Structure and electronics properties of novel antimalarial molecules: Comparative study of ferrotriborodiazoquine and ferrodiborotriazoquine with ferroquine using density functional theory

Polyhedron 119 (2016) 471–482

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Polyhedron journal homepage: www.elsevier.com/locate/poly

Structure and electronics properties of novel antimalarial molecules: Comparative study of ferrotriborodiazoquine and ferrodiborotriazoquine with ferroquine using density functional theory Nabila Triaki a, Sihem Zaater b, Soraya Abtouche a, Meziane Brahimi a,⇑ a b

Laboratoire de Physico Chimie Théorique et de Chimie Informatique, Faculté de Chimie, USTHB, BP N° 32 El Alia, Alger, Algerie Ecole Préparatoire des Sciences Techniques d’Alger (EPSTA), Algerie

a r t i c l e

i n f o

Article history: Received 22 March 2016 Accepted 25 July 2016 Available online 20 September 2016 Keywords: DFT Ferrocene Ferroquine Ferroborazenes Ferrotriborodiazoquine Ferrodiborotriazoquine

a b s t r a c t The research of new ferrocene analogous compounds, by replacing one or more carbon atoms of the cyclopentadienyl, by another element, such as P, Si, Ge, B, N, has developed significantly and made the preparation of new drugs more efficiently. This work aims to find a new organometallic complex that may have antimalarial and/or anticancer properties. To that end, we substituted, in cyclopentadienyl ring, one or more carbon by boron and/or nitrogen atoms. Moreover, the ferrocene in ferroquine has been substituted by our new compounds. These new species could lead to novel classes of antimalarial and/or anticancer molecules. Ó 2016 Elsevier Ltd. All rights reserved.

1. Introduction Ferrocene (g5-H5C5)2Fe is the most popular iron sandwich complex of the metallocene family. It is an organometallic compound where two cyclopentadienyl (Cp) ring anions bound on opposite sides of a central metal ion (Fe2+). It was unexpectedly discovered by Kealy and Pauson [1], whereas its sandwich structure was elucidated by Fischer and Wilkinson, who were awarded the Nobel Prize for their pioneering work on the chemistry of sandwich complexes [1,2]. Ferrocene has found extensive applications in different fields of material science, such as asymmetric catalysis, large-scale olefin polymerization, luminescence and fluorescence. Its electrochemical properties make it attractive for use in drug design [3]. It offers a promising approach to the development of new anticancer [4–7] and antimalarial drugs [8–10] as well as novel inhibitors of hepatitis C virus [11]. Malaria is one of the major infectious disease killers throughout the tropical regions of the planet, despite being preventable and curable [12]. Plasmodium falciparum is the most dangerous parasite species. It is responsible for the majority of deaths attributed to malaria. Recent observations have alerted that the parasite is

⇑ Corresponding author. E-mail address: [email protected] (M. Brahimi). http://dx.doi.org/10.1016/j.poly.2016.07.032 0277-5387/Ó 2016 Elsevier Ltd. All rights reserved.

becoming resistant to almost all traditional treatments such as Chloroquine (CQ) [13], which have encouraged the synthesis of many ferrocenyl derivatives of the antimalarial molecule by the research team of Professor Brocard. Their work led to the synthesis of ferroquine (FQ, SSR97193) [14], which resulted from the insertion of a ferrocenyl group inside the chain of chloroquine, but the increasing resistance of P. falciparum malaria [15] has enhanced the need to develop new structures. Many works are devoted to modifying the chloroquine part of ferroquine to design novel antimalarial drugs [16–19]. The research of new ferrocene analogous compounds when replacing one or more carbon atoms of the cyclopentadienyl by another element, such as P, Si, Ge, B, N [18–26], is developing significantly and made the preparation of new drugs more efficiently. Among these studies, the theoretical work of 1-ferrogermene published by Zaater et al. [27] and the work of Bridgeman and Rothery [26] have conducted a theoretical study of the sandwich compound (g5-N3B2H4)2Fe, which was synthesized in 1967 by Nöth et al. [28]. As for ferrocene, this compound can be found in both eclipsed and staggered conformations. The conformation adopted by the rings is staggered with the N1 atoms of each ring diametrically opposite to one another. The rotation barrier was calculated ca. 90 kJ/mol [26]. The present work aim is to find a new organometallic complex that may have antimalarial and/or anticancer properties. To that end, we substituted, in cyclopentadienyl ring, one or more carbon

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by boron and/or nitrogen atoms. Moreover, the ferrocene in ferroquine has been substituted by our new compounds. These new species could lead to novel classes of antimalarial and/or anticancer molecules. The following compounds are the resulting structures: (NC4H4)2Fe1-10 , (NC4H4)2Fe1-20 , (NC4H4)2Fe1-30 , (BC4H4)2Fe1-10 , (BC4H4)2Fe1-20 , (BC4H4)2Fe1-30 , (N3B2H4)2Fe and (N2B3H4)2Fe. 2. Method of calculations All calculations were performed using the Gaussian 03 program [29], using the Density Functional Theory (DFT) method [30,31] and GaussView 3.1 [32] visualization program. The exact exchange functional of Becke (B3) [33] was combined with the functional gradient correlation of Lee-Yang-Par (LYP) [34]. The Gaussian basis

sets used are: cc-pvtz and 6-31 + G⁄. Computations Frequency has been performed on the optimized geometries to confirm the nature of the stationary points as equilibrium structures with all real frequencies or transition states with only one imaginary frequency. Zero point energy (ZPE) corrections are evaluated at the same level of theory. Due to the much larger computational cost of MP2 calculations, the medium quality 6-31 + G(d) basis set was adopted for test calculations on the optimized structures using B3LYP (CAM-B3LYP)/631 + G (d) level of theory. The obtained results of the ad hoc calculations are almost similar to those of DFT, particularly for geometry and energy related calculations. Even there is no formal proof of the availability of Koopmans’ theorem within DFT, allowing the approximation of the ionization

  Fig. 1. Structures and relative energy in kcal/mol of the C5H6 (194.174115 u.a), C5H 5 , NC4H6 (210.801202 u.a), NC4H5 , BC4H6 (180.898652 u.a), BC4H5 structures obtained at B3LYP/cc-pvtz levels.

