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N-[(4-Fluorophenyl)sulfanyl]phthalimide (C14H8FNO2S, FP) was synthesized and characterized using X-ray crystallography. It was then investigated via quantum chemical analysis using the density functional theory (DFT) approach, as well as spectrochemically using FT–IR and 1H and 13C NMR spectroscopy, and elemental analysis. The observed and stimulated spectra are in very good agreement for the DFT method. The in vitro antimicrobial activity of FP against three Gram-positive bacteria, three Gram-negative bacteria and two fungi were determined using the serial dilution method, and FP showed the highest antibacterial activity against E. coli, with a MIC of 128 µg ml−1. Druglikeness, ADME (absorption, distribution, metabolism and excretion) and toxicology studies were carried out to theoretically examine the drug properties of FP.
Keywords: sulfenimide; phthalimide; XRD; antimicrobial activity; spectroscopic studies; ADMET; crystal structure.
Supporting information
 | Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229623003418/zo3030sup1.cif |
 | Structure factor file (CIF format) https://doi.org/10.1107/S2053229623003418/zo3030Isup2.hkl |
 | Portable Document Format (PDF) file https://doi.org/10.1107/S2053229623003418/zo3030sup3.pdf |
 | Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229623003418/zo3030Isup4.cml |
CCDC reference: 2215029
Computing details top
Data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT (Bruker, 1998); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: SHELXTL (Bruker, 2006) and ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: SHELXTL (Bruker, 2006).
2-[(4-Fluorophenyl)sulfanyl]isoindole-1,3-dione top
Crystal data top
| C14H8FNO2S | Z = 2 |
| Mr = 273.27 | F(000) = 280 |
| Triclinic, P1 | Dx = 1.491 Mg m−3 |
| a = 7.5224 (18) Å | Mo Kα radiation, λ = 0.71073 Å |
| b = 8.4415 (18) Å | Cell parameters from 9583 reflections |
| c = 10.820 (3) Å | θ = 3.1–28.2° |
| α = 91.437 (9)° | µ = 0.27 mm−1 |
| β = 104.157 (10)° | T = 293 K |
| γ = 112.754 (8)° | Block, colourless |
| V = 608.8 (2) Å3 | 0.16 × 0.13 × 0.12 mm |
Data collection top
| Bruker APEXII CCD diffractometer | 2134 reflections with I > 2σ(I) |
| φ and ω scans | Rint = 0.030 |
| Absorption correction: multi-scan (PLATON; Spek, 2020) | θmax = 26.0°, θmin = 3.1° |
| Tmin = 0.692, Tmax = 0.746 | h = −9→9 |
| 28088 measured reflections | k = −10→10 |
| 2390 independent reflections | l = −13→13 |
Refinement top
| Refinement on F2 | Hydrogen site location: inferred from neighbouring sites |
| Least-squares matrix: full | H-atom parameters constrained |
| R[F2 > 2σ(F2)] = 0.033 | w = 1/[σ2(Fo2) + (0.0316P)2 + 0.2822P] where P = (Fo2 + 2Fc2)/3 |
| wR(F2) = 0.085 | (Δ/σ)max = 0.001 |
| S = 1.06 | Δρmax = 0.25 e Å−3 |
| 2390 reflections | Δρmin = −0.22 e Å−3 |
| 173 parameters | Extinction correction: SHELXL2018 (Sheldrick, 2015a), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
| 0 restraints | Extinction coefficient: 0.049 (4) |
Special details top
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
