Effect of the side chain on the properties from cidofovir to brincidofovir, an experimental antiviral drug against to Ebola virus disease

1 Introduction

At the moment, our investigation group has centered the interest in the physicochemical, structural and vibrational studies of compounds with pharmacological and/or medicinal applications such as, potential antiviral, antimicrobial, anticancer and antihypertensive drugs (Romano et al., 2013a, 2013b, 2014; Raschi et al., 2014; Márquez and Brandán, 2014; Márquez et al., 2015; Checa et al., 2014) because a technique that results easy and quick to identify and quantify different systems by using the infrared and Raman spectra is the vibrational spectroscopy, as reported broadly in the literature (Pulay et al., 1979; Keresztury et al., 2002). Besides, in the case of molecules with unknown structures, the computational simulation is of great aid to find the most stable structure in order to perform the complete assignment of the vibrational spectra (Márquez and Brandán, 2014; Romano et al., 2014; Márquez et al., 2015; Checa et al., 2014). When the structural studies are combined with the scaled quantum mechanical (SQM) methodology (Rauhut and Pulay, 1995) by means of the normal internal coordinates together with an adequate program (Sundius, 2002) it is possible to carry out a complete and reliable assignment of all the vibration normal modes of a molecule. This task is not easy in especial when the molecule in study has 90 atoms, as in the case of brincidofovir and, therefore, 264 vibration normal modes are expected for this molecule. In this work, we have studied two antiviral agents, brincidofovir and cidofovir because both have a common skeleton but brincidofovir is different from cidofovir by the large side chain: —(CH₂)₃—O—(CH₂)₁₅—CH₃. Structurally, brincidofovir is the [(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid while chemically is named hexadecyloxypropyl cidofovir (HDP-CDV) with a molecular formula of C₂₇H₅₂N₃O₇P. On the other hand, cidofovir (CDV) is the [(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethylphosphonic acid which has a simpler molecular formula, C₈H₁₄N₃O₆P. Many authors have recently reported that the addition of that large side chain in HDP-CDV, in reference to CDV, improves their activity in vitro and in vivo against certain virus types (Hostetler, 2009, 2010; Quenelle et al., 2010; Beadle and Aldern, 2002; Keith et al., 2004; Kern, 2003; Kern et al., 2004). Obviously, the incorporation of that large side chain to CDV has produced changes in the chemical properties of HDP-CDV and, so far, many of them are ignored. At the present time there are great quantities of works related to the cidofovir and brincidofovir activities against DNA viruses (Erice, 1999; Andrei and Snoeck, 2010; Abdulkarim et al., 2003; Lanier et al., 2013; Florescu and Keck, 2014; Olson et al., 2014) but, few studies were found related to their structures and/or properties (Kumar et al., 2014; Atabey and sari, 2014), for these reasons, only some of those works were here considered. In this context, it is interesting to know the structural, electronic, topological and vibrational properties of both forms HDP-CDV and CDV to understand the relation that exists between their structures and properties in connection with the biological activities of both compounds. Hostetler (Hostetler, 2009) studying the effect of alkyl chain length has reported that alkoxyalkyl esters with shorter chains (12–16 atoms) or long chains (24 atoms) exhibit less antiviral activity. The purpose of this work is to follow the changes that experiment some of their properties going from cidofovir to brincidofovir because the side chain changes from zero up to 19 C atoms. In this sense, we studied the properties of five different systems increasing the number of C atoms from zero (cidofovir) to 5, 11, 17 up to 19 C atoms, whose final structure corresponds to brincidofovir. Here, the available experimental infrared of cidofovir (Sonvico et al., 2009) was used in combination with the theoretical DFT calculations in gas phase in order to produce the complete assignment of the bands observed to the corresponding vibration normal modes. The hybrid B3LYP/6-31G^∗ method was used to optimize the different structures proposed (Becke, 1993; Lee et al., 1988). Besides, NBO (Reed et al., 1988; Glendening et al., 1996), AIM (Bader, 1990; Biegler-Köning et al., 2001), HOMO–LUMO orbitals (Parr and Pearson, 1983) and MEP calculations (Besler et al., 1990) were computed to investigate atomic charges, stabilization energies, bond orders, topological properties, electrophilic and nucleophilic reaction sites in the different structures. In addition, a series of descriptors (Márquez and Brandán, 2014; Checa et al., 2014; Parr and Pearson, 1983) were also calculated in order to predict the reactivities and behaviors of all the systems considered. All the properties of these series of systems were compared and analyzed and eventually the changes performed in the properties with the longitude of the side chain were graphically presented. The studied properties in this work partly justify the higher ability of brincidofovir to traverse biological membranes more rapidly than cidofovir and, also provide a new insight to study molecules containing large side chains.

