Synthesis and structural elucidation of novel antifungal N-(fluorophenyl)piperazinyl benzoxaboroles and their analogues

Journal of Molecular Structure 1181 (2019) 587e598

Contents lists available at ScienceDirect

Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc

Synthesis and structural elucidation of novel antifungal N-(fluorophenyl)piperazinyl benzoxaboroles and their analogues
ska a, Krzysztof M. Borys a, 1, Alicja Matuszewska a, 1, Dorota Wieczorek b, Karolina Kopczyn zniak a, * Jacek Lipok b, Izabela D. Madura a, Agnieszka Adamczyk-Wo
a b

Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland Faculty of Chemistry, Opole University, Oleska 48, 45-052 Opole, Poland

a r t i c l e i n f o

a b s t r a c t

Article history: Received 17 October 2018 Received in revised form 4 January 2019 Accepted 4 January 2019 Available online 7 January 2019

Series of novel N-(fluorophenyl)piperazine derivatives of phenylboronic compounds including benzoxaboroles, phenylboronic acids and phenylboronic methyl monoester have been obtained by facile synthetic methods starting from 2-formylphenylboronic acid. Molecular and crystal structures of those novel derivatives have been investigated by single crystal X-ray diffraction method. The Bond Valence Vector Model was used to describe strains in the boron coordination sphere. Microbiological activity of novel benzoxaboroles as well as their corresponding acid analogues against: A. niger, A. terreus, P. ochrochloron, C. tenuis and F. dimerum has been evaluated. The presence of heterocyclic benzoxaborole ring has been shown to be crucial for the studied activity. © 2019 Published by Elsevier B.V.

Keywords: Benzoxaborole Phenylboronic acid Piperazine Fluorophenyl Organoboron Antifungal activity

1. Introduction Phenylboronic acids as well as benzoxaboroles containing heterocyclic amine unit are promising receptors of biologically important analytes, such as sugars or catecholamines [1]. Benzoxaboroles emerged several years ago as potent antifungal agents, with AN2690 being already used as a drug in the US [2e4]. Very recently, benzoxaboroles were also investigated as anticancer agents. It was found that they display antiproliferative and proapoptotic properties, with high activity of 3-morpholino-5fluorobenzoxaborole [5]. On the other hand, piperazine is at the 4th place among ring systems presented in Small Molecule Drugs from the FDA Orange Book [6]. Compounds containing piperazine moiety exhibit antifungal [3], antibacterial [7], antitumor [8], as well as antidepressant properties [9]. Substituted N-phenylpiperazines were found to significantly increase inhibition of acetylocholinoesterase [10] and to improve glucose detection [11]. Substitution on the phenyl ring of piperazine can be used to enhance selectivity of pharmacophores. For instance, electron

* Corresponding author. E-mail address: [email protected] (A. Adamczyk-Wo
zniak). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.molstruc.2019.01.018 0022-2860/© 2019 Published by Elsevier B.V.

donating group on C-2 position and electron withdrawing group on C-4 position result in higher anti-HIV activity, while for substitution on C-3 position no positive effect was observed [12]. Introduction of a fluorine atom to phenyl ring on C-2 and C-4 positions boosts antitubercular [13,14] and anti-HIV potency [12]. In case of the antiproliferative activity, introduction of the fluorine substituent in C-4 position results in higher potency, whereas its introduction in C-2 position results in drop of efficiency in comparison with the parent compound [15]. Similarly, studies on the influence of arylpiperazine moiety on the activity at the A1 adenosine receptor showed that moving the fluorine atom from position C-4 to C-2 is detrimental to the activity [16]. Also the 5-HT7 receptor activity of N-(fluorophenyl)piperazines has been shown to be higher for the 4F substitution in comparison with the 2-F isomer [17]. It is worth mentioning that 4-(fluorophenyl)piperazine (pFPP) is a metabolite of niaprazine [18], which is used to treat insomnia (drug name Nopron). Niaprazine binds to the alpha 1 and 5-HT2 receptors, whereas pFPP activates the 5-HT1 receptors [19]. Since the 1st April 2008, pFPP has been classified as Class C controlled drug in New Zealand, along with several other piperazine compounds [20]. Since numerous phenylboronic compounds as well as N-(fluorophenyl)piperazines display biological activity [21], we have decided to synthesize N-(fluorophenyl)piperazine derivatives of

588

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

Scheme 1. Synthesis of 1 and 1a starting from 2-formylphenylboronic acid.

Scheme 2. Synthesis of 2 and 2a in the amination-reduction reaction. Solvents, reducing agents as well as yields are given in the text.

benzoxaboroles (1, 1a, Scheme 1) and their boronic acid analogues (2, 2a, 3a, Schemes 2 and 3). Due to simplicity as well as high versatility of the synthesis, the amination [22] and aminationreduction reactions [23] have been chosen to obtain the desired structures. Crystal structures of several phenylboronic piperazine derivatives have been recently described [24], yet none of the so far reported structures contain fluorine atoms at the piperazine fragment. Since determination of the crystal structure is important in the rational design of drug-like molecules [25], all the newly obtained compounds have been crystallized and studied by singlecrystal XRD. 2. Results and discussion 2.1. Synthesis and spectral characterization The benzoxaboroles 1 and 1a have been obtained in the reaction of 2-formylphenylboronic acid with the corresponding N-(fluorophenyl)piperazine under dehydrative conditions (Scheme 1) [22]. The corresponding phenylboronic acids 2 and 2a have been synthesized under amination-reduction conditions starting from 2formylphenylboronic acid (Scheme 2). The main issue in the applied amination-reduction protocole is a

successful removal of the expected by-product of the reaction unsubstituted benzoxaborole (1b) resulting from reduction of 2formylphenylboronic acid followed by dehydration of the benzylalcohol. It has been achieved by selective extraction from the acidic aqueous solution according to the previously reported procedure [22]. The position of fluorine atom on the phenyl ring affected the reaction. Amination-reduction protocol with 2-(fluorophenyl) piperazine required 2 equivalents of 2-formylphenylboronic acid in methanol to give pure product 2 in 39% yield. It was possible to improve the yield of 2 up to 76% by using milder reducing agent NaBH(OAc)3, acetic acid as a catalyst and molecular sieves as dehydrating agent. The observed improvement of the reaction performance is consistent with previous findings concerning the amination-reduction reaction [22,26]. The synthesis of 2a according to a standard procedure [22] with NaBH4 in methanol resulted in a product contaminated by the starting 4-(fluorophenyl)piperazine. Changing the solvent to acetonitrile resulted in pure 2a with moderate yields (44%). Despite the presence of two hydroxyl groups in 2a, its crystallization from methanol surprisingly led to esterification of only one of them, resulting in methyl monoester 3a (Scheme 3). The result indicates that the hydroxyl groups in 2a are non-identical. Possible explanation of this issue is the presence of the OH … N hydrogen bond not only in the solid state (see the

Scheme 3. Formation of methyl monoester (3a) by crystallization of 2a from methanol.