N. Triaki et al. / Polyhedron 119 (2016) 471–482

potential (I) and the electron affinity (A) using the EHOMO and ELUMO, its validity is highly considered. Assuming the validity of the aforementioned theorem, the chemical potential (l), global hardness (g) and electrophilicity index (x) can be calculated with the following equation:

473

l ¼ ðI þ AÞ=2; g ¼ ðI  AÞ=2; x ¼ l2 =2g Where I = (E+  E°) is the ionization energy and A = (E  E°) is the electron affinity of the species. I and A are the energies of oxidation (X ? X+ + 1e) and reduction (X + 1e ? X) reactions respectively. The electrophilicity x is a measure of the species’

Fig. 2a. Structures and relative energy in kcal/mol of the N3B2H5 (a), N2B2H4N (a1), N2B2H4N (a2), N3BH4B (a3), obtained at B3LY/cc-pvtz levels.

Fig. 2b. Structures and relative energy in kcal/mol of the N3B2H5 (b), N2B2H4N (b1), N2B2H4N (b2), N2B2H4B (b3), obtained at B3LY/cc-pvtz levels.

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N. Triaki et al. / Polyhedron 119 (2016) 471–482 Table 2 Optimized structural parameters (distances in Å, valence angle in degrees) of the N2B2H4N, N3B2H5, N2B2H4B and N2B3H5 at B3LYP/cc-pvtz levels. N2B2H4N

N2B2H4B

Bond length B–N1 B–N2 N2–N2 B–H N2–H

1.41 1.47 1.44 1.22 1.01

Bond length N–B1 N–B2 B2–B2 N–H B2–H

1.51 1.42 1.71 1.01 1.21

Bond angles N1–B–N2 B–N1–B B–N2–N2 H–B–N1 B–N2–H

113 103 104 129 120

Bond angles B1–N–B2 N–B1–N N–B2–B2 H–N–B1 N–B2–H

113 103 103 119 122

N3B2H5

Scheme 1. Three deprotonation possibilities of N3B2H5(a) and N2B3H5(b) species. Relatives energies are calculated in references with the energy of N3B2H5 = 217.127486 u.a and the energy of N2B3H5 = 187.258525 u.a.

electrophilic power. When two species react with another, one molecule behaves as a nucleophilic while the other acts as an electrophile. The quantum molecular descriptors are also evaluated with the Koopmans approximations where I = E(HOMO) and A = E (LUMO). These results are comparable to those obtained without the previous approximations. To better describe the hydrogen bond of the ferroquine, ferrotriborodiazoquine and ferrodiborotriazoquine, a DFT calculation, using the long-range corrected. CAM-B3LYP functional [35] with the polarized and diffuse 6-31 + G⁄ basis set, were employed. Those calculations are carried out using the Gaussian 09 program [36]. The interaction energy DEint of a complex is defined as the electronic energy difference between the energy of the complex E(A,B) and the energies of the isolated molecules (EA, EB). The interaction energy DEint is shown in the following equation:

DEint ¼ DEðABÞ ¼ EðA; BÞ  ðEðAÞ þ EðBÞÞ

N2B3H5

Bond length B–N1 B–N2 N2–N2 B–H N1–H N2–H

1.43 1.42 1.41 1.18 1.00 1.00

Bond length N–B1 N–B2 B2–B2 N–H B1–H B2–H

1.44 1.42 1.74 1.01 1.19 1.19

Bond angles N1–B–N2 B–N1–B B–N2–N2 H–B–N1 H–N1–B B–N2–H

106 109 109 129 125 129

Bond angles B1–N–B2 N–B1–N N–B2–B2 H–N–B1 H–B1–N N–B2–H

112 111 103 123 121 125

3. Results and discussion 3.1. The free ligands: C5H6, NC4H6, BC4H6, N2B3H5 and N3B2H5 Fig. 1 illustrates the geometric parameters and the relative deprotonation energies of C5H6, NC4H6 and BC4H6 as well as their respective anions. The deprotonation of BC4H6 (362.3 kcal mol1) costs about the same energy as for C5H6 (365.9 kcal mol1), in contrast to the deprotonation of NC4H6 (398.9 kcal mol1), which means that the  formation of NC4H 5 and C5H5 is similarly favorable, the formation of Fe-(BC4H5)2 is favorable that Fe-(C5H5)2 complex. Fig. 2 shows the geometric structures of N3B2H5 and N2B3H5 rings as well as their respective anions with the relative deprotona-

Table 1 Optimized structural parameters (bond lengths in Å, valence angle in degrees) and Mulliken charges of B2N2H4N and B2N2H4NH. N2B2H4N Parameters Bond length B–N1 B–N2 N2–N2 B–H N2–H Bond angles N1–B–N2 B–N1–B B–N2–N2 H–B–N1 B–N2–H

(a) (b)

N3B2H5 (a)

3LYP/cc-pvtz (b)

1.45 1.42 1.38 1.21 1.04

1.41 1.47 1.44 1.22 1.01

96 121 114 126 125

113 103 104 129 120

Results obtained at B3LYP/GTO sets of double-f quality, Ref. [23]. Our results.