2 Computational details

The structures of all the systems studied containing different quantity of C atoms together with the corresponding names and R groups belonging to the side chain can be seen in Table 1 while Fig. S1 shows the PO—R bond that was modified in the initial structure of cidofovir. Taking into account that cytosine forms part of the structure of cidofovir and, that according to the reported data in the literature their structures present three tautomers, amino-oxo, imino-oxo and imino-hydroxy (Sambrano et al., 2001; Brandán et al., 2008), as shown in Fig. S1, these three structures were also here considered. For the amino-oxo structure, the potential energy surface curves were studied modifying the N12—C1—C3—O22, N12—C1—C3—C5, C1—C3—O22—C23, C1—C3—C5—C16 and C3—O22—C23—P26 dihedral angles. Thus, Fig. 1 shows the most stable amino oxo structure of cidofovir which represents the common structure in all the systems proposed. Note that the final structure with 19 C atoms corresponds to the structure of brincidofovir. All these structures were modeled with the GaussView program (Nielsen and Holder, 2008) and, later, they were optimized at the B3LYP/6-31G^∗ level of theory (Becke, 1993; Lee et al., 1988) with the Gaussian 09 program (Frisch et al., 2009). Here, we have considered only the amino-oxo tautomer with bigger population analysis (97.85%), as indicated in Table 2. It is important to clarify that the structures proposed from II up to V were optimized as sodium salts because brincidofovir is available commercially as that salt. For all the structures, two charge types were analyzed, they are the natural population atomic (NPA) and the charges derived from Merz-Kollman (Besler et al., 1990). Later for all the systems, the bond orders and the stabilization energies were also computed with the NBO 3.1 program (Glendening et al., 1996) while the AIM2000 software (Biegler-Köning et al., 2001) was used to calculate their topological properties. On the other hand, the harmonic force fields for the systems I and II were evaluated using the same level of theory and the SQMFF methodology (Rauhut and Pulay, 1995) with the Molvib program (Sundius, 2002). The definitions of the natural internal coordinates for cidofovir (I) and the II compound are similar to those reported in the literature (Romano et al., 2013a, 2013b; Márquez and Brandán, 2014; Romano et al., 2014; Checa et al., 2014) and, for this reason, only for cidofovir are listed in Table S1. In this way, the complete assignments for those two compounds were performed from the resulting force fields taking into account the potential energy distribution components (PED) ⩾ 10%. The properties observed for all the series of molecules studied were graphically compared in function of the number of C atoms of the side chain.

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Figure 1

Theoretical structure of cidofovir together with the atoms numbering.

