Solubility and Transfer Processes of Some Hydrazones in Biologically

Article pubs.acs.org/jced

Solubility and Transfer Processes of Some Hydrazones in Biologically Relevant Solvents German L. Perlovich,†,§,* Vladimir P. Kazachenko,† Nadezda N. Strakhova,† Klaus-J. Schaper,‡,⊥ and Oleg A. Raevsky† †

Department of Computer-Aided Molecular Design, Institute of Physiologically Active Compounds of Russian Academy of Sciences, 142432, Chernogolovka, Russia ‡ Division of Structural Biochemistry, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Parkallee 1-40, D-23845 Borstel, Germany § Krestov’s Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia ABSTRACT: Solubility values of 20 hydrazones in water, 1-octanol and hexane were determined by the isothermal saturation method. Thermophysical characteristics of fusion processes (melting points and fusion enthalpies) of the selected substances were measured by DSC method. The impact of structural modification of the molecules on solubility processes in the solvents was analyzed. Transfer processes from water to 1-octanol and from water to hexane were analyzed. Correlation equations connecting the transfer coefficients with physicochemical descriptors were obtained.

1. INTRODUCTION Interest in the study of heterocyclic hydrazones has been growing because of their antimicrobial, antimycobacterial, and antitumor activities.1−10 Hydrazones of the type shown in Scheme 1 play an important role in inorganic chemistry, as they easily form very stable complexes with most of the transition metal ions.11−16

investigated the antiviral activity of N-arylaminoacetyl hydrazones against Herpes simplex virus-1 and Hepatitis-A virus (HAV), Walcourt et al.21 demonstrated the antimalarial activity of 2-hydroxy-1-naphthaldehyde isonicotinoylhydrazone and Savini et al.22 have reported on the antitumor activity of 3and 5-methylthiophene-2-carboxaldehyde α-(N)-heterocyclic hydrazone derivatives. On the basis of experimental results it is assumed4,5,7,8 that 2acylpyridine α-(N)-heterocyclic hydrazones are inhibitors of ribonucleotide reductase (RR). RR is an enzyme that contains metal atoms (Fe in gram-negative cells,23−26 Mn in grampositive cells,24−28 Co in algae24−26,29) in the active site as well as a stable free radical substructure.23,30,31 This “RRassumption” is consistent with our observation that hydrazones that are active against mycobacteria (M.tuberculosis, M.avium, the M.leprae model strain M.luf u) on the one hand have to be tridentate chelators (Schaper, unpubl. results). On the other hand they also have to be able to react with radicals.4,5 For instance our compounds 5−7 in Figure 1 are not tridentate ligands and compound 4 as well as derivatives of 2 (with NH replaced by NCH3, not shown in Figure 1) are unable to react with radicals.5 The consequence is that all these derivatives are inactive toward mycobacteria. Sjöberg et al.31 found that the tyrosyl radical of RR from E.coli is buried in the protein matrix

Scheme 1

The development of the field of bioinorganic chemistry has increased the interest in hydrazone complexes, since it has been recognized that many of these complexes may serve as models for biologically important species.17 Coordination compounds derived from aroylhydrazones have been reported to act as enzyme inhibitors and are useful due to their pharmacological applications.18 Hydrazones possessing an azomethine −NH− NCH− proton constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized such compounds as target structures and evaluated their biological activities. Hydrazones and their metal complexes are biologically very active compounds. For example Ragavendran et al.19 have reported on the anticonvulsant activity of 4-aminobutyric acid hydrazone, Abdel-Aal et al.20 © 2013 American Chemical Society

Received: June 16, 2013 Accepted: July 28, 2013 Published: August 12, 2013 2659

dx.doi.org/10.1021/je400557z | J. Chem. Eng. Data 2013, 58, 2659−2667

Journal of Chemical & Engineering Data

Article

Figure 1. Structural formulas of the compounds studied.