Parameters Bond length B–N1 B–N2 N2–N2 B–H N1–H N2–H Bond angles N1–B–N2 B–N1–B B–N2–N2 H–B–N1 H–N1–B B–N2–H

(a)

B3LYP/cc-pvtz (b)

1.44 1.44 1.41 1.19 1.02 1.02

1.43 1.42 1.41 1.18 1.00 1.00

105 110 110 130 125 132

106 109 109 129 125 129

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N. Triaki et al. / Polyhedron 119 (2016) 471–482 Table 3 Mulliken charge of N2B2H4N, N3B2H5, N2B2H4B and N2B3H5 species at the B3LYP/cc-pvtz level. Mulliken charges N2B2H4N B N1 N2 HB HN

N2B2H4B 0.060 0.360 0.190 0.140 +0.080

N B1 B2 HB HN

N3B2H5 0.080 0.430 0.190 0.110 +0.090

B N1 N2 HB HN1 HN2

N2B3H5 0.000 0.160 0.140 0.010 +0.150 +0.150

N B1 B2 HN HB1 HB2

0.150 +0.090 0.050 +0.150 0.000 +0.000

Fig. 3. Structures and relative energy in kcal/mol of the (NC4H4)2Fe1-10 , (NC4H4)2Fe1-20 , (NC4H4)2Fe1-30 , (BC4H5)2Fe1-10 , (BC4H4)2Fe1-20 , and BC4H5)2Fe1-30 , complexes obtained at B3LY/cc-pvtz level.

tion energies in kcal mol1. The deprotonation of those species occurs the way given in Scheme 1: The full optimization of the species, without any geometrical constraints, was performed at the MP2 and B3LYP levels with the 6-31 + G⁄ and cc-pVTZ basis sets. The calculations showed that the two levels of theory lead to the same conclusions. Several studies have concluded that the Cp anion is aromatic [37,38]; it forms a plane with equal C2–C3 and C3–C4 bond lengths. If the small difference between the two bond lengths, the planarity of species and the first deprotonation energy considered as criteria for the formation of sandwich complexes, we can conclude that all the mono anions are susceptible of forming the same complexes that the ferrocene

one with an advantage for Fe-(BC4H5)2 and Fe-(N3B2H4)2, see Fig. 1 and Scheme 1. Our results have been compared with those given in the literature [26] for B2N2H4NH and B2N2H4N species. The obtained results, using B3LYP/cc-pvtz, are summarized in Table 1. The symmetry of N3B2H5 is C2h. The deprotonation does not result in the same symmetry. In fact, the hydrogen H7 is out of the plane with a dihedral angle of 46.9°. Deprotonation only slightly affects the bond lengths, whereas the valence angles are strongly affected. The angle N1BN2 dropped from 106 degrees in the neutral form to 113 degrees for ionic form. Our results, concerning the geometric parameters, are very close to the results obtained by Blackie et al. [26].

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Table 4 B3LYP/cc-pvtz computed structural parameters for the (NC4H4)2Fe1-10 , (NC4H4)2Fe1-2’ and (NC4H4)2Fe1-30 . Bond lengths are in angstroms, angles in degrees and dipole moment in Debye. Parameters (NC4H4)2Fe1-10

(NC4H4)2Fe1-20

(NC4H4)2Fe1-30

Bond length N1–C2 C3–C2 C3–C4 C4–C5 C5–N1 N1–H6 C2–H7 C3–H8 C4–H9 C5–H10 N1–Fe C2–Fe C3–Fe C4–Fe C5–Fe

1.411 1.406 1.415 1.406 1.412 1.006 1.074 1.076 1.076 2.074 2.009 2.042 2.179 2.178 2.042

Bond length N1–C2 C3–C2 C3–C4 C4–C5 C5–N1 N1–H6 C2–H7 C3–H8 C4–H9 C5–H10 N1–Fe C2–Fe C3–Fe C4–Fe C5–Fe

1.467 1.427 1.424 1.415 1.460 1.013 1.080 1.078 1.077 1.080 2.059 2.012 2.085 2.027 2.092

Bond length N1–C2 C3–C2 C3–C4 C4–C5 C5–N1 N1–H6 C2–H7 C3–H8 C4–H9 C5–H10 N1–Fe C2–Fe C3–Fe C4–Fe C5–Fe

1.443 1.339 1.470 1.448 1.453 1.007 1.076 1.078 1.080 1.088 2.117 2.937 2.915 2.127 2.864

Non-bonded distances (C4H4N)...(C4H4N)0 Fe. . .(C4H4N) N1. . .N01 C2. . .C02 C3. . .C03 C4. . .C04 C5. . .C05 H6. . .H06 H7. . .H07 H8. . .H08 H9. . .H09 H10. . .H010

3.519 1.713 3.864 3.328 3.539 3.539 3.326 3.566 3.439 3.665 3.664 3.438

Non-bonded distances (C4H4N). . .(C4H4N)’ Fe. . .(C4H4N) N1. . .N01 C2. . .C02 C3. . .C03 C4. . .C04 C5. . .C05 H6. . .H06 H7. . .H07 H8. . .H08 H9. . .H09 H10. . .H010

3.510 1.816 3.895 3.375 3.496 3.558 3.420 3.673 3.589 3.786 3.732 3.565

Non-bonded distances (C4H4N). . .(C4H4N)0 Fe. . . (C4H4N) N1. . .C01 C2. . .C02 C3. . .N03 C4. . .C04 C5. . .C05 H6. . .H06 H7. . .H07 H8. . .H08 H10. . .H010 H10. . .H010