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3 Results and discussion

3.1

3.1 Geometrical parameters

Table 3 shows a comparison of the calculated geometrical parameters for the different species studied at the B3LYP/6-31G* level of theory with those experimental reported by Borodi (Borodi et al., 2001) for hydrated sodium cytidine-5′-monophosphate and, with the calculated values for the aminoethyl phosphonic acid (Roldán et al., 2013) because so far, the structures of cidofovir and brincidofovir were not experimentally reported. The root-mean-square deviation (RMSD) values were also included in Table 3. Obviously, slightly variations are observed in the bond length and angles values, as it was expected because the theoretical and experimental structures are different among them but, when cidofovir is compared with the values reported by Kumar (Kumar et al., 2014) by using the B3LYP/6-311++G* method a very well concordance is observed. Analyzing the graphics of bond lengths and angles in function of the number of C atoms (Figs. 2 and 3) we observed that the P26—O28 and P26—O29 bonds and the O22—P26—O27, C23—P26—O27, C23—P26—O28 and C23—P26—O29 angles present the higher variations, as it is expected because these parameters are related to the PO—R bonds that are modified, as shown in Fig. S1. Fig. 3 shows that the dihedral angles practically remain constant with the increase in the number of C atoms in side chain. A comparison of the total energy, dipole moment and volume values for all the systems studied in gas phase can be seen in Table 2 while the variations of both properties in function of the C atoms are shown in Fig. 4. The volumes for all the structures were calculated by using the Moldraw program (Ugliengo, 1998). Note that the volume variation with the longitude of the side chain is practically lineal, with a very good coefficient correlation (0.9912) while the dipole moment values increase quickly up to a side chain of five C atoms and, then, remain almost constant when increasing the C atoms up to 19. Hence, the lengthening of the side chain generates clearly an increase in the dipole moment value from cidofovir to brincidofovir of practically twice their value. These results suggest that brincidofovir could penetrate more deeply into the bilayer interior, as reported by Sachs and Woolf (2003) that larger anions penetrate more deeply into a more heterogeneous and hydrophobic molecular region.

Table 3 Comparison of the calculated geometrical parameters for the different studied compounds.

B3LYP/6-31G∗a						Exp.b,c
Compounds
Parameters	0	5	11	17	19
Bond lengths (Å)
C1—N12	1.464	1.466	1.466	1.466	1.466	1.457b
C3—O22	1.440	1.436	1.436	1.436	1.436
C5—O16	1.427	1.427	1.427	1.427	1.427
C6—O14	1.226	1.227	1.227	1.227	1.227	1.242b
C7—N18	1.367	1.370	1.370	1.370	1.370	1.299b
C7—N13	1.320	1.320	1.320	1.320	1.320	1.346b
C23—P26	1.839	1.854	1.854	1.854	1.854	1.826c
P26—O27	1.490	1.500	1.500	1.500	1.500	1.479c
P26—O28	1.632	1.721	1.721	1.721	1.721	1.638c
P26—O29	1.839	1.528	1.528	1.528	1.528	1.604c
RMSD	0.087	0.050	0.050	0.050	0.050
Bond angles (°)
C3—C5—O16	106.9	107.3	107.3	107.3	107.3
C3—O22—C23	114.7	114.7	114.8	114.6	114.6
O22—C23—P26	110.0	113.2	113.3	113.2	113.2
C23—P26—O27	116.5	112.1	112.1	112.1	112.1	117.2c
C23—P26—O28	106.5	102.0	102.1	102.1	102.1	100.1c
C23—P26—O29	99.9	108.3	108.3	108.3	108.3	104.4c
RMSD	4.5	3.9	3.9	3.9	3.9
Dihedral angle (°)
N12—C1—C3—O22	−160.7	−159.3	−159.3	−159.3	−159.2
C3—O22—C23—P26	−82.7	−81.4	−81.3	−81.2	−81.2
C1—C3—C5—O16	−171.7	−171.0	−170.7	−171.0	−171.0
O22—C23—P26—O27	43.1	39.3	39.7	39.1	39.0
O22—C23—P26—O28	−82.8	−77.1	−76.6	−77.3	−77.4
O22—C23—P26—O29	170.9	178.8	179.2	178.5	178.5

a This work.

b From reference Borodi et al. (2001).

c From reference Roldán et al. (2013).

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Figure 2

Variation of the bond lengths (upper) and angles (bottom) in function of the numbers of C atoms of the different structures proposed in gas phase at the B3LYP/6-31G^∗ level of theory.

