Fluvoxamine: First comprehensive insights into its molecular characteristics and inclusion complexation with β-cyclodextrin

Abstract

Fluvoxamine (FXM) is a well-known selective serotonin reuptake inhibitor (SSRI) for treating depression and has recently been repurposed for efficacious treatment of coronavirus disease 2019. Although cyclodextrin (CD) encapsulation effectively improves the physicochemical properties of structurally diverse SSRIs, the molecular understanding of their associations is deficient. This comprehensive study used single-crystal X-ray diffraction integrated with density functional theory (DFT) calculation to provide deep insights into the conformationally flexible FXM and its inclusion complexation with β-CD. X-ray analysis revealed the first crystallographic evidence of the uncomplexed 3FXM-H⁺·3maleate^- (1). Three FXM-H⁺ ions are counter-balanced by three planar maleate^- ions to form a thin layer stabilized by infinite fused H-bond rings R₄ ⁴(12) and R₆ ⁴(16) and the interplay of π⋯π, CF⋯π and F⋯F interactions. For 2β-CD·2FXM-H⁺·maleate^2-·23·2H₂O (2), the tail-to-tail β-CD dimer encapsulates two FXM-H⁺ 4-(trifluoromethyl)phenyl moieties, which are charge-balanced by the rare non-planar maleate^2- and stabilized by N/OH⋯O H-bonds and F⋯F interactions. This is a host-guest recognition pattern uniquely observed for all β-CD complexes with halogen (X)-bearing SSRIs, indicating the essence of X⋯X interactions and the shielding of X-containing moieties in the wall of the β-CD dimer. DFT calculations unveiled that the monomeric and dimeric β-CD-FXM complexes and FXM isomers are energetically stable, which alleviates the numbness and bitterness of the orally administered drug as previously patented. Additionally, an insightful conformational analysis of FXM emphasizes the importance of drug structural adaptation in pharmacological functions.

Keywords: Conformational flexibility; DFT calculation; Fluvoxamine maleate; SSRIs; X-ray analysis; β-Cyclodextrin.

Graphical abstract

Fig. 1

Chemical structures and atom numbering schemes of fluvoxamine (FXM; 2-[(E)-[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine) and β-cyclodextrin (β-CD). Selective serotonin reuptake inhibitors (SSRIs) are commercially available in various salt forms, i.e., sertraline (STL) HCl, fluoxetine (FXT) HCl, paroxetine (PXT) HCl, citalopram (CTP) HBr, escitalopram (SCTP) oxalate, and FXM maleate. Clomipramine (CPM) HCl, a halogen-containing tricyclic antidepressant (TCA) commonly to SSRIs, is given for comparison. Different rings and chiral centers of SSRIs are marked. The SSRI selectivity-order is shown with orange arrowheads. The X-ray-derived inclusion modes of distinct antidepressant drug (ADD) moieties embedded with respect to O6–H and O2–H/O3–H sides of the β-CD cavity are highlighted in magenta [[18], [19], [20],39].

Fig. 2

Molecular structures and systematic numbering schemes of (E)-fluvoxamine (FXM) in free maleate salt form (1) and encapsulated in the β-cyclodextrin (β-CD) dimeric cavity (2). ORTEP plots are drawn at the 30% probability level (see also Fig. 1). Doubly disordered CF₃ groups on the B-ring of five FXM–H⁺ in 1 and 2 and O61–H group of β-CD #2 in 2 are labeled as sites A and B. The connecting blue lines indicate the intramolecular O3–H⋯O2 H-bond stabilizing the three maleate⁻ in 1; ions of the adjacent asymmetric units are in italics. Several intramolecular O3(n)⋯O2(n + 1) H-bonds maintaining the round CD conformation are absent because of the relevant OH groups H-bond with surrounding water sites. The intermolecular N–H⋯O H-bonds between various FXM–H⁺ and planar maleate⁻/non-planar maleate²⁻ are shown with magenta lines.