3.780 1.695 3.464 3.384 3.623 4.335 4.150 3.501 3.897 3.890 4.770 4.586

Bond angles C3–C2–N1 C4–C3–C2 C2–N1-C5 H6–N1–Fe C4–C5–N1 C3–C4–C5

108.0 108.0 107.9 133.3 108.0 108.0

Bond angles C3–C2–N1 C4–C3–C2 C2–N1–C5 H6–N1–Fe C4–C5–N1 C3–C4–C5

108.5 104.8 95.5 96.7 108.9 105.4

Bond angles C3–C2–N1 C4–C3–C2 C2–N1–C5 H6–N1–Fe C4–C5–N1 C3–C4–C5

107.0 108.4 109.4 125.9 100.3 108.0

Dihedral angles C4–C3–C2–N1 C2–C3–C4–C5 Dipole moment

2.9 0.0 4.359

Dihedral angles C4–C3–C2–N1 C2–C3–C4–C5 Dipole moment

25.9 0.4 4.321

Dihedral angles C4–C3–C2–N1 C2–C3–C4–C5 Dipole moment

2.8 13.9 2.267

In Tables 2 and 3, are gathered the results concerning the optimized geometrical parameters and Mulliken charges for N2B3H5,  N2B3H 4 , N3B2H5 and N3B2H4 respectively. We note that the symmetry of N2B2H4BH is C2h. Removing a proton from the molecules moves the boron atom out of the plane with a dihedral angle of 14.9 degrees. Thus, for Mulliken charges, we observe that the charge of N decreases in absolute values (0.150e in the neutral form and 0.080e in the ionic form). For B1 and B2 atoms, the charge increases from 0.090e to 0.430e and from 0.050e to 0.190e respectively. 3.2. Comparative studies of ferroboron and ferroazote with ferrocene Density functional theory is a cost effective and an accurate method to study electronic structures and properties of ferrocene [39,40]. Comparing our results with theoretical studies previously performed on ferrocene, we note that the DFT and coupled-cluster calculations give results that are very similar and very close to experimental data, but the coupled-cluster approach is computationally very expensive [41]. In Tables 6 and 7 we included our results, obtained at B3LYP/cc-pvtz levels, concerning the geometric parameters and dipole moments of the structures (NC4H4)2Fe1-10 , (NC4H4)2Fe1-20 , (NC4H4)2Fe1-30 , (BC4H4)2Fe1-10 , (BC4H4)2Fe1-20 , and (BC4H4)2Fe1-30 respectively. The latter structures are illustrated in Fig. 3.

Ferroboron and ferroazote are present in each of the three stable compounds. The order of the relative energies of the obtained structures is as follows: (NC4H5)2 Fe1-10 < (NC4H5)2 Fe1-20 < (NC4H5)2Fe1-30 , for the first set of conformers. (BC4H5)2 Fe1-10 < (BC4H5)2 Fe1-20 < (BC4H5)2Fe1-30 , for the second set of conformers. Note that, over the two nitrogen (or boron) atoms are far one from, the other in the molecules, the latter is more stable (see Fig. 3). In ferrocene, the distance between the iron atom and the cyclopentadienyl center is estimated theoretically to be 1.654 Å [27] and experimentally to 1.661 Å [43]. The distance Fe. . . (C4H4N) varies between 1.679 Å and 1.682 Å (see Table 4), while the distance Fe. . .(C4H4B) varies between 1.653 Å and 1.659 Å (see Table 5). So, we can conclude that the second set of structures gives similar results to those obtained from the first set. 3.3. Comparative studies of (N3B2H4)2Fe and (B3N2H4)2Fe with (C5H5)2Fe Table 6 shows the theoretical values of the structural parameters and the dipole moments of Fe(N3B2H4)2, Fe(B3N2H4)2 and Fe(C5H5)2. From the results given in Table 4, we note that the Fe. . .N distance is 1.990 Å and the Fe. . .B distance is 2.210 Å, so that a

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Table 5 B3LYP/cc-pvtz computed structural parameters for the (BC4H4)2Fe1-1’, (BC4H4)2Fe1-2’ and (BC4H4)2Fe1-3’ Bond lengths are in angstroms, angles in degrees and dipole moment in Debye. Parameters (BC4H4)2Fe1-10

(BC4H4)2Fe1-20

(BC4H4)2Fe1-30

Bond length B1–C2 C3–C2 C3–C4 C4–C5 C5–B1 B1–H6 C2–H7 C3–H8 C4–H9 C5–H10 B1–Fe C2–Fe C3–Fe C4–Fe C5–Fe

1.546 1.412 1.436 1.412 1.546 1.189 1.080 1.080 1.080 1.080 2.324 2.129 2.076 2.075 2.128

Bond length B1–C2 C3–C2 C3–C4 C4–C5 C5–B1 B1–H6 C2–H7 C3–H8 C4–H9 C5–H10 B1–Fe C2–Fe C3–Fe C4–Fe C5–Fe

1.554 1.427 1.424 1.413 1.548 1.280 1.079 1.081 1.080 2.267 2.054 2.091 2.113 2.118 2.171

Bond length B1–C2 C3–C2 C3–C4 C4–C5 C5–B1 B1–H6 C2–H7 C3–H8 C4–H9 C5–H10 B1–Fe C2–Fe C3–Fe C4–Fe C5–Fe

1.542 1.422 1.416 1.429 1.550 1.187 1.081 1.080 1.083 1.080 2.226 2.119 2.107 2.101 2.068

Non-bonded distances (C4H4B). . .(C4H4B)0 Fe. . .(C4H4B) B1. . .B01 C2. . .C02 C3. . .C03 C4. . .C04 C5. . .C05 H6. . .H06 H7. . .H07 H8. . .H08 H9. . .H09 H10. . .H010

3.460 1.748 4.201 3.501 3.048 3.049 3.503 4.663 3.468 2.672 2.676 3.475

Non-bonded distances (C4H4B). . .C4H4B)0 Fe. . .(C4H4B) B1. . .C01 C2. . .B02 C3. . .C03 C4. . .C04 C5. . .C05 H6. . .H06 H7. . .H07 H8. . .H08 H9. . .H09 H10. . .H010

3.442 1.728 3.801 3.803 3.452 3.313 3.451 4.261 4.263 3.632 3.376 3.629

Non-bonded distances (C4H4B). . .(C4H4B)0 Fe. . .(C4H4B) B1. . .C01 C2. . .C02 C3. . .B03 C4. . .C04 C5. . .C05 H6. . .H06 H7. . .H07 H8. . .H08 H9. . .H09 H10. . .H010