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Figure 3

Variation of the dihedral angles in function of the numbers of C atoms of the different structures proposed in gas phase at the B3LYP/6-31G^∗ level of theory.

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Figure 4

Variation of the dipole moment (upper) and volume (bottom) in function of the numbers of C atoms of the different structures proposed in gas phase at the B3LYP/6-31G^∗ level of theory.

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3.2

3.2 Atomic charges, molecular electrostatic potentials, bond orders

Here, the MK and NPA charge studied for all the systems are summarized in Tables S2 and S3, respectively while the corresponding values for the C, O and N atoms in function of the C atoms are represented in Figs. 5 and 6, respectively. Analyzing the MK charges on the C atoms we observed that the charges on the C1 atoms present the higher variations with the increase of C atoms in the side chain while on the O22, O28 and O29 atoms, an increase was observed quickly up to a side chain of five C atoms and, later the values remain almost constant up to a side chain of 19 C atoms. In relation to the N atoms, note that the MK charges on the N12 atoms have the least negative values and present the highest modifications with the side chain. Obviously, this observation is justified because the N12 atom is directly linked to the side chain that changes. In contrast, when we considered the NPA charges of Fig. 6 we observed that the charges on the O16 present the highest changes with the side chain while the charges on the N atoms remain practically constant with the increase in the number of C atoms and, also the NPA charges on the N12 atoms have the least negative values, in accordance with the MK charges. The exhaustive analysis of the molecular electrostatic potential (MEP) values presented in Table S4 and Fig. 7 shows clearly that the MEP values on the O29 atoms present the highest changes with an increase in the number of C atoms, as it was expected because the PO—R bond is the bond modified by the increment of different groups in the side chain. Thus, the MEP values decrease quickly up to a side chain of five C atoms and, later the values remain almost constant up to a side chain of 19 C, as observed in Fig. 7. The MEP surface mapped for cidofovir (I structure with R⚌H) seen in Fig. S2, shows a strong red color on the O14, N13 and O27 atoms indicating the nucleophilic sites because these regions are acceptor sites of H bonds while on the H atoms belonging to the NH₂ and O28—H32 groups, strong blue colors are observed indicating electrophilic sites due to the fact that they are donor sites of H bonds. The mapped MEP surface for brincidofovir presents a green color (inert or inactive site) on practically all the surface of the large side chain and only a strong blue color is observed on the sodium atom indicating that this site is strongly donor, for this reason, the graphic is not presented here. The study of the bond orders, by using the Wiberg indexes can be seen in Table S5 and Fig. S3. The figures show clearly that the C23 atoms have the lowest values while the O29 atoms present the highest modifications in the bond order values because they are linked to the different R groups of the side chain. On the other hand, the values of the O28 atoms increase with the number of C atoms while the values of O29 decrease quickly up to a side chain of five C atoms and, later the values remain almost constant up to a side chain of 19 C. In relation to the N atoms, the low bond order values are observed in the N12 atoms because these atoms are directly linked to the side chain. The graphics reveal clearly that from cidofovir up to a side chain of 5 C, atoms increase the MK charges on the O28 and O29 atoms belonging to the PO₃ groups and also increase the MEP on the O29 atoms and, as a consequence a decrease in the bond order for the O29 atoms is observed. This study shows that the hydrophobic side chains from 11 up to 19 C atoms together with the nucleophilic and electrophilic sites determine the chemical and biological behaviors, as reported by Immel (1995).

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Figure 5

Variation of the MK charges on the C (upper), O (medium) and N (bottom) atoms in function of the numbers of C atoms of the different structures proposed in gas phase at the B3LYP/6-31G^∗ level of theory.

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Figure 6

Variation of the NPA charges on the C, O (upper)and N (bottom) atoms in function of the numbers of C atoms of the different structures proposed in gas phase at the B3LYP/6-31G^∗ level of theory.

