14)	−0.0066 (12)	0.0055 (13)
O8	0.0256 (14)	0.0171 (11)	0.0241 (13)	0.0030 (11)	−0.0068 (10)	−0.0031 (10)
O9	0.0422 (17)	0.0163 (12)	0.0286 (14)	−0.0042 (12)	−0.0100 (12)	0.0088 (11)
O10	0.0360 (17)	0.0123 (12)	0.0278 (15)	0.0059 (11)	0.0017 (12)	0.0014 (9)
N1	0.0174 (16)	0.0104 (13)	0.0156 (14)	−0.0006 (12)	0.0031 (12)	0.0002 (10)
N2	0.0195 (17)	0.0167 (14)	0.0216 (15)	−0.0006 (13)	0.0074 (12)	0.0003 (11)
C1	0.0171 (19)	0.0266 (18)	0.0157 (17)	0.0024 (17)	0.0003 (13)	0.0039 (15)
C2	0.020 (2)	0.0226 (18)	0.0231 (17)	0.0043 (16)	0.0063 (14)	0.0057 (14)
C3	0.022 (2)	0.024 (2)	0.0163 (18)	−0.0008 (16)	0.0047 (14)	0.0014 (14)
C4	0.0165 (18)	0.0184 (16)	0.0155 (17)	−0.0043 (15)	0.0074 (14)	0.0011 (13)
C5	0.021 (2)	0.0224 (19)	0.0172 (17)	0.0023 (16)	0.0071 (14)	0.0027 (14)
C6	0.021 (2)	0.0226 (19)	0.025 (2)	−0.0049 (16)	0.0098 (16)	−0.0051 (15)
C7	0.016 (2)	0.0159 (17)	0.0143 (17)	0.0013 (15)	0.0017 (14)	−0.0006 (13)
C8	0.017 (2)	0.0240 (18)	0.0133 (17)	0.0017 (15)	0.0025 (14)	0.0031 (14)
C9	0.020 (2)	0.038 (2)	0.026 (2)	0.0080 (18)	0.0108 (16)	0.0090 (16)
C10	0.018 (2)	0.0233 (19)	0.0172 (18)	−0.0011 (15)	0.0049 (14)	−0.0035 (14)
C11	0.0104 (19)	0.0146 (16)	0.0175 (17)	−0.0006 (13)	0.0049 (14)	−0.0004 (12)
C12	0.026 (2)	0.0299 (19)	0.0196 (18)	0.0028 (17)	−0.0092 (15)	−0.0077 (14)
C13	0.018 (2)	0.0153 (16)	0.0172 (17)	−0.0019 (14)	0.0007 (14)	−0.0019 (13)
C14	0.023 (2)	0.0296 (19)	0.0151 (17)	−0.0078 (17)	0.0075 (15)	−0.0036 (14)
C15	0.032 (2)	0.0138 (17)	0.026 (2)	−0.0065 (16)	0.0123 (16)	−0.0048 (13)
C16	0.027 (2)	0.037 (2)	0.0168 (18)	−0.0055 (18)	−0.0061 (16)	−0.0012 (16)

Geometric parameters (Å, º) top

O1—C5	1.200 (4)	C2—H1c2	0.96
O2—C9	1.316 (4)	C3—C7	1.377 (4)
O2—H1o2	0.92 (3)	C3—C15	1.387 (4)
O3—C6	1.324 (4)	C3—H1c3	0.96
O3—H1o3	0.92 (2)	C4—C6	1.503 (4)
O4—C6	1.216 (4)	C5—C7	1.510 (4)
O6—C5	1.334 (4)	C8—C9	1.524 (5)
O6—C16	1.468 (4)	C8—C14	1.361 (4)
O7—C9	1.203 (4)	C10—C11	1.511 (4)
O8—C10	1.335 (4)	C11—C13	1.380 (4)
O8—C12	1.470 (3)	C12—H1c12	0.96
O9—C10	1.190 (4)	C12—H2c12	0.96
N1—C4	1.365 (4)	C12—H3c12	0.96
N1—C11	1.351 (4)	C13—H1c13	0.96
N2—C7	1.365 (4)	C14—C15	1.382 (4)
N2—C8	1.370 (4)	C14—H1c14	0.96
C1—C2	1.379 (4)	C15—H1c15	0.96
C1—C4	1.373 (4)	C16—H1c16	0.96
C1—H1c1	0.96	C16—H2c16	0.96
C2—C13	1.406 (4)	C16—H3c16	0.96