3.432 1.760 4.056 3.535 3.196 3.051 3.482 4.573 3.765 3.020 2.666 3.480

Bond angles C3–C2–B1 C4–C3–C2 C2–B1–C5 H6–B1–Fe C4–C5–B1 C3–C4–C5

107.7 110.2 102.6 126.5 107.7 110.2

Bond angles C3–C2–B1 C4–C3–C2 C2–B1–C5 H6–B1–Fe C4–C5–B1 C3–C4–C5

106.8 110.6 102.1 129.8 108.2 110.3

Bond angles C3–C2–B1 C4–C3–C2 C2–B1–C5 H6–B1–Fe C4–C5–B1 C3–C4–C5

109.1 109.5 102.0 127.1 107.5 110.9

Dihedral angles C4–C3–C2–B1 C2–C3–C4–C5 Dipole moment

7.4 0.0 2.846

Dihedral angles C4–C3–C2–B1 C2–C3–C4–C5 Dipole moment

10.2 1.9 1.599

Dihedral angles C4–C3–C2–B1 C2–C3–C4–C5 Dipole moment

3.2 3.2 1.620

Table 6 Structure parameters (distances in Å, valence angle in degrees) for the (N3B2H4)2Fe, (N2B3H4)2Fe and (C5H5)2Fe at the B3LYP/ cc-pvtz level. (N3B2H4)2Fe(a)

(N3B2H4)2Fe(b)

(B3N2H4)2Fe(c)

Bond length B–N1 B–N2 N–N B–H N2–H Fe–N1 Fe–N Fe–B

1.45 1.42 1.38 1.21 1.04 2.16 2.02 2.23

Bond length B–N1 B–N2 N2–N2 B–H N2–H Fe–N1 Fe–N2 Fe–B

1.411 1.495 1.422 1.184 1.009 2.174 1.990 2.210

Bond length N–B1 N–B2 B2–B2 N–H B2–H Fe–B1 Fe–B2 Fe–N

1.471 1.453 1.695 1.008 1.190 1.835 1.571 2.303

Bond angle N1–B–N2 B–N1–B H–B–N1 B–N2–N2 B–N2–H

96 121 126 114 125

Bond angle N1–B–N2 B–N1–B H–B–N1 B–N2–N2 B–N2–H

106.9 110.1 133.4 107.4 134.9

Bond angle B1–N–B2 N–B1–N H–N–B1 N–B2–B2 N–B2–H

110.9 109.3 122.9 103.6 120.2

Non-bonded distances Fe. . .(B2N3H4) (B2N3H4). . .(B2N3H4) Dipole moment (a)

(C5H5)2Fe(d)

Ref. [26];

(b) (c)

,

and

(d)

Our work;

(e)

Non bonded distances 1.724 3.423 8.656

experimental values [42,43].

Fe. . .(B3N2H4) (B3N2H4). . .(B3N2H4) Dipole moment

(C5H5)2Fe(e)

Bond length C–H C–C Fe–C

1.077 1.423 2.078

Bond angle H6–C1–Fe C1–C2–C3

124.8 108.0

Non bonded distances 1.879 3.568 2.340

Fe. . .(C5H5) (C5H5). . .(C5H5) Dipole moment

1.692 3.384 0.006

Bond length Fe–C1 C1–C2 C1–H6

2.054 [42] 1.435 [42] 1.080 [42]

Non bonded distances Fe. . .(C5H5)

1.661 [43]

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Fig. 4. Fe(N3B2H4)2, Fe(N2B3H4)2 and Fe(C5H5)2 structures at the B3LYP/cc-pvtz levels.

comparison with results from the literature [26] shows differences of about 0.03 and 0.02 Å, respectively. Furthermore, the comparison between (N3B2H4)2Fe and (C5H5)2Fe structures shows that the distance Fe. . .N takes the smallest value of 1.990 Å with respect to the Fe. . .B distance of 2.210 Å, in contrast to the Fe. . .C distance which is 2.078 Å. For Fe (N2B3H4)2, the distance Fe. . .N (2.303 Å) has the highest value compared to Fe. . .B and Fe. . .C distances which are respectively 1.835 Å and 2.078 Å. We note that the distances Fe...triborodiazodiényle (1.879 Å) and Fe. . .diborotriazodiényle cycle (1.724 Å) are larger than the distance Fe...pentadienyl (1.692 Å), which would make the iron available for Fenton-type reactions and thus increases the antimalarial activity of the new compounds. Moreover, it is observed that the distances Fe. . .(N3B2H4) and Fe. . .(N2B3H4) increase of 0.03 Å and 0.187 Å respectively, with respect to the Fe. . .(C5H5) distance, whereas the dipole moment decreases with the increasing number of boron atoms (see Fig. 4). 3.4. Frontier molecular orbitals Fig. 5 shows the shapes of the frontier molecular orbitals HOMO and LUMO for ferrocene and the structures investigated in this work as well as energy gaps (Egap = ELUMO  EHOMO), obtained at B3LYP/ cc-pvtz levels. By analyzing the results, we state that the structures (NC4H5)2Fe1-10 , (NC4H5) 2Fe1-20 , (NC4H5)2 Fe1-30 , (NC4H5)2Fe1-20 and (N3B2H4) 2 Fe share the same LUMO shape with the ferrocene except for the structures (BC4H5)2Fe1-10 , (BC4H5)2 Fe1-20 , (BC4H5)2 Fe1-30 and (N2B3H4)2Fe. As for the HOMO, the only structure that has the same shape as ferrocene is (N3B2H4)2 Fe. Fig. 5 shows that ferrocene has the largest energy gap. However, a decrease in the HOMO–LUMO energy gap indicates a decrease in the kinetic stability. For all our compounds, we note that the HOMO is located essentially on the iron, the HOMO shape of the structure (N3B2H4)2 Fe is similar to that of ferrocene and the distribution of electron density for the other structures is opposite to that of ferrocene. From the previous results, we deduce that the compound (N3B2H4)2Fe is the most similar compound to ferrocene. 3.5. Studies of ferroquine, ferrotriborodiazoquine and ferrodiborotriazoquine 3.5.1. Comparative studies of ferroquine, ferrotriborodiazoquine and ferrodiborotriazoquine The optimized molecular structures of ferrotriborodiazoquine and ferrodiborotriazoquine compared to that of ferroquine, using