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Figure 7

Variation of the MEP values on the C (upper), O (medium) and N (bottom) atoms in function of the numbers of C atoms of the different structures proposed in gas phase at the B3LYP/6-31G^∗ level of theory.

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3.3

3.3 NBO and AIM studies

The stabilities of all the structures proposed were analyzed by NBO (Reed et al., 1988; Glendening et al., 1996) and AIM calculations (Bader, 1990; Biegler-Köning et al., 2001). In this way, Table S6 shows the main delocalization energies for the five structures in gas phase by using 6-31G^∗ basis set while Fig. S4 shows the graphics of these delocalizations in function of the number of C atoms. Note that the LP(2)O29 → ^∗C23—P26 delocalization is only observed in the structures different from cidofovir (I) because only this species has a PO—H bond instead of the PO—R bond that has the remaining structures. Besides, the total energy slightly increases with the increase of C atoms of the side chain. Thus, taking into account the total energy, the stability increases slightly from I up to V, it is from cidofovir up to brincidofovir. The structure with 11 C atoms in the side chain has the highest stability (2687.14 kJ/mol), as observed in Table S6.

The AIM calculations were used to study the different interactions of all the species proposed by means of their topological properties. Thus, the parameters in the bond critical points (BCPs) and ring critical points (RCPs) such as, the electron density distribution, ρ(r), the Laplacian, ∇²ρ(r), the eigenvalues (λ1, λ2, λ3) of the Hessian matrix and, the λ1/λ3 ratio values are observed in Table S7. The latter ratio allows the description of the character of interaction between atoms (Bushmarinov et al., 2009). Hence, when λ1/λ3 > 1 and ∇²ρ(r) < 0 the interaction is typical of covalent bonds (called shared interaction) with high values of ρ(r) and ∇²ρ(r) while when λ1/λ3 < 1 and ∇²ρ(r) > 0 the interaction is called closed-shell interaction and it is typical of ionic, highly polar covalent and hydrogen bonds as well as of the van-der-Waals and specific intermolecular interactions. Table S7 shows the analysis of BCPs and RCPs for all the structures while Fig. 8 shows the variations of ρ(r) in the H bond interactions observed for all the molecules in function of the longitude of the side chain. Note that the O25- - -H16 interaction is only observed in cidofovir (I) while the O22- - -H33 interaction is observed in the remaining compounds. The graphic clearly shows that the densities in the O27- - -H2 and O27- - -H11 interactions present the highest variations with the number of C atoms, increasing quickly their densities from (I) up to a side chain of five C atoms and, later all the values remain almost constant up to a side chain of 19 C. The proximities between the atoms involved in those two interactions justify the increase in their density values, as it can be seen in Table S7. Fig. S5 shows the molecular graphic of cidofovir in gas phase at B3LYP/6-31G^∗ level of calculation. This study shows clearly that the high density values of the O27- - -H2 and O27- - -H11 interactions and the existence of seven BCPs for brincidofovir (V) support their highest stability, in relation to cidofovir (I) which presents only five BCPs.

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Figure 8

Variation of the density values (in a.u.) of the H bond interactions in function of the numbers of C atoms of the different structures proposed in gas phase at the B3LYP/6-31G^∗ level of theory.