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

589

crystal structure of 2a described further) but also in methanol solution. All the compounds have been characterized by NMR spectroscopy (1H, 13C, 11B and 19F NMR spectra). Compounds 1 and 2 have been dissolved in acetone-d6 while 3 in methanol-d4 due to its insufficient solubility in acetone. The 11B NMR shifts confirm trigonal form of the boron atom in all the investigated compounds. In case of 2a considerable dehydration of the sample took place upon drying, which resulted in broadening and multiplying some of the NMR signals, as it was previously reported [24,27]. The spectrum got simplified upon addition of a drop of D2O to the acetone solution. At least partial dehydration of the samples took place also on melting, therefore the determined melting temperatures are relatively broad [28].

2.2. Molecular and crystal structure of benzoxaboroles 1 and 1a

Fig. 1. Ortep [29] drawings of 1 and 1a molecules with the atom numbering scheme shown on the molecule of 1. Hydrogen atoms connected to carbon atoms are omitted for clarity. The ellipsoids are shown at 50% probability.

Molecules of 1 and 1a crystallize in P21/n and Pbca space symmetry groups, respectively (Table S1 in the Supplementary Materials). In both cases the asymmetric part of the unit cell contains one molecule (Fig. 1). Additionally, in case of 1a a disordered diethyl ether solvent molecule is present (Fig. 2). The molecules contain the asymmetric C7 atom, therefore R- and S-enantiomers generated by the crystallographic inversion centre are present in both crystal structures. In molecules, the fused six- (phenyl) and five- (oxaborole) membered rings are flat with the largest deviation from the least square plane not exceeding a few hundredths of an

Fig. 2. Basic structural motives and crystal packing in 1 and 1a. The solvent oxygen atom is presented with the space-filling model in the packing diagram of 1a.

590

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

respectively. While the dihedral angle between the piperazine ring and the aromatic, fluorine substituted ring (C12 ÷ C17 atoms) amounts to 44.33 (6) and 28.12 (13) for 1 and 1a, respectively. In both cases the piperazine ring shows a chair conformation with Cremer and Pople total puckering parameter Q [32] measuring the deviation from the perfectly flat six-membered ring equal to 0.598 (1) and 0.583 (2) Å, for 1 and 1a, respectively. Contrary to many other structurally characterized benzoxaboroles [2], in 1 the hydroxyl group interacts with the piperazine fragment forming an intermolecular O1eH1/N2 hydrogen bonds (Table S3 in the Supplementary Materials). This leads to the formation of primary 1D synthon being a chain with C (9) graph set notation [33] (Fig. 2). In the synthon, molecules are related by 21 screw axis and the chain propagates along [010] direction forming left- and right-handed helices composed of enantiomers of particular type (R or S) (Fig. 2). There are no further meaningful interactions between molecules (Table S3) so the helix can be regarded as the basic synthon. Between helices the weak interactions, such as C3eH3 … F1, CeH … O and CeH … p hydrogen bonds, p … p stacking, and B … p interactions are present. The latter are separated by 3.65 Å and they are comparable to these observed in fluorosubstituted phenylboronic catechol esters [34]. In crystals of 1a the primary interaction is between the solvent oxygen atom (diethyl ether) and benzoxaborole OH group forming a definite motif D [33] (Fig. 2). There are only weak interactions between these H-bonded pairs (Table S3), among which C9eH9B … F1 hydrogen bonds indicate a role of fluorine atom as a proton acceptor. Nevertheless, other weak contacts are also present, connecting the molecules of 1a into a double layer structure located

angstrom. The boron atom in 1 and 1a is in trigonal environment and slight deviations from an “ideal” sp2 geometry are best described by the Bond-Valence-Vector (BVV) model [30]. Application of the model for boronic acid derivatives has been presented in a recent paper by
ska et al. [31]. In molecules of 1 the vy and vx components of Czerwin the resultant bond-valence vector describing in-plane deformations equal to 0.05 and
0.09 v.u., whereas the vz component, connected with a pyramidalization of the boron atom, equals to 0.01 v.u. These values mean that the resultant BVV is directed towards the fivemembered ring and it is associated with C1B1O2 angle narrowing to the value of 108.7 (1) from the expected 120 (Table 1). Moreover, an effect of the location of the hydrogen atom in the syn position is also observed in this structure when comparing to other structurally characterized benzoxaboroles [31]. Low quality data for crystal of 1a preclude this molecule to be a subject of detailed BVV model analysis, however, the estimated values (vy ¼ 0.05, vx ¼
0.08, vz ¼
0.01 v.u.) for the components of the resultant vector clearly indicate that the strains existing in this molecule are similar to 1. What is more, they may serve as an indicator confirming the proper assignment of the hydrogen atom position in 1a. It should be noted that the strongest strains in the boron coordination sphere have been found in benzoxaboroles comparing to the other crystalline boronic acid derivatives with CBO2 skeleton [31]. These strains might be related to the proved activity of AN2690 drug, which molecule in crystal shows BVV parameters akin to 1. Further, the dihedral angle between planes defined by C1 ÷ C6, B1 (the borole fragment) and N1, N2, C8 ÷ C11 (the piperazine ring) atoms amounts to 89.54 (5) and 74.46 (12) for 1 and 1a,

Table 1 Selected geometrical parameters for 1, 1a, 2, 2a and 3a molecules.

B1eC1 B1eO1 B1eO2 O2eC7 N1eC7 N1eC8 N1eC11 N2eC9 N2eC10 N2eC12 F1eC(x) O1eB1eO2 C1eB1eO1 C1eB1eO2 B1eC1eC2 B1eC1eC6 C1eC6eC7 C6eC7eN1 C7eN1eC8 C7eN1eC11 C8eN1eC11 C9eN2eC12 C10eN2eC12 C9eN2eC10 O1eB1eC1eC2 O1eB1eC1eC6 O2eB1eC1eC2 O2eB1eC1eC6 B1eC1eC6eC7 B1eO2eC7eC6 O2eC7eC6eC1 O2eC7eC6eC5 C1eC6eC7eN1 C6eC7eN1eC8 C6eC7eN1eC11

1

1a

2

2a

3a

I

II

1.564 (2) 1.355 (2) 1.377 (2) 1.465 (1) 1.439 (1) 1.465 (1) 1.463 (1) 1.475 (1) 1.482 (1) 1.429 (1) 1.358 (1) 123.5 (1) 127.9 (1) 108.7 (1) 136.7 (1) 104.6 (1) 111.4 (1) 112.7 (1) 114.3 (1) 113.6 (1) 109.9 (1) 115.7 (1) 111.8 (1) 109.3 (1) 3.8 (2)
179.1 (1)
177.5 (1)
0.4 (1) 1.3 (1) 1.5 (1)
1.8 (1)
60.8 (2) 121.0 (1) 164.3 (1)
68.5 (1)

1.554 (4) 1.341 (4) 1.372 (3) 1.460 (3) 1.427 (3) 1.453 (3) 1.460 (3) 1.469 (3) 1.459 (3) 1.416 (3) 1.365 (3) 123.6 (3) 127.9 (2) 108.5 (2) 136.0 (2) 104.8 (2) 111.1 (2) 114.6 (2) 113.6 (2) 115.8 (2) 108.9 (2) 114.5 (2) 116.2 (2) 111.1 (2)
1.0 (5) 179.8 (3) 179.1 (3)
0.1 (3)
1.2 (2)
2.1 (2) 2.0 (2)
178.2 (2) 127.0 (2) 175.3 (2)
57.4 (3)