| x | y | z | Uiso*/Ueq | ||
| F1 | 1.08584 (18) | 0.27078 (19) | 1.04625 (12) | 0.0741 (4) | |
| S1 | 0.24164 (6) | 0.03934 (6) | 0.75602 (5) | 0.04823 (16) | |
| C9 | 0.4981 (2) | 0.1126 (2) | 0.84284 (15) | 0.0387 (3) | |
| N1 | 0.24898 (19) | 0.19405 (16) | 0.65697 (13) | 0.0392 (3) | |
| O2 | 0.2293 (2) | 0.04387 (15) | 0.46792 (13) | 0.0545 (3) | |
| C3 | 0.2391 (2) | 0.33495 (19) | 0.47696 (15) | 0.0363 (3) | |
| C2 | 0.2496 (2) | 0.44593 (19) | 0.57772 (16) | 0.0377 (3) | |
| C4 | 0.2384 (2) | 0.17202 (19) | 0.52546 (15) | 0.0371 (3) | |
| C14 | 0.6203 (3) | 0.0477 (2) | 0.80124 (16) | 0.0437 (4) | |
| H14 | 0.568390 | −0.031704 | 0.726927 | 0.052* | |
| C1 | 0.2542 (2) | 0.3584 (2) | 0.69453 (16) | 0.0426 (4) | |
| C10 | 0.5759 (3) | 0.2315 (2) | 0.95385 (16) | 0.0477 (4) | |
| H10 | 0.493970 | 0.274654 | 0.981995 | 0.057* | |
| C13 | 0.8189 (3) | 0.1008 (2) | 0.87014 (18) | 0.0494 (4) | |
| H13 | 0.901880 | 0.057755 | 0.843328 | 0.059* | |
| O1 | 0.2617 (2) | 0.40926 (19) | 0.80103 (13) | 0.0677 (4) | |
| C5 | 0.2537 (2) | 0.6089 (2) | 0.55945 (19) | 0.0480 (4) | |
| H5 | 0.260788 | 0.683851 | 0.626745 | 0.058* | |
| C8 | 0.2312 (2) | 0.3813 (2) | 0.35505 (17) | 0.0457 (4) | |
| H8 | 0.223630 | 0.306183 | 0.287729 | 0.055* | |
| C6 | 0.2467 (3) | 0.6564 (2) | 0.4369 (2) | 0.0537 (5) | |
| H6 | 0.249923 | 0.765388 | 0.421991 | 0.064* | |
| C12 | 0.8907 (3) | 0.2184 (2) | 0.97887 (16) | 0.0481 (4) | |
| C7 | 0.2351 (3) | 0.5449 (2) | 0.33686 (19) | 0.0530 (5) | |
| H7 | 0.229807 | 0.579836 | 0.255700 | 0.064* | |
| C11 | 0.7746 (3) | 0.2856 (2) | 1.02229 (17) | 0.0527 (4) | |
| H11 | 0.828517 | 0.365883 | 1.096213 | 0.063* |
Atomic displacement parameters (Å2) top
| U11 | U22 | U33 | U12 | U13 | U23 | |
| F1 | 0.0543 (7) | 0.1016 (10) | 0.0582 (7) | 0.0325 (7) | 0.0002 (5) | 0.0060 (6) |
| S1 | 0.0412 (2) | 0.0455 (3) | 0.0608 (3) | 0.01677 (19) | 0.0191 (2) | 0.0183 (2) |
| C9 | 0.0441 (8) | 0.0374 (8) | 0.0414 (8) | 0.0196 (7) | 0.0179 (7) | 0.0137 (6) |
| N1 | 0.0398 (7) | 0.0356 (7) | 0.0453 (7) | 0.0184 (6) | 0.0121 (6) | 0.0053 (5) |
| O2 | 0.0691 (8) | 0.0373 (6) | 0.0608 (8) | 0.0255 (6) | 0.0189 (6) | −0.0032 (5) |
| C3 | 0.0279 (7) | 0.0316 (7) | 0.0456 (8) | 0.0112 (6) | 0.0058 (6) | 0.0004 (6) |
| C2 | 0.0280 (7) | 0.0336 (7) | 0.0497 (9) | 0.0135 (6) | 0.0062 (6) | −0.0002 (6) |
| C4 | 0.0315 (7) | 0.0329 (7) | 0.0453 (8) | 0.0130 (6) | 0.0086 (6) | −0.0004 (6) |
| C14 | 0.0492 (9) | 0.0394 (8) | 0.0458 (9) | 0.0198 (7) | 0.0161 (7) | 0.0015 (7) |
| C1 | 0.0396 (8) | 0.0431 (9) | 0.0480 (9) | 0.0215 (7) | 0.0102 (7) | −0.0016 (7) |
| C10 | 0.0627 (11) | 0.0534 (10) | 0.0427 (9) | 0.0347 (9) | 0.0229 (8) | 0.0104 (8) |
| C13 | 0.0513 (10) | 0.0541 (10) | 0.0542 (10) | 0.0300 (8) | 0.0203 (8) | 0.0078 (8) |
| O1 | 0.0969 (11) | 0.0733 (9) | 0.0502 (8) | 0.0506 (9) | 0.0245 (7) | 0.0001 (7) |
| C5 | 0.0386 (9) | 0.0340 (8) | 0.0699 (12) | 0.0167 (7) | 0.0102 (8) | −0.0031 (8) |
| C8 | 0.0420 (9) | 0.0445 (9) | 0.0459 (9) | 0.0149 (7) | 0.0085 (7) | 0.0043 (7) |