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3.4

3.4 Frontier orbitals and descriptors analyses

The reactivities and behaviors of all the species proposed were predicted by using the gap energy values and some important descriptors reported in the literature (Márquez and Brandán, 2014; Checa et al., 2014; Parr and Pearson, 1983). Thus, Table S8 shows the calculated HOMO and LUMO orbitals, energy band gap, chemical potential (μ), electronegativity (χ), global hardness (η), global softness (S) and global electrophilicity index (ω) for all the species at B3LYP/6-31G^∗ level of theory. Fig. S6 shows the variation of the frontier orbital and gap energy values in function of the numbers of C atoms of the different series of molecules proposed while in Fig. 9 the variations of those descriptors can be seen in function of the number of C atoms of the side chain. Fig. S6 shows that the increment in the number of C atoms generates a notable reduction in the gap values and, as a consequence the reactivity increases from cidofovir up to brincidofovir. Here, as observed in some properties above, the reactivity from cidofovir increases quickly up to a side chain of five C atoms and, later the values remain approximately constant up to a side chain of 19 C. On the other hand, Fig. 9 shows clearly that the electrophilicity index is higher in brincidofovir than cidofovir, then, the increase in the activity of HDP-CDV in reference to CDV is probably related to this index. The highest electrophilicity index and the lowest gap energy observed for a side chain of 5 C atoms probably predicted that the compound II could act as a drug with better properties than brincidofovir. On the other hand, comparing brincidofovir with thymidine, the first compound has lower gap value (−3.7715 eV) and higher electrophilicity index (3.5474 eV) than thymidine whose values are −5.4748 and 2.0728 eV, respectively.

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Figure 9

Variation of the descriptor values in function of the numbers of C atoms of the different structures proposed in gas phase at the B3LYP/6-31G^∗ level of theory.

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4 Vibrational analysis

The optimized molecule’s series have C₁ symmetries. Cidofovir has 90 vibration normal modes while the II structure has a total of 138 vibration normal modes where all the vibration modes are infrared and Raman active. Fig. S7 shows a comparison between the available experimental infrared spectra of cidofovir taken from Sonvico (Sonvico et al., 2009) and those predicted at B3LYP/6-31G^∗ level of theory for the structures with 11, 17 and 19 C atoms in the side chains. The observed and calculated wavenumbers and assignments for cidofovir and the (II) compound in gas phase are observed in Table 4 while in Table S9 the experimental and predicted wavenumbers are compared for the most important vibration modes of cidofovir with those calculated for all the molecules of the series. The assignment of the experimental bands to the normal modes of vibration was performed by using the SQMFF methodology (Rauhut and Pulay, 1995) at the B3LYP/6-31G^∗ level of theory and taking into account the Potential Energy Distribution (PED) calculated with the Molvib program (Sundius, 2002). Table S10 summarizes the PED contributions and assignments for cidofovir in gas phase. The exhaustive comparisons of the IR spectra show that, in general, in the 3047–2800 cm⁻¹ region the intensities of the bands predicted evident clear modifications with the increment of CH₂ groups in the side chains especially in those regions attributed to the CH₂ stretching modes, as was observed by us in a series of seven N-benzylamides (Chain et al. submitted to Spectrochim. Acta, 2015). Fig. S8 shows the variation of the intensities corresponding to the antisymmetrical and symmetrical CH₂ and to the C3—H4 stretching modes of the five species studied in function of the numbers of C atoms. Note that the highest intensities are observed for the CH₂ antisymmetrical modes belonging to the C23 atom that increase quickly from cidofovir up to a side chain of 11 C atoms and, later slightly decrease up to 19 C atoms. On the other hand, the intensities corresponding to the symmetrical modes present an oscillatory behavior, as observed in Fig. S8. The analysis of the Raman spectra (Figs. S9 and S10) for all the species was presented in the Supporting material. Evidently, these vibrational studies reveal that the CH₂ groups linked to the PO₃ groups undergo the highest modifications as a consequence of the lengthening of the side chain in one of the PO—H bonds. Moreover, Table 4 shows that when the side chain increases in five C atoms slight changes, principally in the vibration modes assigned to the PO₃ groups, are observed. The calculated harmonic force fields for cidofovir and the II compound can be obtained upon request. Below, a brief discussion of the assignment of the main vibration modes of cidofovir is presented.