1.583 (2) 1.353 (2) 1.358 (2) e 1.471 (2) 1.467 (2) 1.463 (2) 1.454 (2) 1.465 (2) 1.410 (2) 1.356 (2) 119.6 (1) 117.1 (1) 123.2 (1) 117.0 (1) 126.0 (1) 122.9 (1) 114.59 (1) 110.3 (1) 112.4 (1) 109.9 (1) 116.9 (1) 116.5 (1) 109.8 (1)
19.0 (2) 162.9 (1) 159.3 (1)
18.8 (2)
6.3 (2) e e e 63.4 (2)
176.8 (1) 60.2 (1)

1.580 (3) 1.353 (2) 1.348 (2) e 1.470 (2) 1.464 (2) 1.462 (2) 1.457 (2) 1.453 (2) 1.412 (2) 1.360 (2) 119.0 (2) 117.8 (2) 123.2 (1) 117.8 (1) 124.9 (1) 122.4 (1) 113.0 (1) 111.6 (1) 111.8 (1) 107.9 (1) 115.8 (1) 117.3 (1) 110.0 (1)
20.7 (2) 160.6 (2) 158.1 (2)
20.6 (3)
3.3 (2) e e e 64.0 (2)
175.3 (1) 63.7 (2)

1.582 (2) 1.351 (2) 1.352 (2) e 1.472 (2) 1.461 (2) 1.461 (2) 1.455 (2) 1.464 (2) 1.417 (2) 1.366 (2) 119.5 (1) 116.3 (1) 124.0 (1) 115.6 (1) 126.8 (1) 122.8 (1) 114.3 (1) 111.1 (1) 112.6 (1) 108.5 (1) 116.2 (1) 115.1 (1) 110.6 (1)
22.1 (2) 162.3 (2) 153.4 (2)
22.2 (3)
8.9 (2) e e e 61.3 (2)
175.9 (1) 62.2 (2)

1.594 (2) 1.368 (2) 1.345 (2) e 1.474 (1) 1.468 (1) 1.468 (1) 1.467 (1) 1.466 (1) 1.413 (1) 1.367 (1) 119.7 (1) 115.1 (1) 125.2 (1) 116.2 (1) 126.4 (1) 123.9 (1) 116.0 (1) 113.1 (1) 109.4 (1) 107.9 (1) 116.5 (1) 115.9 (1) 112.0 (1) 17.6 (1)
163.9 (1)
159.2 (1) 19.3 (2) 9.0 (2) e e e
57.3 (1) 172.1 (1)
67.5 (1)

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

perpendicularly to [001] direction. Solvent molecules decorate both sides of the layer (Fig. 2). 2.3. Molecular and crystal structure of phenylboronic acids 2 and 2a Molecules of 2 and 2a crystallize in centrosymmetric groups of the monoclinic system (Table S1). The asymmetric part of the unit cell of 2 contains one molecule whereas in 2a two independent molecules are present (2aI and 2aII). In 2a crystal a high residual electron density observed during refinement indicated a presence of severely disordered or diffused solvent but no satisfactory model could be applied. Therefore, the solvent masking procedure in OLEX2 was used [35]. In all molecules (2, 2aI and 2aII) the syn-anti conformation of hydrogen atoms at B(OH)2 functional group has been assumed based on the residual electron density in proximity of oxygen atoms and values of the resultant BV vectors’ components. Concerning the boron coordination sphere in the discussed molecules, the average BVV components, vy and vx, equal to
0.03 and 0.04 v.u., respectively. The systematic deviation from zero vector is observed with the resultant BVV directed along the B1eO1 (syn) bond. It is simultaneously connected with the widening of the C1eB1eO2 angles to the mean value of 123.5 (Table 1). Hence, the analyzed 2 and 2a boronic acids molecules locate in the scatter plot of the resultant bond-valence vectors for [CBO2] skeletons in the area assigned to boronic acid with syn-anti conformation of hydrogen atoms [31]. In the discussed molecules the twist of B(OH)2 moiety in respect to the phenyl ring is observed, amounting to 19.15 (17) in 2, and 20.9 (2) and 24.08 (19) in 2aI and 2aII, respectively. This may be a result of the presence of intramolecular OeH/N hydrogen bond with S (7) graph designator (Fig. 3). Similarly to benzoxaboroles 1 and 1a as well as previously

Fig. 3. Ortep [29] drawings of 2, 2a molecules. The atom numbering scheme is shown on the molecule of 2. The hydrogen atoms connected to carbon atoms are omitted for clarity. In the case of 2a only the molecule I from the asymmetric part of the unit cell is depicted, atom numbers of molecule II are derived from these of I by adding 20. The ellipsoids are shown at 50% probability.

591

described analogues [24], piperazine ring shows a chair conformation and it is almost perpendicularly oriented with respect to the phenylboronic fragment (Table 1). In both 2 and 2a the H-bonded dimer is a primary 0D synthon. In 2a the dimer is formed between independent molecules and it can be described with DD first level graph descriptor [33], however, at the higher order graph level [36], a characteristic R22 (8) synthon appears indicating the similarity to other homologues and to the dimer in 2. Compared to previously described piperazine substituted phenylboronic acids [24], the dimers can be also approximated with the Z-shape due to the almost perpendicular orientation of two dissent parts of the molecules (Table 1, Fig. 4). The packing of dimers in 2 and 2a differs a bit from the other acids [24] and it is consistent with our conclusion that weaker, directional interactions are influenced by the nature, number and position of the substituents in piperazine fragment. Closer inspection shows that the dimers in 2 are further joined via weaker interaction, including these with fluorine atom acting as an acceptor, into a 1D structure. (Table S4). The consecutive ribbons are surrounded by six ribbons (Fig. 4b) that may be regarded as a close to hexagonal packing of rods. This in turn, underlines secondary role of numerous contacts found in the crystal (Table S4). Similarly to 2, the existence of secondary CeH/F and weak CeH … p interactions has been found (Table S4). The 3D structure is formed as a result of the cooperation of all these interactions linking the primary synthons i.e. dimers. As it has been already mentioned in the crystal structure of 2a severely disordered or diffused solvent molecules are present. Their location in the crystal structure is depicted as pink voids in Fig. 4. 2.4. Molecular and crystal structure of monomethyl 2-((4-(4fluorophenyl)piperazin-1-yl)methyl)phenylboronate (3a) Molecules of 3a crystallize in P21/n space symmetry group of the monoclinic system (Table S1). The asymmetric part of the unit cell contains one molecule with syn-anti conformation of the boronic functional group with the proton in the anti position (Fig. 5). The B(OH)2 moiety is twisted by 18.35 (12) with respect to the phenyl ring. The boron atom is in trigonal environment with the deviation from the plane defined by O1, O2, C1 atoms amounting to 0.02 (1) Å (vz ¼ 0.03 v.u.). It is the largest deviation from planarity in the discussed series of compounds. In 3a, the vy and vx components equal to
0.04 and 0.04 v.u., respectively. Molecules of 3a have a relatively long BeC bond (1.594 Å) comparing to the mean value of 1.573 Å for the group of acyclic hemiesters found previously [31]. This may be the reason of slightly different value of vy component in contrast to the value
0.02 v.u. for the whole group of acyclic hemiesters [31]. The values of the resultant BVV indicate the same direction of strains as in the case of the acids with syn-anti conformation at boronic group. Similarly to benzoxaboroles 1 and 1a as well as the acids 2 and 2a, the dihedral angle between planes defined by C1 ÷ C6, B1 and N1, N2, C8 ÷ C11 atoms amounts to 88.03 (5) . The formation of intramolecular O2eH2/N1 hydrogen bond is observed, so it precludes formation of other, “classical” intramolecular hydrogen bonds (Table S5). The helical motif (Fig. 5, middle) can be distinguished in the crystal architecture formed by three coexisting motives formed via not classic hydrogen bonds, i.e. the CeH … O and CeH … p ones. The molecules in the helix are related by 21 screw axis and only very weak CeH … p contacts were identified between helices. However, the close to square-grid arrangement of helices, shown in Fig. 5, indicates that these interactions are more potent than those observed in the structure of 2. What is more, in structure of 3a the fluorine atom does not participate in any important intermolecular interactions. Fig. 6 shows a superposition of the investigated crystal structures.

