# Interactions of Antibacterial Naphthoquinones with Mesoporous Silica Surfaces: A Physicochemical and Theoretical Approach

^{1}

^{2}

^{3}

^{4}

^{*}

## Abstract

**:**

_{2}materials occur.

## 1. Introduction

_{2}) particles, such as SBA-15, have been widely studied as drug-delivery vehicles, taking advantage of their large specific surface area, the ease of modifying their chemical nature, and their high biocompatibility and biodegradability [18,19,20,21,22]. SBA-15 (Santa Barbara amorphous) particles were first obtained by Zhao et al., who reported a material with two-dimensional well-ordered hexagonal structures, large pores, and large surface areas [23]. In the last two decades, the biological applications of SBA-15 focused on drug delivery [24,25], vaccine platforms [26,27], and tissue engineering [28,29] among other applications.

_{2}materials and organic molecules of biological interest have been studied using different computational chemistry techniques ranging from modeling realistic molecular systems to the energy involved in the interaction. In this sense, some authors proposed molecular modeling methodologies that allow obtaining, in the first instance, realistic models of SiO

_{2}. For example, in their work, Ugliengo et al. (2008) proposed the construction of surface models for amorphous silica, starting from the dimensional replication of a unit cell of alpha cristobalite and subsequent saturations with hydroxyl groups [30]. On the other hand, the density functional theory (DFT) allows us to study and evaluate molecular structures, intermolecular interactions, and their associative energies, both for molecules of biological interest [31] and nanomaterials, with an adequate level of chemical precision [32]. Moreover, the combination of DFT and other methodologies, such as the quantum theory of atoms in molecules (QTAIM) [33], has allowed the estimation of the energy of H-bonds [34]. These methodologies have been used to study interactions between SiO

_{2}materials and anticancer drugs [35,36], such antibiotics as ampicillin [37] and β

_{1}-receptor blockers [38], as well as other supports used in drug delivery, such as polyethylene glycol (PEG) xerogels [39] and chitosan [40].

## 2. Materials and Methods

#### 2.1. Chemicals

#### 2.2. Silica Particle Characterization

^{−1}) were measured by Zetasizer Nano ZS90, (Malvern Instruments, Instruments Worcertershire, Worcertershire, UK). The measurements were performed at 25 °C, in triplicate, using disposable polystyrene cuvettes. TEM micrographs were taken with a JEM-JEOL-2100 microscope. The samples were suspended in ethanol and deposited dropwise onto formvar–carbon grids. We used ImageJ v1.53o to measure the length, width, and pore width of SBA-15 particles [41,42]. XRD (X-ray powder diffraction) patterns were measured in a Panalytical EMPYREAN diffractometer using CuKα (λ = 1.54184 Å). The interval of XRD analysis was 5–60° 2θ, with a step size of 0.01° and 1 s of measure time for each step. The diffractograms were analyzed using the X’Pert High Score software [43]. Nitrogen adsorption/desorption experiments were carried out with in a TriStar II-3020 (Micrometrics) device at 77 K. Before analyses, the samples were treated in a vacuum (10

^{3}torr) at 300 °C for four hours using a Micrometrics VacPrep 061−Sample degas system. The specific surface area was estimated using the Brunauer Emmet Teller (BET) model. Pore size distributions were calculated using the Barrett–Joyner–Halenda (BJH) model. The average pore size and volume were estimated based on the desorption branch of each isotherm of nitrogen.

#### 2.3. NQs Adsorption Measurements

^{−1}) was placed at room temperature and constantly stirred. For adsorption isotherms studies, SBA-15 particles were immersed in NQs solutions at different concentrations (5–150 mg L

^{−1}) and stirred for 24 h, which is sufficient time for the mixture to reach equilibrium (data not shown). After reaching equilibrium, samples were filtered and measured by UV-Vis spectrophotometry; the filtrate was immediately analyzed using a Jenway 7305 UV-Vis spectrophotometer (200–700 nm) at room temperature to determine NQ’s free concentrations. The equilibrium adsorption of NQs (q

_{e}= mg NQs per gram of silica) was calculated by Equation (1):

_{0}and C

_{e}(mg L

^{−1}) are the initial and equilibrium concentration, respectively, of any of the three NQs in solution. V (L) is the volume of NQs solution, and m (g) is the mass of the adsorbent SBA-15 particles used in the experiment. The fit of the obtained experimental data to different adsorption isotherm models can be performed using their linear forms after a mathematical transformation of the values as appropriate [44]. However, other authors suggest that such treatments increase the error of the parameters obtained in each model [45,46,47]. In this work, the adsorption isotherm data were fitted to Langmuir, Freundlich, and Temkin isotherm equations in their non-linear forms. Since the methodology for fitting the data by non-linear regression employs the minimization of an error function from the starting parameters, we used the parameters obtained from the fit to the linear form of each model as the starting parameters in each case.

