towards anti-CHIKV
3.4.3 Computational studies
All geometries and energies were calculated using the Gaussian16 package at the B3LYP-D3(BJ)/6-311++G(2d,p) level including implicit solvation (polarisable continuum model, solvent excluded surface and solvent-solute dispersion interaction included) using the standard parameters for water. Normal mode frequency analysis was performed on all ground state structures to confirm the nature of the energy stationary point and estimate free energies.
For tautomer distributions, the molar free energies (ΔG) of each tautomer (relative to that of the lowest) was calculated and isomer distributions derived using the Boltzmann factor:
𝑝𝑖
𝑝0 = ⅇ−Δ𝐺𝑅T
where R is the molar gas constant, T the temperature (37° C = 310.15 K). The results are shown in Table S1.
Electron density and Electrostatic Potential (ESP) cube files were calculated using the Gaussian cubegen utility. ESP mapped onto electron isodensities were generated using the GausView 6.0.16 application (Table 3.3).
Potential Energy Surfaces for the N-Ar torsion for 3.53, 3.54 and 3.55 were calculated at the B3LYP-D3(BJ)/6-311G(2d,p) (Table 3.3) level including implicit solvation (continuum model, solvent excluded surface and solvent-solute dispersion interaction included) using the standard parameters for water. The torsional angle defined by the blue heavy bonds (9,1,a,b) shown below and scanned in 1° increments:
75
Table 3.3: B3LYP-D3(BJ)/6-311++G(2d,p)-(water solvation) calculated free energies and relative concentrations at 37° C for tautomers of the minimal pharmacophores 3.54, 3.54b, 3.55, 3.55a, 3.56a-c.
Tautomer G / Ha ΔG / kJ mol
-1
Relative conc.
3.54 -773.743900 [0] [1]
3.54b -773.728761 40 2.0 10-7
3.55 -757.711628 [0] [1]
3.55b -757.695321 43 6.1 10-8
3.56a -665.434824 9 3.2 10-2
3.56b -665.438199 [0] [1]
3.56c -665.431651 17 1.3 10-3
76 3.4.4 X-ray crystallography
- Single solid X-ray crystallographic data of 3.15
Crystal data. Compound 3.15. C10H10ClFN2O2, M = 244.65, T =153 K, Orthorhombic, Z = 4, a = 4.590 (1), b = 9.619 (2), c = 25.879 (4) Å, V = 1142.6 (4) Å3, Dx = 1.422 Mg m-3, synchrotron radiation, λ = 0.710919 Å, 4577 reflections measured (θ = 1.6–29.1˚), merged to 2330 unique data, R=0.040 [for 2089 data with I > 2σ(I)], R [F2 > 2σ (F2)]= 0.043 [all data], S = 0.99
Structure determination of compound 3.15. Data was collected using Dectris Eiger 16M diffractometer with radiation source: MX1 Beamline Australian Synchrotron.30 Structure solution was by direct methods (SIR92).31 The structure was refined using the CRYSTALS program package.32
- Single solid X-ray crystallographic data of 3.20
Crystal data. Compound 3.20. C10H10ClFN2O2, M = 275.72, T = 153 K, Orthorhombic, Z = 8, a = 15.154 (1), b = 8.056 (10), c = 19.144 (4) Å, V = 2337 (3) Å3, Dx = 1.567 Mg m-3, synchrotron radiation, λ = 0.710919 Å, 26664 reflections measured (θ = 2.1–29.2˚), merged to 2408 unique data, R =0.111 [for 1625 data with I > 2σ(I)], R[F2 > 2σ (F2)] = 0.060 [all data], S = 0.90.
- Structure determination of compound 3.20. Data was collected using Dectris Eiger 16M diffractometer with radiation source: MX1 Beamline Australian Synchrotron.30 Structure solution was by direct methods (SIR92).31 The structure was refined using the CRYSTALS program package.32
77
- Single solid X-ray crystallographic data of 3.24
Crystal data. Compound 3.24. C9H8BrClN2O, M = 275.53, T = 153 K, Orthorhombic, Z = 4, a = 8.821 (6), b = 25.123 (15), c = 4.560 (4) Å, V = 1010.5 (13) Å3, Dx = 1.811 Mg m-3, synchrotron radiation, λ = 0.710919Å, 12004 reflections measured (θ = 1.6–29.0˚), merged to 2334 unique data, R=0.093 [for 2022 data with I > 2σ(I)], R [F2 > 2σ (F2)] = 0.046 [all data], S = 1.01.
Structure determination of compound 3.24. Data was collected using Dectris Eiger 16M diffractometer with radiation source: MX1 Beamline Australian Synchrotron.30 Structure solution was by direct methods (SIR92).31 The structure was refined using the CRYSTALS program package.32
- Single solid X-ray crystallographic data of 3.23
Crystal data. For compound 3.23 C18H18N4O4 (M =354.36 g/mol): monoclinic, space group P21/n (no. 14), a = 16.2162(9) Å, b = 5.5670(3) Å, c = 19.1376(13) Å, β = 96.256(6)°, V = 1717.37(19) Å3, Z = 4, T = 100(2) K, μ(CuKα) = 0.824 mm-1, Dcalc = 1.371 g/cm3, 11249 reflections measured (7.564° ≤ 2Θ ≤ 145.012°), 3326 unique (Rint = 0.0503, Rsigma = 0.0396) which were used in all calculations. The final R1 was 0.0575 (I > 2σ(I)) and wR2 was 0.1665 (all data).
Structure determination of compound 3.23: Data was collected using SuperNova, Dual, Cu at home/near, Atlas diffractometer. Using Olex2 33, the structure was solved with the olex2.solve34 structure solution program using Charge Flipping and refined with the ShelX35 refinement package using Least Squares Minimization.
78 - Single solid X-ray crystallographic data of 3.39
Crystal data. Compound 3.39. C15H13BrN4O2, M = 361.20, T = 153 K, Monoclinic, Z = 4, a = 4.668 (1), b = 21.780 (2), c = 14.348 (2) Å, β = 93.379 (6)°, V = 1456.2 (5) Å3, Dx = 1.647 Mg m-3, synchrotron radiation, λ = 0.710919 Å, 19044 reflections measured (θ = 1.7–29.2˚), merged to 2876 unique data, R
=0.053 [for 2544 data with I > 2σ(I)], R [F2 > 2σ (F2)] = 0.031 [all data], S = 0.99.
Structure determination of compound 3.39. Data was collected using Dectris Eiger 16M diffractometer with radiation source: MX1 Beamline Australian Synchrotron.30 Structure solution was by direct methods (SIR92).31 The structure was refined using the CRYSTALS program package.32
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