592

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

There is a significant difference in orientation of the phenyl and piperazine rings in benzoxaboroles 1 and 1a and the corresponding boronic acids 2 and 2a. Interestingly, the acyclic hemiester 3a molecule shows an intermediate orientation (Fig. 6). 2.5. Biological activity Microbiological activity of the synthesized novel benzoxaboroles (1 and 1a) as well as their corresponding acid analogues (2 and 2a) has been evaluated against A. niger, A. terreus, P. ochrochloron, C. tenuis and F. dimerum. Antifungal activity of all the studied boronic compounds has been evaluated by the diffusion agar method as well as by the determination of the Minimal Inhibitory

Concentration (MIC) values [37]. For the diffusion agar method 0.5 mL of inoculum containing 106e107 spores was spread on the surface of the solidified Czapek or potato dextrose medium and allowed to dry. Amounts of 100, 50, 25 and 10 mg of the tested compounds dissolved in DMSO were placed in 2 mm diameter holes, which were cut into the media (Fig. 7). Holes in control cultures were filled with DMSO or a solution of 50 mg amphotericin B. The duration of incubation of the fungi was dependent on the vigour of their growth and was established as 48 h for Aspergillus strains and 72 h for other examined fungi. The optimal temperature for the incubation was 27  C for Fusarium strains and 30  C for other strains. Each experiment, including control, was carried out in at least three repetitions. Antifungal

Fig. 4. Basic dimeric motives and crystal packing in 2 and 2a. Simplified model of primary motif is derived by connection (in line with H-bonds) of nodes (centers of gravity of phenyl rings). Red and blue colours of nodes represent the boronic and piperazine fragments, respectively. The positions of voids in crystal of 2a is depicted with pink surfaces.

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

activity was evaluated by the diameter of the clear zone surrounding the holes (Fig. 7, Table 2, values in parentheses), or a zone with partial inhibition of growth (Table 2, values without parentheses). Diameter of the zone of totally inhibited growth of the fungus (no mycelium within the growth medium) is shown in parentheses. The values before parentheses relate to the diameter of the zone of limited growth of the fungus; n/d - not determined. According to data shown in Table 2, the studied benzoxaboroles 1 and 1a revealed antifungal activity, whereas their phenylboronic acid analogues 2 and 2a were inactive at the studied concentrations. It is worth noting that compound 1 (at concentration 50 mg/ mL) was shown to inhibit the growth of A. terreus almost three times more efficient than amphotericin B used as a standard antifungal agent. On the contrary, isomer 1a displayed only limited activity against A. terreus. 1a is also almost inactive against C. tenuis, whereas 1 displays relatively high activity against this fungus even at low concentrations. It should be noted that in case of A. niger, compounds 1 and 1a did not inhibit but only limit its growth (Table 2, values without parentheses, Fig. 8, shadowed bars). Both 1 and 1a show very low activity against F. dimerum, only at concentration as high as 100 mg/mL. Similarly, limited activity of 1 and 1a against P. ochrochloron was observed. It is worth mentioning that none of the starting piperazines, neither 2-(fluorophenyl)piperazine nor 4-(fluorophenyl)piperazine, displayed any activity against five studied fungi strains at 100 mg/mL concentration. MIC values were determined using the serial dilution method [37]. The investigated compounds were dissolved in DMSO and placed in the liquid Czapek medium (2 mL), ensuring the necessary concentration (final concentration ranged from 10 to 100 mg/ml). Media were inoculated with 2  106 fungal spores and incubated at 25  C on a rotary shaker (60 rpm). The MIC endpoints were read visually following 72 h of incubation and were defined as the lowest concentration at which no visible growth of fungal mycelium was observed. Each experiment (control or compoundcontaining medium) was repeated three times. The MIC values determined for 1 and 1a compounds (Table 3) confirm their moderate fungicidal activity against tested fungi. It is worth mentioning that the activity of 1 and 1a is much lower than that previously reported for AN2690 as well as its isomers [4].

593

4. Experimental 4.1. Materials and methods All reactions were performed under air, using undried glassware and undistilled solvents. The reported yields correspond to isolated products. Reagents and solvents were obtained from commercial sources (Sigma-Aldrich, POCh, ChemPur) and used without further purification. Deuterated solvents were obtained from Armar Chemicals and used as received. NMR spectra were recorded on a Varian Inova 500 MHz spectrometer in deuterated solvents. Chemical shifts are reported in parts per million (ppm), relative to the residual undeuterated solvent signal as an internal standard. All signals are reported as follows: chemical shift (multiplicity, number of corresponding nuclei). Abbreviations used: s ¼ singlet, d ¼ doublet, t ¼ triplet, td ¼ triplet of doublets, m ¼ multiplet, br ¼ broad signal. Elemental analyses were obtained using a Perkin Elmer 2400 apparatus. Melting points are given uncorrected. FTIR spectra have been recorded on the Negus Spectrometer (Nicolet) in KBr and mass spectra on the Microtof - QII Spectrometer (Bruker Daltonics). Czapek medium components of the highest available purity, and DMSO, were obtained from POCh. Medium potato dextrose agar, amphotericin B and Tween 80 were purchased from Sigma-Aldrich. Five fungal strains were used for the experiments. Aspergillus niger LOCK 0440 and Aspergillus terreus LOCK 64 were purchased from the Institute of Fermentation Technology and Microbiology
d
(Ło z University of Technology), while Penicillium ochrochloron F337 were obtained from the Czech Collection of Microorganisms (CCM). Fusarium dimerum DAE-1001, originally isolated from the surface of carrot seeds, was obtained from the collection of microorganisms of the Department of Analytical and Ecological Chemistry (Opole University, Faculty of Chemistry). Aspergillus and Penicillium strains were routinely maintained in potato dextrose agar, while Fusarium strains grew in Czapek agar medium. Spore suspensions used in experiments were prepared by washing the surface of 10- to 14-day-old cultures with sterile distilled water containing 0.05% Tween, and quantified using the Thom's chamber. 4.2. Synthetic procedures and characterization data 4.2.1. 3-[4-(2-Fluorophenyl)piperazin-1-yl]benzoxaborole (1)

3. Conclusions A set of N-(fluorophenyl)piperazinyl phenylboronic compounds was prepared starting from 2-formylphenylboronic acid. Dehydrative conditions led to the formation of benzoxaboroles (1 and 1a), while amination-reduction protocol provided ortho-(aminomethyl)phenylboronic acids (2 and 2a). Crystallization of 2a from methanol surprisingly gave its methyl monoester 3a. The position of fluorine atom influences the relative orientation of the benzene and the piperazine rings and its role is connected with the diversified array of weak intermolecular interactions in which the fluorine atom is engaged. No interactions with fluorine were however observed in the case of 3a. The Bond Valence Vector Model analysis clearly indicates that the strongest strains are observed in benzoxaboroles 1 and 1a and this may be associated with their antifungal activity. Microbiological evaluation of the studied compounds performed against A. niger, A. terreus, P. ochrochloron, C. tenuis and F. dimerum confirmed moderate antifungal activity of benzoxaboroles and no such activity of their phenylboronic analogues.