the DFT/UB3LYP level with 6-31 + G(d,p) basis set, are depicted in Fig. 6. The optimized parameters are bond lengths, bond angles and dihedral angles were summarized in Table 7. The experimental structures of our compounds have not reported yet. Therefore, we have compared the calculated values of ferrotriborodiazoquine and ferrodiborotriazoquine with the available experimental and theoretical results of ferroquine as a parent compound [44–46]. Ferroquine has been the subject of several active research works, such as the work of Chavain et al. [47], which studied the Redox behavior of ferroquine. In our case, the focus was on the hydrogen bond. FQ structure was stabilized by the intermolecular hydrogen bond between the hydrogen H17 and the non binding lone pair of N34 with a distance of 2.273 (2.227Å), obtained at the B3LYP (CAM-B3LYP)/6-31 + G⁄ levels. The experimental value of the solid state is 2.173 Å. Our calculation overestimates the hydrogen bonding by an order of 0.1 Å with the B3LYP functional and by an order of 0.05 Å with the CAM-B3LYP functional. The intramolecular hydrogen bond gives the FQ a bent conformation that makes the ferrocene available [48]. New studies have shown that the bent conformation of FQ helps in establishing some binding interactions in the digestive vacuole of the parasite [49]. The analysis of our results has led us to the same findings. Indeed, the F(N2B3)2Q and F(N3B2)2Q are stabilized by a strong intramolecular hydrogen bond between the hydrogen H17 and the lone pair of the nitrogen N34. The predicted NH. . .N distances of the compounds is, respectively, 2.168 (2.125) Å for the F (N2B3)2Q molecule and 2.163 (2.123) Å for the F(N3B2)2Q molecule, using the B3LYP(CAM-B3LYP)/6-31 + G(d,p) levels. This hydrogen bond is overestimated by about 0.05 Å with the CAM-B3LYP functional, whereas the values thereof to be 2.075 and 2.073 Å respectively, for F(N2B3)2Q and F(N3B2)2Q. The intramolecular hydrogen bond gives a bent conformation that can leave the ion Fe2+ uncovered. This would give a more pronounced elbow appearance for the new structures, so high availability of Fe2+ ion to the Fenton reactions and therefore a greater antimalarial activity. It should be noted that the hydrogen bond is stronger in the case of our new species than in the case of FQ. This may assume that, if the hydrogen bond is important in the antimalarial activity, our new molecules have a better activity than the activity of ferroquine (see Fig. 6). Moreover, the triborodiazodienyl...triborodiazodienyl (3.56–3.58 Å) and diborotriazodienyl...diborotriazodienyl (3.42– 3.31 Å) distances, obtained with the CAM-B3LYP functional, are greater than the pentadienyl...pentadienyl ones. The interaction energies, obtained at the CAM-B3LYP/6-31 + G⁄ levels of theory, of the optimized complexes are reported in Table 8. The corresponding geometries are drawn in Fig. 6.

N. Triaki et al. / Polyhedron 119 (2016) 471–482

479

Fig. 5. Plots of HOMO, LUMO structure and energy Gap for the ferrocene and (N3B2H4)2Fe species obtained at the B3LYP/cc-pvtz levels.

We state that, the interaction energy between the two compound FQ and F(N3B2)2Q are similar, with a difference of 1.52 kcal mol1. While for F(N2B3)2Q, this difference is 106.66 kcal mol1. Which means that the ferrodiborotriazoquine can present a new antimalarial class and/or anti-cancer molecules?

3.5.2. Electronic properties EHOMO is associated with the electron-donating ability of a molecule, whereas ELUMO indicates its ability to accept electrons. The HOMO–LUMO gap characterizes the reactivity and the kinetic stability of a molecule. Using B3LYP/6-31 + G⁄ level of theory, some electronic properties of FQ, F(N2B3)2Q and F(N3B2)2Q were investigated. Fig. 7 illustrates the shapes of the frontier molecular orbitals (HOMO and LUMO) for ferroquine (FQ), ferrotriborodiazoquine (F (N2B3)2Q) and ferrodiborotriazoquine (F(N3B2)2Q) as well as their energies in (eV). The positive and negative parts are visualized in green and red colors, respectively. The HOMO is largely delocalized in the Iron center for the FQ and F(N3B2)Q molecules, whereas the LUMO is largely delocalized in the iron center of the F(N2B3)Q molecule. The Calculated values, using B3LYP/6-31G + (d, p), for the EHOMO, ELUMO, energy Gap, chemical potential (l), global hardness (g), electrophilicity index (x) in (eV) and dipole moments lt in Debye (D), are given in Table 9. We note that the energy gaps of the FQ and F(N3B2)2Q are almost equal, unlike the one of the F(N2B3)2Q which took a smaller value. We conclude that F(N2B3)2Q is more reactive and has a higher biological activity. The FQ has a higher chemical potential and a lower hardness value compared to the other compounds.

The values of the quantum molecular descriptors are in the same order with and without Koopmans approximations (values in parentheses). The reactivity of molecules increases with the increase of electrophilicity [50]. We deduce that F(N2B3)2Q is more reactive (see Fig. 8) and may present a good antimalarial activity compared to FQ and F(N3B2)2Q. Therefore, we conclude that the compound (N3B2H4)2Fe is the most similar species to Ferrocene.