| C6 | 0.0397 (9) | 0.0357 (9) | 0.0847 (14) | 0.0165 (7) | 0.0127 (9) | 0.0173 (9) |
| C12 | 0.0476 (10) | 0.0564 (10) | 0.0407 (9) | 0.0230 (8) | 0.0091 (7) | 0.0125 (8) |
| C7 | 0.0426 (9) | 0.0517 (10) | 0.0606 (11) | 0.0166 (8) | 0.0100 (8) | 0.0195 (9) |
| C11 | 0.0674 (12) | 0.0562 (11) | 0.0367 (9) | 0.0291 (9) | 0.0117 (8) | 0.0020 (8) |
Geometric parameters (Å, º) top
| F1—C12 | 1.357 (2) | C2—C5 | 1.385 (2) |
| S1—N1 | 1.7031 (14) | C2—C1 | 1.480 (2) |
| S1—C9 | 1.7744 (17) | C14—C13 | 1.382 (2) |
| C9—C14 | 1.388 (2) | C1—O1 | 1.200 (2) |
| C9—C10 | 1.391 (2) | C10—C11 | 1.380 (3) |
| N1—C4 | 1.409 (2) | C13—C12 | 1.370 (3) |
| N1—C1 | 1.419 (2) | C5—C6 | 1.390 (3) |
| O2—C4 | 1.2042 (19) | C8—C7 | 1.389 (2) |
| C3—C8 | 1.379 (2) | C6—C7 | 1.380 (3) |
| C3—C2 | 1.386 (2) | C12—C11 | 1.369 (3) |
| C3—C4 | 1.483 (2) | ||
| N1—S1—C9 | 101.48 (7) | N1—C4—C3 | 105.85 (12) |
| C14—C9—C10 | 119.94 (16) | C13—C14—C9 | 120.07 (16) |
| C14—C9—S1 | 119.73 (13) | O1—C1—N1 | 124.67 (16) |
| C10—C9—S1 | 120.32 (13) | O1—C1—C2 | 129.59 (16) |
| C4—N1—C1 | 111.15 (13) | N1—C1—C2 | 105.74 (13) |
| C4—N1—S1 | 124.57 (11) | C11—C10—C9 | 120.05 (16) |
| C1—N1—S1 | 124.18 (12) | C12—C13—C14 | 118.46 (16) |
| C8—C3—C2 | 121.71 (15) | C2—C5—C6 | 117.57 (16) |
| C8—C3—C4 | 129.67 (15) | C3—C8—C7 | 117.33 (17) |
| C2—C3—C4 | 108.63 (14) | C7—C6—C5 | 121.21 (16) |
| C5—C2—C3 | 120.89 (16) | F1—C12—C11 | 118.60 (16) |
| C5—C2—C1 | 130.49 (15) | F1—C12—C13 | 118.40 (16) |
| C3—C2—C1 | 108.62 (13) | C11—C12—C13 | 122.99 (17) |
| O2—C4—N1 | 125.15 (15) | C6—C7—C8 | 121.29 (18) |
| O2—C4—C3 | 129.00 (16) | C12—C11—C10 | 118.49 (17) |
| N1—S1—C9—C14 | −94.43 (14) | S1—N1—C1—C2 | −177.35 (10) |
| N1—S1—C9—C10 | 87.09 (14) | C5—C2—C1—O1 | 0.3 (3) |
| C9—S1—N1—C4 | 102.84 (13) | C3—C2—C1—O1 | −179.48 (18) |
| C9—S1—N1—C1 | −81.20 (14) | C5—C2—C1—N1 | −179.31 (15) |
| C8—C3—C2—C5 | −0.3 (2) | C3—C2—C1—N1 | 0.90 (17) |
| C4—C3—C2—C5 | 179.63 (13) | C14—C9—C10—C11 | 0.3 (2) |
| C8—C3—C2—C1 | 179.50 (14) | S1—C9—C10—C11 | 178.80 (13) |
| C4—C3—C2—C1 | −0.56 (16) | C9—C14—C13—C12 | −0.3 (3) |
| C1—N1—C4—O2 | −178.85 (15) | C3—C2—C5—C6 | 0.0 (2) |
| S1—N1—C4—O2 | −2.4 (2) | C1—C2—C5—C6 | −179.75 (15) |
| C1—N1—C4—C3 | 0.59 (16) | C2—C3—C8—C7 | 0.3 (2) |
| S1—N1—C4—C3 | 177.00 (10) | C4—C3—C8—C7 | −179.68 (15) |
| C8—C3—C4—O2 | −0.7 (3) | C2—C5—C6—C7 | 0.3 (3) |
| C2—C3—C4—O2 | 179.41 (16) | C14—C13—C12—F1 | −179.83 (15) |
| C8—C3—C4—N1 | 179.94 (15) | C14—C13—C12—C11 | 0.0 (3) |
| C2—C3—C4—N1 | 0.00 (16) | C5—C6—C7—C8 | −0.4 (3) |
| C10—C9—C14—C13 | 0.1 (2) | C3—C8—C7—C6 | 0.1 (3) |
| S1—C9—C14—C13 | −178.37 (13) | F1—C12—C11—C10 | −179.74 (16) |
| C4—N1—C1—O1 | 179.44 (16) | C13—C12—C11—C10 | 0.5 (3) |
| S1—N1—C1—O1 | 3.0 (2) | C9—C10—C11—C12 | −0.6 (3) |
| C4—N1—C1—C2 | −0.91 (17) |
Quantum chemical parameters calculated at the B3LYP/6-311G(d,p) level for
FP top
| Quantum chemical parameters | eV |
| ELUMO | -2.54 |
| EHOMO | -7.06 |
| ΔE = ELUMO – EHOMO | 4.58 |
| Υ = -ELUMO | 2.54 |
| I = -EHOMO | 7.06 |
| φ = Y+1/2 | 4.80 |
| Ψ = 1-Y/2 | 2.26 |
| S = 1/Ψ | 0.44 |
| ω = φ2/2Ψ | 4.44 |
| ε = 1/ω | 0.23 |