Fig. 3

Various intermolecular interactions contribute to the stability of 5.3-Å-layer stacking along the b-axis in the ribbon-like crystals of 3FXM–H⁺·3maleate⁻ (1). ORTEP plots are drawn at the 30 % probability level. (A) Infinite fused H-bond rings R₄⁴(12) and R₆⁴(16) along the a-axis; the asymmetric unit is in a ball-and-stick model with atoms labeled in red. (B) Interactions of adjacent 4-(trifluoromethyl)phenyl moieties include face-to-face (F2F; along the b-axis) and edge-to-face (E2F; along the a–c-plane) π⋯π, CF⋯π, and F⋯F interactions. FXM: fluvoxamine.

Fig. 4

Radar plots depicting the variation of key structural parameters in the glucose units (G1–G7) of β-cyclodextrin (β-CD) #1, #2 (dimeric motif) upon encapsulating fluvoxamine (FXM) (2), fluoxetine (FXT) (i [18]), and citalopram (CTP) (ii [20]). (A) Glucose tilt angles. (B) Intramolecular, interglucose O3(n)⋯O2(n + 1) distances. For comparison, data of the 1:1 β-CD–(–)-epicatechin (EC) ([44], β-CD–clomipramine (CPM) [39], and β-CD·12H₂O (iii [43]) are also incorporated; angles and distances are in ° and Å. Structure overlays of β-CD monomers and dimers. (C) Side and (D) top views of seven β-CD monomers. (E) Three tail-to-tail β-CD dimers in 2, i and ii. (F) Summary of the RMS fits, see also Fig. 5 and Table S2.

Fig. 5

Dimeric nature of β-cyclodextrin (β-CD) inclusion complexes with selective serotonin reuptake inhibitors (SSRIs). (A) 3D-arrangements in channel structures are built from T2T β-CD dimers encapsulating fluvoxamine (FXM) and sertraline (STL) molecules and stabilized by intermolecular face-to-face π⋯π and halogen⋯halogen interactions. The primary O6–H side (tail; T) and secondary O2–H/O3–H side (head; H) of β-CD are marked. (B) ORTEP plots of the tail-to-tail (T2T) β-CD–FXM dimeric complex (30% probability level). For clarity, FXM molecules are shown in a space-filling model.

Fig. 6

Illustration of the summary of the key density functional theory (DFT) results. (A, C) Monomeric and (B) dimeric inclusion complexes of β-cyclodextrin (β-CD)–fluvoxamine (FXM) base from DFT full-geometry optimization using B3LYP and M06-2X functionals in vacuum and polarizable continuum model (PCM) water. For better comparison, the energy of complex (E_cpx) and stabilization energy (ΔE_stb) are given in respective units of Hartree (H) and kcal/mol; see also Fig. S1 and Tables S5, S6, and S8. The complexes are stabilized by intramolecular O–H⋯O H-bonds (maintaining the round β-CD macrocycles; blue lines) and intermolecular N/O–H⋯O H-bonds (maintaining the β-CD dimeric structure and the FXM inclusion geometries; magenta lines).

Fig. 7

Partial structure overlays of fluvoxamine (FXM) in distinct lattice environments. (A) 3FXM–H⁺·3maleate⁻ (1). (B) 2β-CD·2FXM–H⁺·maleate²⁻·23·2H₂O (2). (C) Different FXM molecules in three protein-binding pockets indicated by PDB codes 4MM9 [34], 4ENH [35], and 6AWP [36]; for more details, see Table 1, footnote (i). (D) From free salt form, on the way during transport in β-cyclodextrin (β-CD) cavity until to the target-binding protein of FXM. Reference structures are shown in blue wireframes with their names marked in gray areas and only non-H atoms of the rigid B-ring linked with C11–C8N1 group are considered for the calculation of RMS fits. The corresponding RMS fit for each structure pair is indicated by nearby distance. Only site A of the twofold disordered CF₃ group in 1 and 2 is shown.