To a stirred solution of 2-formylphenylboronic acid (500 mg, 3.34 mmol, 1.00 eq) and 1-(2-fluorophenyl)piperazine (601 mg, 3.34 mmol, 1.00 eq) in diethyl ether (20.0 mL), sodium sulfate (3.00 g, 21.1 mmol, 6.33 eq) was added in one portion immediately after mixing the reagents. The resulting heterogeneous mixture was stirred for 20 h at room temperature. The solid was removed by filtration and another portion of sodium sulfate (3.00 g, 21.1 mmol, 6.33 eq) was added to the clear filtrate. The mixture was stirred for the next 24 h. The solid was filtered off, the resulting clear ethereal solution was concentrated to ca 20% of its starting volume and left for 2 days. The formed solid was filtered off and dried in air for 2 days, affording the product as a white powder (0.811 g, 2.60 mmol, 78% yield). Crystals suitable for X-Ray measurements have been obtained by crystallization from diethyl ether.

594

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

Fig. 6. The superposition of investigated molecules in crystals.

m.p. 157e161  C

4.2.2. 3-[4-(4-Fluorophenyl)piperazin-1-yl]benzoxaborole (1a)

To a stirred solution of 2-formylphenylboronic acid (300 mg, 2.0 mmol, 1.00 eq) and 1-(4-fluorophenyl)piperazine (361 mg, 2.0 mmol, 1.00 eq) in diethyl ether (20.0 mL), sodium sulfate (1.42 g, 10.0 mmol, 5.0 eq) was added in one portion immediately after mixing the reagents. The resulting heterogeneous mixture was stirred for 71 h at room temperature. The solid was filtered off, diethyl ether was evaporated under reduced pressure, resulting solid product was dissolved in diethyl ether and left for 1 day. The formed solid was filtered off and dried in air for 2 days, affording the product as a yellowish white crystals (0.253 g, 0.80 mmol, 40% yield). Crystals suitable for X-Ray measurements have been obtained by crystallization from acetone. 1

Fig. 5. Ortep drawing [29] of the acyclic hemiester's molecule 3a. The ellipsoids are shown at 50% probability. Only the hydrogen atoms of hydroxyl groups are given for the clarity of the picture (top). The basic helical motif formed by weak interactions only (middle). The packing of motives, view on plane (010), is shown at the bottom.

1 H NMR (400 MHz, acetone-d6) d 7.72 (d, 1H), 7.51 (td, 1H), 7.42 (m, 2 H), 7.03 (m, 3H), 6.93 (m, 1H), 5.90 (s, 1H), 3.05 (t, 4H), 2.83 (m, 2H), 2.71 (m, 2H). 13 C NMR (100 MHz, acetone-d6) d 157.7, 155.3, 153.9, 141.3, 131.8, 130.9, 129.1, 125.5, 123.6, 123.1, 120.0, 116.6, 97.2, 51.5, 47.6. 11 B NMR (160 MHz, acetone-d6) d 32.1. 19 F NMR (376 MHz, acetone-d6) d
122.49. Elemental analysis (C, H, N) C17H18BFN2O2 calcd: C (65.41%), H (5.81%), N (8.97%); found: C (65.13%), H (5.80%), N (8.63%) FTIR (1.5 mg, KBr pellet, cm-1): 3383 (broad), 2848, 2836, 1497, 1415, 1237, 1150, 903. MS (ESI, dissolved in CH3CN) m/z ¼ 313.15 (100%, M þ Hþ)

H NMR (500 MHz, acetone-d6) d 8.06 (1H, br), 7.73 (d, 1H), 7.52 (td, 1H), 7.45e7.39 (m, 2H), 6.99e6.93 (m, 4H), 5.91 (s, 1H), 3.10 (m, 4H), 2.81 (m, 2H), 2.69 (m, 2H) 13 C NMR (125 MHz, acetone-d6) d 158.6, 154.0, 131.8, 130.9, 129.1, 123.6, 118.6, 118.5, 116.1, 115.9, 97.2, 50.8, 47.6 11 B NMR (80 MHz, acetone-d6) d 33 19 F NMR (376 MHz, acetone-d6) d
121.37 Elemental analysis (C, H, N) C17H18BFN2O2 calcd: C (65.41%), H (5.81%), N (8.97%); found: C (65.62%), H (5.95%), N (8.65%) FTIR (KBr pellet, cm-1): 3422 (broad), 2830, 1510, 1454, 1346, 1233, 827. MS (ESI, dissolved in CH3CN) m/z ¼ 313.15 (100%, M þ Hþ) m.p. 119e123  C

4.2.3. 2-{[4-(2-Fluorophenyl)piperazin-1-yl]methyl}phenylboronic acid (2)

To a stirred solution of 2-formylphenylboronic acid (840 mg,

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

595

Fig. 7. Photographs of agar diffusion tests for benzoxaboroles (1, 1a) and the corresponding boronic acid (2) against A. niger.

Table 2 The average diameter of the zone of inhibited growth of the examined fungi [mm]. Fungus Benzoxaborole 1 A. niger A. terreus P. ochrochloron C. tenuis F. dimerum Benzoxaborole 1a A. niger A. terreus P. ochrochloron C. tenuis F. dimerum Phenylboronic acid 2 A. niger A. terreus P. ochrochloron C. tenuis F. dimerum Phenylboronic acid 2a A. niger A. terreus P. ochrochloron C. tenuis F. dimerum

10 mg

25 mg

50 mg

100 mg

Amphotericin B50 mg

DMSO

8 0 0 16 0

15 16 11 20 (9) 0

20 (29) 19 22 (14) 0

27 (36) 31 23 (20) 6

(13) 12 (10) (11) n/d 4

0

0 0 0 0 0

20 16 0 0 0

28 25 20 0 n/d

35 31 24 (13) 10 19 (10)