5 Force constants

The force fields for cidofovir and the II compound were calculated from the corresponding force fields at B3LYP/6-31G^∗ level of theory by using the SQM methodology (Rauhut and Pulay, 1995) and the Molvib program (Sundius, 2002). The values can be seen in Table 5 compared with those reported for compounds containing similar groups (Romano et al., 2013b; Márquez and Brandán, 2014; Checa et al., 2014; Brandán et al., 2011). Note that the f(νN—H) force constant values for cidofovir and the II species present similar values to the conformers of other antiviral agent zalcitabine but, higher values than the corresponding to the three conformers of thymidine are observed because the latter compound has a N—H group in its structure instead of a NH₂ group. However, when the values are compared with other molecules that contain NH₂ groups such as, acetazolamide (6.45 mdyn Å⁻¹) (Brandán et al., 2011) or 5-difluoromethyl-1,3,4-thiadiazole-2-amino (6.64 mdyn Å⁻¹) (Romano et al., 2013b) the values of these constants are slightly different, too. These differences can be explained by the bond angles because in cidofovir the H—N—H angle has a value of 117.0°, similar to zalcitabine and in II a value of 116.6°, in azetazolamide the value is 111.5° and in the thiadiazole derivative is of 113.3°. The differences among these values are directly related to the geometry of the molecules because the NH₂ group in azetazolamide is linked to a SO₂ group tetrahedral while in the thiadiazole derivative, that group is linked to a five member ring and, in our case and in zalcitabine the group is linked to a six member ring. Evidently, the value of the constant related to the NH₂ group is strongly dependent of the group or ring to which it is linked. In general, the values calculated for cidofovir are higher than those calculated for the II compound, with the exception of the f(νC—C)_A6 and f(νC—O—H) constants whose high values are justified by the increase of C atoms in the side chain. Besides, we observed that the increment in the quantity of C atoms generates a slightly increase in the C—C stretching of the pyrimidine ring and, for this reason, a strong increase in the corresponding force constant is observed. In general, the constant force values are in agreement with those reported in the literature (Romano et al., 2013b; Márquez and Brandán, 2014; Checa et al., 2014; Brandán et al., 2011).

Due to the extension of this work and to the quantity of information to present, the studies in solution will be presented in a next paper.

6 Conclusions

In the present work, the theoretical molecular structures of five members of the series C₈H₁₃N₃O₅PO—R (R⚌H, —(CH₂)₃—O—CH₂—CH₃, —(CH₂)₃—O—(CH₂)₇—CH₃, —(CH₂)₃—O—(CH₂)₁₃—CH₃ and —(CH₂)₃—O—(CH₂)₁₅—CH₃) were determined by using the hybrid B3LYP/6-31G^∗ method in gas phase. Their structural, electronic, topological and vibrational properties were graphically studied in function of the quantity of C atoms in the side chains by using NBO, AIM, HOMO–LUMO, MEP calculations at B3LYP/6-31G^∗ level and the available IR spectrum of cidofovir. This study reveals clearly that the large side chain modifies the structures of the PO₃ groups. Thus, the most negative MK charges on the O atoms and the positive charges on the P atoms belonging to the PO₃ groups are observed for brincidofovir together with the higher MEP on the O29 atoms of those groups. The volume variation with the longitude of the side chain is practically lineal while the dipole moment value of brincidofovir is twice the value of cidofovir. This high polarity in brincidofovir together with the large side chain could support the ability of brincidofovir to traverse biological membranes more rapidly than cidofovir and, on the other hand, the low bond order that presents the O29—R bond suggests that the lipid side chain is removed inside the cell releasing high levels of cidofovir, as reported in the literature, where finally cidofovir is phosphorylated to the active antiviral cidofovir diphosphate. The NBO study shows a slightly increase in the stability from I up to V in gas phase while the AIM study suggests a higher stability of brincidofovir in relation to a cidofovir (I) in the same medium. Brincidofovir presents a higher electrophilicity index and a higher reactivity than cidofovir. The complete assignment of the 90 vibration modes of cidofovir was proposed for the first time by using the available experimental infrared spectrum and the SQM methodology. The theoretical assignment for the 138 vibration modes of the II compound was reported together with the corresponding force fields of these two structures. Finally, the main force constant of those two structures is reported here.