#### 2.4. Spectroscopic Characterization of SBA-15 and NQs

^{−1}resolution across the 400–4000 cm

^{−1}range.

#### 2.5. Theoretical Approach

_{2}. The SiO

_{2}cluster starts from an α-cristobalite crystal model reported by [50]. To obtain a reactive region, we take the crystallographic plane with the (111) Miller indices using the atomistic simulation environment (ASE) from the Python library [51]. Subsequently, we replicate this surface model two times in the “x” and “z” directions. Finally, we saturate broken bonds with the hydroxyl groups. This cluster is representative of a neutral surface with adsorption sites as it exhibits oxygen atoms, hydroxyl groups, or silicon atoms. Since the DFT has been used for the study of drug adsorptions onto SBA-15 [30], we evaluated the nature of NQ adsorptions onto SBA-15 with the B3LYP hybrid functional [52] in conjunction with the basis set 6-31+G(d,p) [53,54]. The geometrical optimization of all molecules was performed with the B3LYP/6-31+G(d,p) method, and their vibrational frequencies were calculated at the same level of theory to ensure that the optimized geometry corresponds to a minimum on the potential energy surface. Gaussian 09W software was utilized for all calculations [55]. The adsorption of NQs onto SBA-15 particles was modeled using a cluster approach assuming that the NQ− and SiO

_{2}−optimized models had 1:1 interactions. The resulting models were optimized at the same level of the theory. The QTAIM topology analysis was realized to determine the nature of the intermolecular interaction. QTAIM analyses were carried out using Multiwfn software (free access software, Beijing Kein Research Center for Natular Sciences, Beijing, China) [56].

## 3. Results

#### 3.1. TEM Images of SBA-15 Particles

#### 3.2. FT–IR of NQ, 2NQ, and 5NQ onto SBA-15 Particles

^{−1}and 808 cm

^{−1}when assigned to asymmetric and symmetric Si-O-Si stretching, respectively. On the other hand, the IR spectra obtained from the three naphthoquinone derivatives show the following typical absorption bands: 1656 cm

^{−1}stretching of the carbonyl functional group C=O, 1603 cm

^{−1}corresponding to C=C stretching, 1300 cm

^{−1}corresponding to C-C stretching, and 766 cm

^{−1}corresponding to out-of-plane flutter. The IR band’s designation for SBA-15 in this work is according to the IR information that is widely reported in the literature [61,62,63]. On the other hand, the IR spectrum corresponding to 5NQ (Figure 3B) shows a band in the region of 3161 cm

^{−1}and 3060 cm

^{−1}assigned to O-H stretching. Then, the 5NQ interaction on SBA-15’s surface is observed in the blue regions in Figure 3. First, Si-O-Si stretches the characteristic of SBA-15 at 1060 cm

^{−1}, and 808 cm

^{−1}remains, but the intensity decreased in both bands. Then, a broad and flattened band at 3366 cm

^{−1}was assigned to O-H and C-H stretches. One more band at 1637 cm

^{−1}corresponding to the C=O stretch of NQs appeared in 5NQ@SBA-15. For NQ@SBA-15 and 2NQ@SBA-15, the O-H and C-H stretches appear at 3397 cm

^{−1}and 3366 cm

^{−1}, respectively, and the C=O stretch appeared at 1630 cm

^{−1}and 1636 cm

^{−1}(Figures S1 and S2).

_{2}thermal adsorptions. The obtained data are shown in Figure 4. According to the BET model, SBA-15 was characterized by the adsorption–desorption isotherm (type IV) that is typical for mesoporous materials with a type H1 hysteresis loop [69,70] and a surface area of 597.25 m

^{2}g

^{−1}. In addition, the pore diameter’s distribution curve presented mesopores with an average diameter of 9.7 nm (see insertion in Figure 4A). Note that these data correlate well with those reported by other authors for commercial SBA-15 [71,72].