(13) 12 (10) (11) n/d 4

0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

(13) 12 (10) (11) n/d 4

0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

(13) 12 (10) (11) n/d 4

0

5.60 mmol, 2.00 eq) in acetonitrile (25.0 mL) at 0  C, 1-(2fluorophenyl)piperazine (505 mg, 2.80 mmol, 1.00 eq), molecular sieves 3 Å (0.5 g) and acetic acid (337 mg, 5.60 mmol, 2.00 eq) were added, white solid precipitated. The resulting heterogeneous mixture was stirred for 1 h, followed by addition of NaBH(OAc)3 (1.188 g, 5.60 mmol, 2.00 eq), and the molecular sieves and remaining solid were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in 3 M HCl (10 mL), H2O (10 mL) and MeOH (5 mL) and stirred for 10 min. Benzoxaborole side-product was removed by extraction with three portions of diethyl ether, according to the previously reported method [22]. The remaining aqueous phase was neutralized with NH3aq (pH ca. 7). The desired boronic acid was extracted with diethyl ether. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure resulting in white solid product (665 mg, 3.1 mmol, 76%). Crystals

suitable for X-ray measurements were obtained by crystallization from acetone. 1 H NMR (500 MHz, acetone-d6 þ drop of D2O) d 7.87 (dd, 1H), 7.37e7.26 (m, 3H), 7.10e7.02 (m, 3H), 6.98e6.94 (m, 1H), 3.69 (s, 2H), 3.09 (br, 4H), 2.67 (br, 4H) 13 C NMR (125 MHz, acetone-d6 þ drop of D2O) d 157.4, 155.4, 142.0, 140.7, 136.9, 131.5, 130.4, 127.9, 125.5, 120.0, 116.7, 116.6, 64.5, 52.7, 50.8 11 B NMR (80 MHz, acetone-d6 þ drop of D2O) d 31 19 F NMR (376 MHz, acetone-d6 þ drop of D2O) d
124.10 Elemental analysis (C, H, N) C17H20BFN2O2 calcd: C (64.99%), H (6.42%), N (8.92%); found: C (65.01%), H (6.47%), N (8.96%) FTIR (KBr pellet, cm-1): 3 (broad), 2824, 1502, 1380, 1247, 764. MS (ESI, dissolved in CH3CN) m/z ¼ 315.16 (100%, M þ Hþ) m. p. 227e230  C

596

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598 13

C NMR (100 MHz, acetone-d6) d 156.0, 156.6, 148.9, 142.0, 136.9, 131.5, 130.5, 127.9, 118.7, 118.6, 116.1, 115.9, 64.4, 52.6, 50.1 11 B NMR (64 MHz, acetone-d6) d 28 19 F NMR (376 MHz, acetone-d6) d
124.92 Elemental analysis (C, H, N) C17H20BFN2O2 calcd: C (64.99%), H (6.42%), N (8.92%); found: C (64,81%), H (6.40%), N (8.90%) FTIR (KBr pellet, cm-1): 3365 (broad), 2821, 1510, 1371, 1229, 829, 819. MS (ESI, dissolved in CH3CN) m/z ¼ 337.15 (100%, M þ Naþ) m. p. 234e236  C

4.2.5. 2-{[4-(4-Fluorophenyl)piperazin-1-yl]methyl}phenylboronic acid methyl ester (3a)

Fig. 8. Activity of benzoxaboroles 1 and 1a as well as amphotericin B against A. niger, A terreus and P. ochrochloron at 50 mg/mL. Shadows stand for limited growth of the microorganisms.

Table 3 Minimal inhibitory concentration (MIC) for the examined fungi. Fungus

Compound 1

1a

2a

2aa

62.5 62.5 62.5

>125 >125 >125

>125 >125 >125

MIC

mg/ml A. niger A. terreus P. ochrochloron

62.5 62.5 n/d

a Compounds 2 and 2a do not dissolve in DMSO at concentrations higher than 125 mg/mL

4.2.4. 2-{[4-(4-Fluorophenyl)piperazin-1-yl]methyl}phenylboronic acid (2a)

1 H NMR (400 MHz, methanol-d4) d 7.60e7.57 (m, 1H), 7.27e7.16 (m, 3H), 7.01 (s, 2H), 6.99 (s, 1H), 6.99 (s, 1H), 4.07 (s, 2H), 3.34 (s, 3H), 3.25 (m, 4H), 3.04 (m, 4H) 13 C NMR (101 MHz, methanol-d4) d 131.6, 130.2, 130.1, 129.3, 120.5, 120.1, 117.4, 117.2, 117.0, 64.6, 54.8, 53.3, 51.8 11 B NMR (64 MHz, methanol-d4) d 19 19 F NMR (376 MHz, methanol-d4) d
126.41 Elemental analysis (C, H, N) C18H22BFN2O2 calcd: C (65.88%), H (6.76%), N (8.54%); found: C (65.93%), H (6.79%), N (8.54%) m.p. 126e132  C

4.3. X-ray diffraction measurements All diffraction data were collected on Rigaku Oxford Diffraction

k-CCD Gemini An Ultra diffractometer (in the Laboratory of Struc-

Solution of equimolar quantities of 2-formylphenylboronic acid (500 mg, 3.34 mmol, 1.00 eq) and 1-(4-fluorophenyl)piperazine (602 mg, 3.34 mmol, 1.00 eq) in acetonitrile (30.0 mL) was prepared at
8  C, followed by addition of NaBH4 (1 eq.) and 20 min of subsequent vigorous stirring. Resulting mixture was acidified with a 3 M HClaq. Unsubstituted benzoxaborole side-product was removed by extraction with three portions of diethyl ether. The extraction procedure was repetead twice. The remaining aqueous phase was neutralized with NH3aq (pH ca. 7). The desired boronic acid was extracted with diethyl ether. The extraction procedure was repetead twice. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under reduced pressure resulting in white solid product (464 mg, 1.4 mmol, 44%). Crystals suitable for X-ray measurements were obtained by crystallization from ethyl acetate. 1 H NMR (400 MHz, acetone-d6) d 7.87 (dd, 1H), 7.36e7.24 (m, 3H), 7.01e6.95 (m, 4H), 3.67 (s, 2H), 3.13 (br, 4H), 2.64 (br, 4H)

tural Research at the Faculty of Chemistry in Warsaw University of Technology) with mirror monochromated CuKa radiation (l ¼ 1.54184 Å). Cell refinement and data collection as well as data reduction were performed with CrysAlisPro software (Version 1.171.38.41 and earlier versions) [38]. The empirical absorption corrections using spherical harmonics, implemented in mutli-scan algorithm, were also performed. The structures were solved by intrinsic phasing using SHELXT program [39] while full-matrix least-squares refinement method against F2 values was carried out using the SHELXL-2014 program [40], implemented in OLEX2 [35] suite. All non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were added to the structure model at geometrically idealized coordinates and refined as riding atoms with Uiso(H) ¼ 1.2  Ueq (CH, CH2) or Uiso(H) ¼ 1.5  Ueq (CH3, OH). The hydrogen atoms of the hydroxyl groups were refined with a restraint of OeH distance equal to 0.84 (1) Å in the case of structures measured in lowered temperature and 0.82 (1) in room temperature (in the case of 1a the proton position was refined as riding atom with Uiso(H) ¼ 1.5  Ueq (OH) due to the interaction of this group with disordered solvent molecule). For the analysis of bond lengths, bond and torsion angles and the geometrical parameters of hydrogen bonds the PLATON [41] program was applied. Molecular diagrams were generated using ORTEP-3 for Windows [29] while supramolecular synthons

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598

and packing diagrams using DIAMOND [35] and Mercury [41] programs. In 1a the severely disordered solvent molecule of diethyl ether is present in crystal structure. The final refinement model contains heavy atoms of the solvent with isotropic displacement parameters only. In 2a the high residual electron density observed during refinement indicated a presence of severely disordered or diffused solvent but no satisfactory model could be applied. The calculated total solvent accessible volume per unit cell amounted to 76.9 Å3 (~2.3%). Therefore the solvent masking procedure in OLEX2 was used. The masked region is defined as the solvent accessible region left by the ordered part of the structure. Any atoms in the voids were thus omitted from the structural model. The electron density was estimated to be 4.2 electrons per unit cell, and correction of the Fobs data to remove its contribution resulted in R1 and wR2 falling to 4.20% and 11.08%, respectively, and the residual electron density below ~0.3 e/Å3. The crystallographic data are summarized in Tables S1 and S2. CCDC 1822972e1822976 files contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif.