4. Conclusions The aim of our study is to search for novel compounds that could lead to new classes of antimalarial and/or anticancer drugs, using the DFT /B3LYP level of theory. The first part of this work involves studying the substitution of one or more carbon atoms within the cyclopentadiene (Cp) anions by one or more boron and/or nitrogen atoms. Our results showed that the formation reaction of the anions    NC4H 5 , BC4H5 , N2B2H4B and B2N2H4N would be as favorable as that of C5H anion. Moreover, we investigated novel ‘‘sandwich” 5 complexes derived by replacing one or more carbon atoms on each cyclopentadienyl ring of ferrocene (Cp) by one or more boron and/ or nitrogen atoms. This substitution led to a novel compound, which is more stable than the ferrocene. In the second part of our work, we replaced the ferrocene in the FQ complex by (N2B3)2Fe and (N3B2)2Fe to obtain novel compounds that may have a similar or better antimalarial activity than that of FQ. We noticed, in the case of ferroquine, that our compounds, ferrotriborodiazoquine and ferrodiborotriazoquine have also been

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Fig. 6. Bond hydrogen of the ferroquine (a), ferrotriborodiazoquine (b) and ferrodiborotriazoquine (c) obtained at the CAM-B3LYP/6-31 + G⁄ levels.

Table 7 Optimized structural parameters (distances in Å, valence angle in degrees) of the ferroquine, ferrotriborodiazoquine and ferrodiborotriazoquine at B3LYP/6-31 + G⁄ and CAMB3LYP/6-31 + G⁄ (values in parentheses) levels. Parameters

FQ

F(N2B3)2Q

Bond length C1–C2 C2–C3 C3–C4 C4–C5 C5–C1 C10 –C20 C20 –C30 C30 –C40 C40 –C50 C50 –C10 C1–H6 C2–H7 C3–C8 C4–C9 C5–H10 C10 –H60 C20 –H70 C30 –H80 C40 –H90 C50 –H100 C8–N16 N16–H17 N16–C18 C22–Cl30 C9–N34 N34–C35 N34–C36 C1–Fe11 C10 –Fe11 C1–C10 C2–C20 C3–C30 C4-C40 C5–C50 N34...H17* N16...N34

1.427 1.431 1.441 1.432 1.427 1.428 1.429 1.428 1.429 1.428 1.083 1.083 1.508 1.505 1.084 1.083 1.083 1.083 1.083 1.083 1.484 1.023 1.397 1.760 1.478 1.463 1.462 2.067 2.072 3.329 3.346 3.362 3.363 3.345 2.273 3.212

(1.421) (1.424) (1.433) (1.425) (1.421) (1.422) (1.423) (1.422) (1.423) (1.422) (1.082) (1.082) (1.504) (1.501) (1.083) (1.082) (1.082) (1.082) (1.082) (1.082) (1.475) (1.022) (1.395) (1.748) (1.468) (1.456) (1.455) (2.052) (2.056) (3.306) (3.316) (3.320) (3.322) (3.316) (2.227) (3.168)

Bond angles C1–C2–C3 C2–C3–C4 C3–C4–C5 C10 –C20 –C30 C20 –C30 –C40 C30 –C40 –C50 C1–C2–H7 C1–C5–H10 C2–C3–C8 C5–C4–C9 C10 –C20 –H70 C3–C8–N16 C4–C9–N34

108.5 107.6 107.6 108.0 108.0 108.0 126.0 126.0 126.6 126.8 126.0 112.8 112.7

(108.4) (107.7) (107.6) (108.0) (108.0) (108.0) (126.1) (126.1) (126.8) (127.0) (126.0) (112.8) (112.5)

F(N3B2)2Q

Bond length B1–N2 N2-B3 B3–B4 B4–N5 N5–B1 B10 –N20 N20 –B30 B30 –B40 B40 –N50 N50 –B10 N2–H6 B3–C8 B4–C9 N5–H10 N20 –H70 B30 –H80 B40 –H90 N50 –H100 C8–N16 N16–H17 N16–C18 C22–Cl30 C9–N34 N34–C35 N34-C36 B1–Fe11 B10 –Fe11 B1–B10 N2–N20 B3–B30 B4–B40 N5–N50 N34...H17* N16...N34

1.459 (1.459) 1.454 (1.445) 1.717 (1.716) 1.454 (1.444) 1.481 (1.478) 1.477 (1.474) 1.457 (1.447) 1.702 (1.701) 1.452 (1.443) 1.459 (1.459) 1.014 (1.014) 1.586 (1.580) 1.588 (1.581) 1.015 (1.013) 1.015 (1.012) 1.196 (1.195) 1.195 (1.194) 1.014 (1.013) 1.464 (1.459) 1.022 (1.021) 1.376 (1.372) 1.761 (1.749) 1.474 (1.466) 1.463 (1.455) 1.462 (1.455) 1.827 (1.806) 1.836 (1.812) 3.526 (3.490) 3.872 (1.827) 3.912 (1.851) 3.978 (3.906) 3.934 (3.877) 2.168 (2.125) 3.183 (3.139)

Bond length N1–B2 B2–N3 N3–N4 N4–B5 B5–N1 N10 –B20 B20 –N30 N30 –N40 N40 –B50 B50 –N10 B2–H7 N3–C8 N4–C9 B5–H10 B20 –H70 N30 –H80 N40 –H90 B50 –H100 C8–N16 N16–H17 N16–C18 C22–Cl30 C9–N34 N34–C35 N34–C36 N1–Fe11 N10 –Fe11 N1–N10 B2–B20 N3–N30 N4–N40 B5––B50 N34...H17* N16...N34