^{2}/g, while the values diminished to 434.88, 441.7, and 438.99 m

^{2}/g for NQ@SBA-15, 2NQ@SBA-15, and 5NQ@SBA-15 samples, respectively. The decrease in surface area values was attributed to the partial blocking of SBA-15’s surface by the adsorbed molecules.

#### 3.3. Adsorption Isotherm Models of NQ Derivatives on SBA-15 Particles

#### 3.3.1. Langmuir Isotherm Model

^{−1}), ${Q}_{0}$ is the monolayer adsorption capacity (mg g

^{−1}), and b is the Langmuir isotherm constant related to the energy of adsorption (L mg

^{−1}). The parameter values of this model can be determined using a linear equation, which is expressed in Equation (3).

#### 3.3.2. Freundlich Isotherm Model

^{−1}). $n$ is the adsorption intensity. The values of $n$ could indicate the favorability of sorption, where n < 1, 1 < n < 2, and 2 < n < 10 represent poor, moderately difficult, and favorable adsorption conditions, respectively [76]. The linear expression of this model is given by Equation (5).

#### 3.3.3. Temkin Isotherm Model

^{−1}mol

^{−1}), T is the temperature (K), ${b}_{T}$ is the Temkin isotherm constant, and $A$ is the equilibrium binding constant (L g

^{−1}). A plot of ${q}_{e}$ versus $log\left({C}_{e}\right)$ enables the determination of the isotherm constant.

^{2}values suggest the best fit for the isotherm’s adsorption is the Freundlich model, where a multilayer of NQ molecules can be adsorbed onto SBA-15, and the best adsorption capacity (K

_{f}) is presented in the 2NQ@SBA-15 system at 32.2276 mg/g with moderate adsorption (n ≈ 1) [78]. These results are in agreement with those reported by other authors for the adsorption of prednisolone by SBA-15 [79] and meloxicam [80] and another system’s adsorption as famotidine by Zinc chloride particles [81].

#### 3.4. Theoretical Evaluation of the Adsorption Mechanism of NQ Derivatives on SBA-15

#### 3.4.1. Molecular Model Optimization Calculation

#### 3.4.2. Calculation of the Interaction Energy (ΔE)

_{2}. Since NQs are planar molecules, we built interaction models by superimposing the NQ molecule in horizontal (H) and vertical (V) positions for the SiO

_{2}surface. The open and closed structures of 2NQ and 5NQ were superimposed only in a horizontal position to the SiO

_{2}surface. To calculate the interaction energy between the molecular models of NQs and the surface’s molecular model, we used Equation (7):

_{2}system (Kcal mol

^{−1}), ${E}_{surface}$ is the SiO

_{2}energy (Kcal mol

^{−1}), and ${E}_{NQ}$ is the NQs energy (Kcal mol

^{−1}). This interaction of energy parameter represents the total energy of the physical or chemical interactions involved in the binding or formation of the adsorption product. Table 3 presents ΔE, where we can observe that the interaction between SiO

_{2}and NQ is stronger in the vertical position (Figure 8B) than in the horizontal position (Figure 8A). For 2NQ, there are no significant differences in the interaction for the closed system (Figure 8C) and the open system (Figure 8D). In contrast, a significant difference was observed for 5NQ, where the open system’s (Figure 8F) interaction is stronger than the closed system (Figure 8E).

^{−1}and it corresponded to the interaction between vertical NQ (V) and SiO

_{2}. As observed in Figure 8B, this interaction is mediated by an H-bond-type interaction and two covalent interactions. One of these covalent interactions occurred between the silicon atom on the surface and the C4 of NQ, which probably promotes a change in C4’s hybridization from sp2 to sp3, as evidenced by a change in the dihedral angle (C8a-C4a-C4-O12; see Figure 6) from 180° in the sp2 configuration to 34° in the model interaction. (2) At −88.92 kcal mol

^{−1}between the open horizontal 5NQ (O.H.) and SiO

_{2}(Figure 8F), in this interaction, we can see two H-bond-type interactions and one covalent interaction between the C3 of 5NQ and a silicon atom on the surface. Additionally, we can observe that the C1 carbonyl group’s substrate obtains a proton from the surface, forming a hydroxyl group at C1. This could explain the modification of the crystalline pattern shown on XRD (see Figure 2D). Finally, (3) at −18.99 kcal mol

^{−1}between the closed horizontal 2NQ (C.H.) and SiO

_{2}(Figure 8C), we can see three H-bonds and one covalent interaction between the C1 carbonyl group of 2NQ and a silicon atom on the surface.