C9—O2—H1o2	113.4 (19)	O2—C9—O7	124.8 (3)
C6—O3—H1o3	106.4 (18)	O2—C9—C8	116.0 (3)
C5—O6—C16	114.9 (2)	O7—C9—C8	119.2 (3)
C10—O8—C12	114.1 (2)	O8—C10—O9	125.0 (3)
C4—N1—C11	121.8 (2)	O8—C10—C11	107.8 (2)
C7—N2—C8	120.2 (2)	O9—C10—C11	127.2 (3)
C2—C1—C4	121.1 (3)	N1—C11—C10	120.2 (3)
C2—C1—H1c1	119.45	N1—C11—C13	119.3 (3)
C4—C1—H1c1	119.45	C10—C11—C13	120.5 (3)
C1—C2—C13	117.9 (3)	O8—C12—H1c12	109.47
C1—C2—H1c2	121.04	O8—C12—H2c12	109.47
C13—C2—H1c2	121.04	O8—C12—H3c12	109.47
C7—C3—C15	121.0 (3)	H1c12—C12—H2c12	109.47
C7—C3—H1c3	119.5	H1c12—C12—H3c12	109.47
C15—C3—H1c3	119.5	H2c12—C12—H3c12	109.47
N1—C4—C1	119.4 (3)	C2—C13—C11	120.4 (3)
N1—C4—C6	121.1 (2)	C2—C13—H1c13	119.79
C1—C4—C6	119.5 (3)	C11—C13—H1c13	119.79
O1—C5—O6	124.8 (3)	C8—C14—C15	121.3 (3)
O1—C5—C7	126.9 (3)	C8—C14—H1c14	119.34
O6—C5—C7	108.3 (3)	C15—C14—H1c14	119.34
O3—C6—O4	123.0 (3)	C3—C15—C14	117.8 (3)
O3—C6—C4	116.8 (3)	C3—C15—H1c15	121.12
O4—C6—C4	120.1 (3)	C14—C15—H1c15	121.12
N2—C7—C3	119.6 (3)	O6—C16—H1c16	109.47
N2—C7—C5	118.9 (3)	O6—C16—H2c16	109.47
C3—C7—C5	121.4 (3)	O6—C16—H3c16	109.47
N2—C8—C9	120.1 (3)	H1c16—C16—H2c16	109.47
N2—C8—C14	120.1 (3)	H1c16—C16—H3c16	109.47
C9—C8—C14	119.8 (3)	H2c16—C16—H3c16	109.47

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C1—H1c1···O4	0.96	2.49	2.794 (4)	98.17
C2—H1c2···O4ⁱ	0.96	2.43	3.330 (4)	155.24
C3—H1c3···O6	0.96	2.36	2.681 (4)	98.80
C3—H1c3···O9ⁱⁱ	0.96	2.35	3.037 (4)	127.80
C13—H1c13···O1	0.96	2.38	3.287 (3)	157.20
C13—H1c13···O8	0.96	2.28	2.626 (3)	100.24
C14—H1c14···O7	0.96	2.49	2.792 (4)	98.24
O3—H1o3···O5	0.92 (2)	1.56 (2)	2.423 (3)	155 (3)
O3—H1o3···N1	0.92 (2)	2.24 (3)	2.806 (3)	120 (2)
O2—H1o2···O10	0.92 (3)	1.60 (3)	2.414 (3)	145 (3)
O2—H1o2···N2	0.92 (3)	2.31 (3)	2.788 (3)	112 (2)

Symmetry codes: (i) −x+3/2, y−1/2, −z+1/2; (ii) x, y−1, z.

Selected bond lengths (Å) and angles (°) for compounds 1 and 2 top

Bond lengths (Å)		Bond angles (°)
1
C1—O5	1.216 (2)	C1—C6—N1	120.0 (1)
C1—O9	1.313 (2)	C3—C2—O10	115.6 (1)
C2—O1	1.238 (2)	C4—C10—N2	109.6 (1)
C2—O10	1.254 (2)	C6—N1—O3	120.2 (1)
C4—O4	1.212 (2)	C10—C4—O4	121.2 (1)
C4—O6	1.298 (2)	O1—C2—O10	128.7 (1)
C5—O8	1.248 (2)	O2—C5—O8	125.7 (1)
C5—O2	1.275 (2)	O2—C5—C9	116.3 (1)
N1—O3	1.349 (2)	O4—C4—O6	126.2 (1)

2
C5—O1	1.199 (4)	C7—N2—O10	120.0 (2)
C5—O6	1.334 (4)	C12—O8—C10	114.1 (2)
C6—O4	1.217 (4)	O1—C5—O6	124.8 (3)
C10—O8	1.335 (4)	O2—C9—O7	124.8 (3)
C10—O9	1.191 (4)	O3—C6—C4	116.8 (3)
O2—C9	1.315 (4)	O4—C6—O3	123.0 (3)
O3—C6	1.323 (4)	O5—N1—C4	118.8 (2)
O5—N1	1.348 (3)	O5—N1—C11	119.4 (2)
O7—C9	1.202 (4)	O9—C10—O8	125.0 (3)
O10—N2	1.335 (3)	O9—C10—C11	127.1 (3)