1.413 (1.407) 1.505 (1.497) 1.448 (1.437) 1.514 (1.505) 1.412 (1.406) 1.417 (1.412) 1.506 (1.499) 1.426 (1.418) 1.499 (1.492) 1.413 (1.407) 1.188 (1.193) 1.468 (1.460) 1.455 (1.449) 1.190 (1.190) 1.188 (1.188) 1.015 (1.013) 1.015 (1.013) 1.094 (1.194) 1.454 (1.447) 1.024 (1.022) 1.409 (1.407) 1.758 (1.746) 1.465 (1.457) 1.466 (1.460) 1.467 (1.459) 2.163 (2.144) 2.175 (2.153) 3.565 (3.529) 3.770 (3.755) 3.545 (3.519) 3.560 (1.529) 3.785 (1.760) 2.163 (2.123) 3.069 (3.459)

Bond angles B1–N2–B3 N2–B3–B4 B3–B4–N5 B10 –N20 –B30 B20 –B30 –B40 B30 –B40 –N50 B1–N2–H7 B1–N5–H10 N2–B3–C8 N5–B4–C9 B10 –N20 –H70 B3–C8–N16 B4–C9–N34

111.8 103.4 103.3 110.2 103.6 104.0 123.2 122.5 120.5 122.7 123.2 113.5 113.5

Bond angles N1–B2–N3 B2–N3–N4 N3–N4–B5 N10 –B20 –N30 B20 –N30 –N40 N30 –N40 –B50 N1–B2–H7 N1–B5–H10 B2–N3–C8 B5–N4–C9 N10 –B20 –H70 N3–C8–N16 N4–C9–N34

108.4 106.4 106.4 106.6 107.4 107.1 133.6 133.3 130.5 130.5 133.6 114.7 113.1

(112.4) (103.2) (103.2) (110.6) (103.5) (103.7) (121.6) (122.4) (120.7) (122.8) (122.8) (113.3) (113.4)

(108.2) (106.5) (106.6) (106.5) (107.4) (107.1) (133.1) (133.6) (130.2) (130.4) (133.6) (114.6) (113.1)

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*

Parameters

FQ

F(N2B3)2Q

N16–H17...N34 C8–N16–C18 C9–N34...H17 C21–C22–Cl30

151.8 (152.3) 120.1 (119.0) 99.7 (100.1) 118.5 (118.5)

N16–H17...N34 C8–N16–C18 C9–N34...H17 C21–C22–Cl30

171.7 127.3 100.0 118.7

F(N3B2)2Q

Dihedral angles C1–C2–C3–C4 C10 –C20 –C30 –C40 C3–C8–N16–C18 C3–C8–N16–H17 C4–C9–N34–C35 C4–C9–N34...H17 C8–N16–H17...N34

0.4 (0.5) 0.1 (0.1) 77.0 (75.0) 52.2 (53.1) 66.8 (66.1) 48.9 (49.7) 1.22 (2.1)

Dihedral angles C1–C2–C3–C4 C10 –C20 –C30 –C40 C3–C8–N16–C18 C3–C8–N16–H17 C4–C9–N34–C35 C4–C9–N34...H17 C8–N16–H17...N34

7.4 (7.1) 9.3 (9.3) 154.5 (152.2) 4.6 (3.8) 68.1 (67.8) 42.3 (41.6) 16.3 (29.9)

(171.6) (126.7) (100.6) (118.6)

N16–H17...N34 C8–N16–C18 C9–N34...H17 C21–C22–Cl30

146.5 119.2 102.1 118.5

(147.1) (118.2) (102.4) (120.1)

Dihedral angles N1–B2–N3–N4 N10 –B20 –N30 –N40 N3–C8–N16–C18 N3–C8–N16–H17 N4–C9–N34–C35 N4–C9–N34...H17 C8–N16–H17...N34

8.3 (8.9) 7.9 (8.4) 73.9 (71.2) 56.9 (58.2) 68.4 (67.8) 50.5 (50.6) 3.8 (0.7)

Hydrogen bond (see Fig. 6).

Table 8 Variation of the interaction energy (in kcal mol1) for a FQ, F(N3B2)2Q and F(N2B3)2Q at the CAM-B3LYP/6-31 + G⁄ level.

CAM-B3LYP/6-31 + G

⁄

DE(FQ)

DE (F(N3B2)2Q)

DE (F(N2B3)2Q)

256.57

255.05

149.91

stabilized by an intramolecular hydrogen bond, which causes these molecules to have a bent shape, making ferrocene no longer available and would help the FQ to take place in the food vacuole of the parasite. This is largely responsible for the greater activity of FQ.

Table 9 Calcul of the global descriptors of the reactivity for the EHOMO, ELUMO, Gap|HOMO-LUMO|, l, g, x in eV and lt in Debye by DFT theory at the B3LYP/6-31 G⁄ for the different structures. Complexes

FQ

F(N2B3)Q

F(N3B2)Q

HOMO LUMO Gap |HOMO-LUMO|

5.71 1.54 4.17 3.67 (3.62) 3.40 (2.08) 1.98 (3.15) 6.77

5.05 2.99 2.49 3.92 (4.20) 1.55 (1.24) 6.67 (7.11) 9.86

6.31 1.97 4.34 4.16 (4.14) 2.77 (2.17) 3.12 (3.95) 8.39

l g x lt

Acknowledgements The Study was supported by the Genome Material Thematic Project Prothème 06/2015N°376 du 15/10/2014 of the ATRST

(DGRSDT-MESRS) of Algeria. Also, many thanks to Pr. Xavier ASSFELD from Université de Lorraine and Nacéra MEZIANE (Electronic Laboratory, USTHB) for their fruitful discussion.

Fig. 7. FMO and Gap |HOMO–LUMO| for the FQ, F(N2B3)2Q and F(N3B2)2Q structures.

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Fig. 8. Electrophilicity for the FQ), F(N2B3)2Q and F(N3B2)2Q complexes obtained at the B3LYP/6-31 + G⁄ levels.

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