_{rBCP}is the electron density at the bond critical point (BCP) corresponding to the H-bond obtained from the topological analysis:

^{−1}. In Table 3, we show the BE calculated at every BCP obtained from the topology analysis of the interaction models. Figure 8 shows the NQ@SiO

_{2}, 2NQ@ SiO

_{2}, and 5NQ@ SiO

_{2}interaction models and the BCP and paths from QTAIM. The QTAIM study confirms the intermolecular hydrogen bond between NQs and SiO

_{2}for all systems, with 5NQ being in a horizontal position relative to SiO

_{2}(Figure 8E,F); it is the system with the strongest hydrogen bond interaction (see Table 3). To relate the length of the H-bond to its binding energy, we plotted L

_{H}vs. BE (Figure 9) and fit the data to the mathematical model proposed in Equation (9):

^{−1}); L

_{H}= H-bond length (Å);

**A**= −929.5 kcal mol

^{−1}is the energy at L

_{H}= 0 Å; and

**B**= 2.72 Å is the critical length at which the strength of the H-bond is too weak (R = 0.89. This model shows that the BE is stronger at small values of L

_{H}and decreases to a critical length of 2.72 Å. The strongest H-bond occurs for the BCP96 at the new hydroxyl formed between the closed 5NQ and SiO

_{2}surfaces (B.E. = −13.7 kcal mol

^{−1}), where L

_{H}is 1.56 Å. In agreement with Buemi and Zucrello, the H-bond could be weak L

_{H}> 2.2 Å, moderate 1.5 Å < L

_{H}< 2.2 Å, and strong 1.2 Å < L

_{H}< 1.5 Å [88].

## 4. Conclusions

^{−1}) with no considerable SBA-15 particle aggregations. The experimental findings are explained by DFT studies that show that 2NQ’s physisorption is mediated by H-bonds, and it is the system with more H-bond interactions. Covalent interactions can also be presented in NQ@SBA-15, 5NQ@SBA-15, and 2NQ@SBA-15 systems. These interactions can promote the deformation of NQ rings, and in the case of 5NQ, they can substrate a hydrogen atom from the surface of SiO

_{2}and, thus, modifying the surface of SiO

_{2}, which is proved by a change in the XRD pattern. We believe that for 5NQ@SBA-15, covalent interactions decrease the adsorption capacity (1.8 mg g

^{−1}). In contrast, a stronger interaction occurs between the carbonyl group of naphthoquinones and the surface of SiO

_{2}. The results of this work establish a basis for elaborating a more robust adsorption/computational model that allows obtaining information on the interactions between molecules with antimicrobial actions and the surface of SBA-15 particles; consequently, this can improve the adsorption’s capacity based on the adsorbate chemical’s structure and the physicochemical characteristics of the particle. Our findings also contribute to understanding the cargo’s chemical structure and the adsorbent material in optimizing the design of drug-delivery systems, which will ultimately increase the probability of therapeutic success and decrease the related adverse effects in preclinical and clinical trials.

## Supplementary Materials

## Author Contributions

## Funding

## Institutional Review Board Statement

## Informed Consent Statement

## Data Availability Statement

## Acknowledgments

## Conflicts of Interest

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**Figure 1.**Morphology of SBA-15 nanoparticles. (

**A**) TEM image of the irregular shape of particles. (

**B**) TEM image of a particle with ordered channels throughout its entire structure.

**Figure 2.**XRD patterns of SBA-15 loaded with NQs. (

**A**) SBA-15, (

**B**) NQ@SBA-15, (

**C**) 2NQ@SBA-15, and (

**D**) 5NQ@SBA-15.

**Figure 4.**Experimental N

_{2}adsorption/desorption isotherms of (

**A**) SBA-15, (

**B**) NQ@SBA-15, (

**C**) 2NQ@SBA-15, and (

**D**) 5NQ@SBA-15.

**Figure 5.**Adsorption isotherms of the (

**A**) NQ@SBA-15, (

**B**) 2NQ@SBA-15, and (

**C**) 5NQ@SBA-15 systems fitted to Langmuir (red) and Freundlich (blue) models.

**Figure 6.**Structure of NQ derivatives and SiO

_{2}molecules. (

**1**) NQ; (

**2a**) closed and (

**2b**) open configuration of 2NQ; (

**3a**) closed and (

**3b**) open configuration of 5NQ; (

**4**) SiO

_{2}molecular model.