Selected hydrogen-bond dimensions (Å, °) in compounds 1 and 2 top

D—H···A	D—H	H···A	D—H···A	D···A
1
O9—H1o9···O3	0.935	1.500	167	2.419 (2)
C8—H1c8···O5ⁱ	0.96	2.44	138.4	3.223 (2)
C7—H1c7···O3ⁱⁱ	0.96	2.36	159.6	3.282 (2)
O6—H1o6···O2ⁱⁱⁱ	0.935	1.519	175	2.451 (1)

N2—H3n2···O10^iv	0.87	2.03	165.11	2.881 (2)
N2—H1n2···O8ⁱⁱ	0.870	2.05	157.98	2.872 (2)

N2—H2n2···O1	0.87	1.97	170.28	2.829 (2)
O7—H1···O10^iv	0.93	1.93	175	2.859 (2)
O7—H2···O8	0.934	1.958	165	2.871 (2)

2
C2—H1c2···O4^v	0.96	2.43	155.24	3.330 (4)
C13—H1c13···O1	0.96	2.38	157.20	3.287 (3)
O3—H1o3···O5	0.92	1.56	155	2.423 (3)

O2—H1o2···O10	0.92	1.60	145	2.414 (3)

Symmetry codes: (i) x-1/2, -y-1, z; (ii) x-1/2, -y, z; (iii) x-1, y, z; (iv) -x+1/2, y, z+1/2; (v) -x+3/2, y-1/2, -z+1/2.

π–π stacking interactions dimensions (Å, °) in compounds 1 and 2 top

	Centroid–centroid distance	Angle between the planes	Perpendicular distance	Slippage	Type
1	3.485	6.39			2,6-H₂pydcO^py···GLY^COO
	3.661	20.14			2,6-H₂pydcO^py···GLY^COO
	3.384	20.37			2,6-H₂pydcO^COO···GLY^COO
2	3.550	2.91			2,6-HMepydcO^py···2,6-HMepydcO^COO

The NBO analysis results for 2,6-H₂pydc^opt, 2,6-H₂pydcO^opt, 2,6-HMepydcO^opt and 2,6-Me2pydcO^opt. The values are the average of charge on similar atoms top

	C^py	C^COO	C^Me	H^py	H^COOH	H^Me	N^py	O^C=O	O^C^═^O(Me)	O^O—H	O^Me	O^N—O
2,6-H₂pydc^opt	-0.09	0.80		0.27	0.51		-0.39	-0.60		-0.68
2,6-H₂pydcO^opt	-0.12	0.80		0.27	0.51		0.13	-0.61		-0.67		-0.41
2,6-HMepydcO^opt	-0.12	0.80	-0.34	0.27	0.51	0.23	0.13	-0.61	-0.60	-0.67	-0.51	-0.43
2,6-Me₂pydcO^opt	-0.11	0.80	-0.34	0.27	,	0.23	0.12		-0.60		-0.51	-0.43

HOMO and LUMO orbitals for the optimized structures of 2,6-H₂pydc^opt, 2,6-H₂pydcO^opt, 2,6-HMepydcO^opt and 2,6-Me2pydcO^opt, along with the calculated the total energy and HOMO/LUMO gap top

	LUMO	HOMO	Total Energy (kcal mol^-1)	HOMO/LUMO Gap (eV)
2,6-H₂pydc^opt	(a)	(b)	-392462.17	5.38
2,6-H₂pydcO^opt	(c)	(d)	-439616.12	4.38
2,6-HMepydcO^opt	(e)	(f)	-464280.44	4.36
2,6-Me₂pydcO^opt	(g)	(h)	-488944.73	4.39

The calculated fitness values for 2,6-H₂pydc^opt, 2,6-H₂pydcO^opt, 2,6-HMepydcO^opt and 2,6-Me2pydcO^opt structures top

	BRAF-Kinase	CatB	DNA-Gyrase	HDAC7	rHA	RNR	TrxR	TS	Top II
2,6-H₂pydc^opt	24.12	18.51	31.19	30.79	27.84	29.11	35.91	27.81	30.77
2,6-H₂pydcO^opt	26.04	19.49	30.04	31.90	29.15	30.97	41.02	30.76	29.00
2,6-HMepydcO^opt	29.68	25.83	33.61	36.77	33.29	36.06	35.88	32.91	33.51
2,6-Me₂pydcO^opt	32.45	23.87	36.18	40.05	36.03	38.15	37.77	37.73	34.89

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Investigation of the effect of the N-oxidation process on the inter­action of selected pyridine compounds with biomacromolecules: structural, spectral, theoretical and docking studies

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Investigation of the effect of the N-oxidation process on the interaction of selected pyridine compounds with biomacromolecules: structural, spectral, theoretical and docking studies