[6] [7]

[8]

[9]

[10]

[11]

[12]

[13]

Conflicts of interest [14]

There are no conflicts to declare. Acknowledgements A.A.-W., J. L. and D.W. kindly acknowledge the support of the Polish National Science Centre (NCN, grant No. 2016/23/B/ST5/ 02847). K.M.B. acknowledges the Ministry of Science and Higher Education of Poland for financial support within “Diamentowy Grant” program [grant no. DI 2012 015042 (0150/DIA/2013/42)]. K.M.B. received financial support from the National Science Centre of Poland within the ETIUDA doctoral scholarship (NCN, project No. 2017/24/T/ST5/00298). This work has been supported by the European Union in the framework of European Social Fund through the Warsaw University of Technology Development Program by the scholarship awarded by the Centre of Advanced Studies to A.M. A. M. would like to thank for financial support within Etiuda scholarship by the Polish National Science Center (NCN, project No. 2016/20/T/ST5/00374). I.D.M. and K.K. kindly acknowledge Faculty of Chemistry, Warsaw University of Technology.

[15]

[16]

[17]

[18]

[19]

[20] [21]

Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.molstruc.2019.01.018.

[22]

References [23] [1] A. Adamczyk-Wo
zniak, K.M. Borys, I.D. Madura, A. Pawełko, E. Tomecka, _ K. Zukowski, Lewis acidity and sugar receptor activity of 3-amino-substituted benzoxaboroles and their ortho-aminomethylphenylboronic acid analogues, New J. Chem. 37 (2013) 188e194, https://doi.org/10.1039/C2NJ40687J. [2] A. Adamczyk-Wo
zniak, K.M. Borys, A. Sporzynski, Recent developments in the Chemistry and biological applications of benzoxaboroles, Chem. Rev. 115 (2015) 5224e5247, https://doi.org/10.1021/cr500642d. [3] D. Wieczorek, J. Lipok, K.M. Borys, A. Adamczyk-Wo
zniak, A. Sporzynski, Investigation of fungicidal activity of 3-piperazine-bis(benzoxaborole) and its boronic acid analogue, Appl. Organomet. Chem. 28 (2014) 347e350, https:// doi.org/10.1002/aoc.3132. [4] A. Adamczyk-Wo
zniak, M.K. Cabaj, P.M. Dominiak, P. Gajowiec, B. Gierczyk, J. Lipok, et al., The influence of fluorine position on the properties of fluorobenzoxaboroles, Bioorg. Chem. 60 (2015) 130e135, https://doi.org/10.1016/ j.bioorg.2015.05.004. [5] M. Psurski, A. Łupicka-Słowik, A. Adamczyk-Wo
zniak, J. Wietrzyk, A. Sporzynski, Discovering simple phenylboronic acid and benzoxaborole derivatives for experimental oncology e phase cycle-specific inducers of apoptosis in

[24]

[25] [26]

[27]