**Figure 7.**Energy obtained along the rotation of the dihedral angles C1-C2-O10-H13 for 2NQ and C4a-C5-O13-H17 for 5NQ.

**Figure 8.**NQs@SiO

_{2}interaction molecular models. (

**A**) Horizontal (H) and (

**B**) vertical (V) interactions of NQ; (

**C**) closed horizontal (C.H.) and (

**D**) open horizontal (O.H.) configuration of 2NQ; (

**E**) closed horizontal (C.H.) and (

**F**) open horizontal (O.H.) configuration of 5NQ. Black labels are the bond critical point (BCP) indices. Yellow lines correspond to bond paths.

**Table 1.**Characteristics of the SBA-15 and systems NQ@SBA-15, 2NQ@SBA-15, and 5NQ@SBA-15 obtained by X-ray diffraction (XRD), dynamic light scattering (DLS), z-potential measurements, and nitrogen adsorption/desorption isotherms.

Sample | Crystallite Size | Hydrodynamic Diameter | Z Potential | Surface Area | Pore Volume | Pore Width |
---|---|---|---|---|---|---|

(Å) | (nm) | (mV) | (m^{2} g^{−1}) | (cm^{3} g^{−1}) | (nm) | |

SBA-15 | 911.23 | 618 | −19.40 | 597.25 | 0.936 | 6.17 |

NQ@SBA-15 | 669.33 | 2301 | −25.17 | 434.88 | 1.15 | 8.57 |

2NQ@SBA-15 | 814.66 | 667 | −28.40 | 441.70 | 1.16 | 8.70 |

5NQ@SBA-15 | 743.52 | 3576 | −22.97 | 438.99 | 1.14 | 8.84 |

**Table 2.**Langmuir, Freundlich, and Temkin isotherm parameters obtained by non-linear fittings for systems NQ@SBA-15, 2NQ@SBA-15, and 5NQ@SBA-15.

Langmuir | Freundlich | Temkin | |||||||
---|---|---|---|---|---|---|---|---|---|

Q_{0} | L | R^{2} | K_{F} | N | R^{2} | A_{T} | B_{T} | R^{2} | |

(mg/g) | (dm^{3}/mg) | (mg/g) | (L/g) | ||||||

NQ @ SBA-15 | 3.9746 | 0.0390 | 0.9576 | 6.3010 | 0.1394 | 0.9592 | 0.2251 | 175.6193 | 0.4083 |

2NQ @ SBA-15 | 51,590.5 | 0.0009 | 0.9836 | 32.2276 | 0.9071 | 0.9847 | 0.0767 | 1.0405 | 0.8289 |

5NQ @ SBA-15 | 3417.4 | 0.0024 | 0.9719 | 1.8176 | 0.7174 | 0.9797 | 2.0352 | 0.0281 | 0.9071 |

**Table 3.**Interaction energy ($\mathsf{\Delta}E$ ), length of H-bond (L

_{H}), bond critical point (BCP) index, all electron densities at BCP (ρ

_{rBCP}), and H-bond binding energy (BE) values obtained from interaction models.