| ω+ = (I+3\Y)2/16(I-Y) | 2.94 |
| ω- = (3I+\Y)2/16(I-Y) | 7.68 |
| Δω± = ω+ + ω- | 10.62 |
| I is the ionization potential, Y is the electron affinity, Φ is the absolute electronegativity, Ψ is the chemical hardness, S is the absolute softness, ω is the electrophilic index, ε is the nucleophilic index, ω+ is the electron-accepting power, ω- is the electron-donating power and Δω± is the net electrophilicity. |
Experimental and calculated 1H and 13C NMR spectral data for FP top
| Atom | Experimental | Calculated |
| H1 | 7.23–7.30 | 7.18 |
| H2 | 7.31–7.33 | 8.22 |
| H3 | 7.89-7.91 | 8.01 |
| H4 | 7.76–7.78 | 7.92 |
| C1 | 148.7 | 174.53 |
| C2 | 118.5 | 121.41 |
| C3 | 128.7 | 146.91 |
| C4 | 144.0 | 141.27 |
| C5 | 170.0 | 173.57 |
| C6 | 130.7 | 137.36 |
| C7 | 126.1 | 129.65 |
| C8 | 133.9 | 140.84 |
The physicochemical properties, druglikeness and the pharmacological properties
with SwissADME prediction of the compounds top
| Physicochemical properties | Druglikeness | Pharmacokinetic properties | |||
| MW | 285.38 | WLogP | 3.13 | GI | High |
| H-A | 3 | ILOGP | 2.53 | BBB | Yes |
| H-D | 0 | XLOGP3 | 2.90 | P-gp substrate | No |
| TPSA | 62.68 | SA | 3.91 | CYP1A2 inhibitor | No |
| Rotatable bonds | 2 | LogS | -3.30 | ||
| MR | 77.92 | CYP2D6 inhibitor | No | ||
| Fraction C(sp3) | 0.86 | LogKp | -5.98 | ||
| N(atoms) | 19 |
| MW is the molecular weight (g mol-1), H-A is the number of hydrogen-bond acceptors, H-D is the number of hydrogen-bond donors, LogS is the solubility, TPSA is the total polar surface area, MR is the molar refractivity, N(atoms) is the number of atoms, WLogP, iLOGP and XLOGP3 are the lipophilicity, SA is the synthetic accessibility, GI is gastrointestinal, BBB is the blood brain barrier, P-gp is P-glycoprotein, CYP1A2 is cytochrome P450 family 1 subfamily A member 2 (PDB entry 2HI4), CYP2D6 is cytochrome P450 family 2 subfamily D member 6 (PDB entry 5TFT) and Log Kp is the skin permeation (cm s-1). |
Toxicity prediction values and results for FP and its
intermediates calculated by T.E.S.T. and ProTox-II top
| Acute toxicity | Developmental toxicity | Mutagenicity | |||
| Oral rat LD50 (mg kg-) | Fat-head minnow LC50 (96 h) (mg l-1) | Predicted value | Predicted result | Predicted value | Predicted result |
| 1046,33 | 0.49 | 0,49 | Developmental NON-toxicant | 0.46 | Negative |
| Organ toxicity | Toxicity end points | ||||
| Hepatotoxicity | Carcinogenicity | Immunotoxicity | Mutagenicity | Cytotoxicity | LD50 (mg kg-1) |
| Inactive | Active | Inactive | Inactive | Inactive | 2500 |
The minimum inhibition concentrations (MICs) of FP and
standard drugs top
| Sample | MIC (µg ml-1) | |||||||
| Gram-staining-positive | Gram-staining-negative | Fungi | ||||||
| B. subtilis | S. aureus | E. faecalis | E. coli | K. pneumoniae | P. aeruginosa | A. niger | C. albicans | |
| FP compound | 1024 | 1024 | 1024 | 128 | 256 | 256 | 256 | 128 |
| Amoxicillin | >1024 | >1024 | >1024 | >1024 | >1024 | >1024 | - | - |
| Tetracycline | 4 | 64 | 64 | 64 | 64 | 64 | - | - |
| Ketoconazole | - | - | - | - | - | - | 1 | 2 |