597

A2780 ovarian cancer cells, Invest. N. Drugs (in press), https://doi.org/10. 1007/s10637-018-0611-z. R.D. Taylor, M. MacCoss, A.D.G. Lawson, Rings in drugs, J. Med. Chem. 57 (2014) 5845e5859, https://doi.org/10.1021/jm4017625. A. Khalaj, N. Adibpour, A.R. Shahverdi, M. Daneshtalab, Synthesis and antibacterial activity of 2-(4-substituted phenyl)-3(2H)-isothiazolones, Eur. J. Med. Chem. 39 (2004) 699e705, https://doi.org/10.1016/j.ejmech.2004. 04.004. M.N. Abu-Aisheh, M.S. Mustafa, M.M. El-Abadelah, R.G. Naffa, S.I. Ismail, M.A. Zihlif, et al., Synthesis and biological activity assays of some new N1(flavon-7-yl)amidrazone derivatives and related congeners, Eur. J. Med. Chem. 54 (2012) 65e74, https://doi.org/10.1016/j.ejmech.2012.04.028. P. Gareri, U. Falconi, P. De Fazio, G. De Sarro, Conventional and new antidepressant drugs in the elderly, Prog. Neurobiol. 61 (2000) 353e396, https:// doi.org/10.1016/S0301-0082(99)00050-7. P. Piplani, C.C. Danta, Design and synthesis of newer potential 4-(N-acetylamino)phenol derived piperazine derivatives as potential cognition enhancers, Bioorg. Chem. 60 (2015) 64e73, https://doi.org/10.1016/j.bioorg.2015.04.004. M.F. Khan, P. Kumar, J. Pandey, A.K. Srivastava, A.K. Tamrakar, R. Maurya, Synthesis of novel imbricatolic acid analogues via insertion of N-substituted piperazine at C-15/C-19 positions, displaying glucose uptake stimulation in L6 skeletal muscle cells, Bioorg. Med. Chem. Lett 22 (2012) 4636e4639, https:// doi.org/10.1016/j.bmcl.2012.05.097. P. Ashok, S. Chander, J. Balzarini, C. Pannecouque, S. Murugesan, Design, synthesis of new b-carboline derivatives and their selective anti-HIV-2 activity, Bioorg. Med. Chem. Lett 25 (2015) 1232e1235, https://doi.org/10.1016/ j.bmcl.2015.01.058. A. Penta, S. Franzblau, B. Wan, S. Murugesan, Design, synthesis and evaluation of diarylpiperazine derivatives as potent anti-tubercular agents, Eur. J. Med. Chem. 105 (2015) 238e244, https://doi.org/10.1016/j.ejmech.2015.10.024. Z. Petkova, V. Valcheva, G. Momekov, P. Petrov, V. Dimitrov, I. Doytchinova, et al., Antimycobacterial activity of chiral aminoalcohols with camphane scaffold, Eur. J. Med. Chem. 81 (2014) 150e157, https://doi.org/10.1016/ j.ejmech.2014.05.007. S.-L. Cao, Y. Han, C.-Z. Yuan, Y. Wang, Z.-K. Xiahou, J. Liao, et al., Synthesis and antiproliferative activity of 4-substituted-piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline, Eur. J. Med. Chem. 64 (2013) 401e409, https://doi.org/10.1016/j.ejmech.2013.04.017. R. Romagnoli, P.G. Baraldi, M.D. Carrion, C.L. Cara, O. Cruz-Lopez, M.K. Salvador, et al., Structureeactivity relationships of 2-amino-3-aroyl-4[(4-arylpiperazin-1-yl)methyl]thiophenes. Part 2: probing the influence of diverse substituents at the phenyl of the arylpiperazine moiety on allosteric enhancer activity at the A1 adenosine receptor, Bioorg. Med. Chem. 20 (2012) 996e1007, https://doi.org/10.1016/j.bmc.2011.11.044. J. Yoon, E.A. Yoo, J.-Y. Kim, A.N. Pae, H. Rhim, W.-K. Park, et al., Preparation of piperazine derivatives as 5-HT7 receptor antagonists, Bioorg. Med. Chem. 16 (2008) 5405e5412, https://doi.org/10.1016/j.bmc.2008.04.023. S. Garattini, T. Mennini, Critical notes on the specificity of drugs in the study of metabolism and functions of brain monoamines, Int. Rev. Neurobiol. 29 (1988) 259e280, https://doi.org/10.1016/S0074-7742(08)60089-6. D. Scherman, M. Hamon, H. Gozlan, J.-P. Henry, A. Lesage, M. Masson, et al., Molecular pharmacology of niaprazine, Prog. Neuro Psychopharmacol. Biol. Psychiatr. 12 (1988) 989e1001, https://doi.org/10.1016/0278-5846(88) 90093-0. L.A. King, Forensic Chemistry of Substance Misuse: A Guide to Drug Control, Royal Society of Chemistry, Cambridge, 2009. A literature search performed with the Reaxys database (date of access: 09/ 03/2018) revealed bioactivity studies on only 255 (3-fluorophenyl)piperazines, compared to 3580 reports on 4-fluoro and 1367 reports on 2-fluoro analogues, therefore we have focused on the N-phenylpiperazine derivatives: 2-(fluorophenyl)piperazine (oPFF) and 4-(fluorophenyl)piperazine (pFPP).
ski, Diverse reacA. Adamczyk-Wo
zniak, I. Madura, A.H. Velders, A. Sporzyn tivity of 2-formylphenylboronic acid with secondary amines: synthesis of 3amino-substituted benzoxaboroles, Tetrahedron Lett. 51 (2010) 6181e6185. https://doi.org/10.1016/j.tetlet.2010.09.091. A. Adamczyk-Wo
zniak, I. Madura, A. Pawełko, A. Sporzynski, A. Z_ubrowska, _ J. Zyła, Amination-reduction reaction as simple protocol for potential boronic molecular receptors. Insight in supramolecular structure directed by weak interactions, Cent. Eur. J. Chem. 9 (2011) 199e205, https://doi.org/10.2478/ s11532-010-0142-8.
ska, I.D. Madura, A. Matuszewska, A. Adamczyk-Wo
zniak, K. Czerwin _ A. Sporzynski, A. Zubrowska-Zembrzuska, Piperazine derivatives of boronic acids e potential bifunctional biologically active compounds, New J. Chem. 39 (2015) 4308e4315, https://doi.org/10.1039/C5NJ00084J. F.H. Allen, R. Taylor, Librarians, crystal structures and drug design, Chem. Commun. 44 (2005) 5135e5140, https://doi.org/10.1039/b511106b. A. Adamczyk-Wo
zniak, R.M. Fratila, I.D. Madura, A. Pawełko, A. Sporzynski, M. Tumanowicz, et al., Reactivity of 2-formylphenylboronic acid toward secondary aromatic amines in aminationereduction reactions, Tetrahedron Lett. 52 (2011) 6639e6642, https://doi.org/10.1016/j.tetlet.2011.10.008. A.Y. Fedorov, A.A. Shchepalov, A.V. Bol shakov, A.S. Shavyrin, Y.A. Kurskii, J.P. Finet, S.V. Zelentsov, Synthesis of (azidomethyl)phenylboronic acids, Russ. Chem. Bull. Int. Ed. 53 (2004) 370e375, https://doi.org/10.1023/B: RUCB.0000030813.05424.1f.

598

K.M. Borys et al. / Journal of Molecular Structure 1181 (2019) 587e598


tusova, I. Madura, P.H. Marek, [28] A. Adamczyk-Wo
zniak, E. Kaczorowska, J. Kreda A. Matuszewska, et al., Dehydration of ortho-, meta- and para-Alkoxy Phenylboronic Acids to their Corresponding Boroxines, Eur. J. Inorg. Chem. 2018 (2018) 1492e1498, https://doi.org/10.1002/ejic.201701485. [29] L.J. Farrugia, WinGXand ORTEP for Windows: an update, J. Appl. Crystallogr. 45 (2012) 849e854, https://doi.org/10.1107/S0021889812029111. [30] J. Zachara, Novel approach to the concept of bond-valence vectors, Inorg. Chem. 46 (2007) 9760e9767, https://doi.org/10.1021/ic7011809.
ska, I.D. Madura, J. Zachara, Geometry of trigonal boron coordina[31] K. Czerwin tion sphere in boronic acids derivatives e a bond-valence vector model approach, Acta Crystallogr. B 72 (2016) 241e248, https://doi.org/10.1107/ S2052520616002262. [32] D. Cremer, J.A. Pople, General definition of ring puckering coordinates, J. Am. Chem. Soc. 97 (1975) 1354e1358, https://doi.org/10.1021/ja00839a011. [33] M.C. Etter, Encoding and decoding hydrogen-bond patterns of organic compounds, Acc. Chem. Res. 23 (2002) 120e126, https://doi.org/10.1021/ ar00172a005.
ska, M. Jakubczyk, A. Pawełko, A. Adamczyk-Wo
[34] I.D. Madura, K. Czerwin zniak, A. Sporzynski, Weak CeH$$$O and dipoleedipole interactions as driving forces in crystals of fluorosubstituted phenylboronic catechol esters, Cryst.

Growth Des. 13 (2013) 5344e5352, https://doi.org/10.1021/cg4012026. [35] O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, OLEX2: a complete structure solution, refinement and analysis program, J. Appl. Crystallogr. 42 (2009) 339e341, https://doi.org/10.1107/S00218898080427 26. [36] M.C. Etter, J.C. MacDonald, J. Bernstein, Graph-set analysis of hydrogen-bond patterns in organic crystals, Acta Crystallogr. B 46 (1990) 256e262, https:// doi.org/10.1107/S0108768189012929. [37] A. Adamczyk-Wo
zniak, O. Komarovska-Porokhnyavets, B. Misterkiewicz, V.P. Novikov, A. Sporzynski, Biological activity of selected boronic acids and their derivatives, Appl. Organomet. Chem. 26 (2012) 390e393, https://doi.org/ 10.1002/aoc.2880. [38] CrysAlisPro Software System, Rigaku, Oxford, UK, 2015. [39] G.M. Sheldrick, SHELXT e integrated space-group and crystal-structure determination, Acta Crystallogr. A 71 (2015) 3e8. [40] G.M. Sheldrick, Crystal structure refinement with SHELXL, Acta Crystallogr. C 71 (2015) 3e8. [41] C.F. Macrae, P.R. Edgington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor, et al., Mercury: visualization and analysis of crystal structures, J. Appl. Crystallogr. 39 (2006) 453e457, https://doi.org/10.1107/S002188980600731X.

́

́