H-Bond | L_{H} | BCP | ρ_{rBCP} | BE | |
---|---|---|---|---|---|

Donnor | Acceptor | (Å) | (Ha) | kcal mol^{−1} | |

NQ@SiO_{2} (H) | (ΔE = −10.74 kcal mol^{−1}) | ||||

SiO_{2}−O_{35} | H_{76}−NQ | 2.23 | 145 | 0.0149 | −2.57 |

NQ−O_{74} | H_{53}−SiO_{2} | 1.80 | 167 | 0.0326 | −6.53 |

NQ@SiO_{2} (V) | (ΔE = −96.08 kcal mol^{−1}) | ||||

SiO_{2}−Si_{15} | H_{80}−NQ | 3.42 | 173 | 0.0034 | −0.16 |

2NQ@SiO_{2} (CH) | (ΔE = −18.99 kcal mol^{−1}) | ||||

SiO_{2}−O_{49} | H_{80}−2NQ | 3.27 | 147 | 0.0307 | −6.11 |

2NQ−O_{76} | H_{53}−SiO_{2} | 2.52 | 88 | 0.0083 | −1.10 |

SiO_{2}−O_{35} | H_{81}−2NQ | 2.04 | 111 | 0.0219 | −4.14 |

2NQ@SiO_{2} (OH) | (ΔE = −16.06 kcal mol^{−1}) | ||||

SiO_{2}−O_{16} | H_{81}−2NQ | 1.83 | 182 | 0.0320 | −6.40 |

SiO_{2}−O_{14} | H_{75}−2NQ | 2.33 | 151 | 0.0130 | −2.15 |

2NQ−O_{73} | H_{59}−SiO_{2} | 1.77 | 99 | 0.0355 | −7.18 |

5NQ@SiO_{2} (CH) | (ΔE = −8.95 kcal mol^{−1}) | ||||

5NQ−O_{75} | H_{81}−5NQ | 1.66 | 159 | 0.0492 | −10.24 |

5NQ−O_{80} | H_{53}−SiO_{2} | 1.86 | 167 | 0.0276 | −5.41 |

SiO_{2}−O_{35} | H_{77}−5NQ | 2.27 | 147 | 0.0097 | −1.42 |

5NQ@SiO_{2} (OH) | (ΔE = −88.92 kcal mol^{−1}) | ||||

SiO_{2}−O_{35} | H_{55}−5NQ | 1.56 | 96 | 0.0648 | −13.70 |

5NQ−O_{73} | H_{59}−SiO_{2} | 2.12 | 118 | 0.0132 | −2.20 |

_{rBCP}= density of all electrons; BE = binding energy; CH = closed horizontal; OH = open horizontal.

**Table 4.**Interaction energy ($\mathsf{\Delta}E$), length of covalent bond (L

_{C}), Mayer bond order (MBO), and fuzzy bond order (FBO) values obtained from interaction models.

Bond | L_{C} | MBO | FBO | |
---|---|---|---|---|

(Å) | ||||

NQ@SiO_{2} (V) | (ΔE = −96.08 kcal mol^{−1}) | |||

SiO_{2}−Si_{48} | C_{69}−NQ | 2.01 | 0.6365 | 0.7950 |

NQ−O_{74} | Si_{36}−SiO_{2} | 1.69 | 0.1579 | 1.3143 |

2NQ@SiO_{2} (C.H.) | (ΔE = −18.99 kcal mol^{−1}) | |||

NQ−O_{74} | Si_{36}−SiO_{2} | 1.73 | 0.9474 | 1.1935 |

5NQ@SiO_{2} (O.H.) | (ΔE = −88.92 kcal mol^{−1}) | |||

SiO_{2}−O_{11} | C_{72}−NQ | 1.89 | 0.7912 | 0.9522 |

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Corpus-Mendoza, C.I.; de Loera, D.; López-López, L.I.; Acosta, B.; Vega-Rodríguez, S.; Navarro-Tovar, G.
Interactions of Antibacterial Naphthoquinones with Mesoporous Silica Surfaces: A Physicochemical and Theoretical Approach. *Pharmaceuticals* **2022**, *15*, 1464.
https://doi.org/10.3390/ph15121464

**AMA Style**

Corpus-Mendoza CI, de Loera D, López-López LI, Acosta B, Vega-Rodríguez S, Navarro-Tovar G.
Interactions of Antibacterial Naphthoquinones with Mesoporous Silica Surfaces: A Physicochemical and Theoretical Approach. *Pharmaceuticals*. 2022; 15(12):1464.
https://doi.org/10.3390/ph15121464

**Chicago/Turabian Style**

Corpus-Mendoza, César Iván, Denisse de Loera, Lluvia Itzel López-López, Brenda Acosta, Sarai Vega-Rodríguez, and Gabriela Navarro-Tovar.
2022. "Interactions of Antibacterial Naphthoquinones with Mesoporous Silica Surfaces: A Physicochemical and Theoretical Approach" *Pharmaceuticals* 15, no. 12: 1464.
https://doi.org/10.3390/ph15121464