close to a dinuclear iron center and a cluster of three hydrophobic amino acid residues. Their results suggest that the major role of the hydrophobic pocket is to stabilize the tyrosyl radical. Thus it is possible to conclude that hydrophobic/ lipophilic inhibitors will have a better chance to interact with the RR-active site. Despite the great scientific interest in the above class of compounds, information about their lipophilicity is still lacking.32 In keeping with a rational approach to the evaluation of the biological activity19−22 of the newly synthesized compounds as a function of their chemical structure, a quantitative descriptor of the lipophilic character of a molecule is needed, as many recent studies, for example, about antimicrobial activity, show. The solubility of organic compounds is a subject of interest not only for fundamental science, but for application purposes as well. This interest can be explained by the fact that solubility

is a key parameter for the development and utilization of drug compounds. Moreover, solubility impacts on such processes in the body as absorption, partitioning, and membrane permeability, which significantly determine bioavailability and, as a consequence, biological activity.33 Unfortunately, systematic investigations of hydrazone solubility in solvents modeling biological media (water, 1-octanol, and hexane), have not yet been carried out. This work is an attempt to correct this deficiency. In addition, the processes of hydrazone transfer from water to octanolic phases (model of gastrointestinal tract membranes) and from water to hexane phases (blood-brain barrier model) have been analyzed. A total of 20 hydrazones with the structural formulas presented in Figure 1 have been chosen as a subject for the study. 2660



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2. EXPERIMENTAL SECTION 2.1. Chemicals. General Procedure for All Compounds. After recrystallization the final products were dried at room temperature under vacuum until the mass was constant. The outlined procedure was repeated several times and the product was checked by TLC and NMR. Compounds 1 (PQ22, 2-Quinolinylhydrazone-(2-pyridinecarboxaldehyde)), 2 (PH22, 2-Pyridinylhydrazone-(2-pyridinecarboxaldehyde), 9 (PH22-4, [1-(2-Pyridinyl)ethylidene]hydrazone-(2(1H)-quinolinone)). These compounds have already been published by C.Pellerano et al.9 Compound 9 has also been published by Konishi and Kuragano.3 The melting points of the obtained compounds are 1, (474 to 476) K; 2, (454 to 456) K; 9, (415 to 417) K. Compounds 3 (PH22-26, (6-Chloro-4-pyrimidinyl)hydrazone-(2-pyridinecarboxaldehyde)), 10 (PH22-6, 1Phthalazinylhydrazone-(2-pyridinecarboxaldehyde, 5-(Phenylmethoxy)−)), 11 (PH22-15, (Phenyl-2pyridinylmethylene)hydrazone-(2(1H)-quinolinone)), 12 (PH22-25, [1-(2-Pyridinyl)propylidene]hydrazone-(1(2H)phthalazinone)), 13 (PH22-34, [1-(2-Pyridinyl)ethylidene]hydrazone-(4(1H)-quinazolinone)). Syntheses of 3, 10−13 are taken from three of our patents.34−36 The melting points of the obtained compounds are 3, (525 to 527) K; 10, (432 to 434) K; 11, (416 to 418) K; 12, (414 to 416) K; 13, (484 to 486) K. Compound 4 (PH22-38), 2-Acetylpyridine O-(6′-Chloropyrimidin-4′-yl)oxime. A 3.63 g sample of 2-acetylpyridine was dissolved in 100 mL of methanol, 2.09 g of hydroxylamine·HCl was added, and portion-wise a saturated solution of (K2CO3 + H2O) was added to the stirred mixture until no further development of CO2 could be observed. The proceeding reaction was followed by TLC. Finally the solvent was removed by evaporation in a rotary evaporator, and the residue was extracted by and recrystallized in (ether + petrol ether) to yield 2-acetylpyridine oxime. A 1.36 g sample of 2-acetylpyridine oxime was dissolved in 50 mL of methanol and added dropwise to a refluxing solution of 1.49 g of 4,6-dichloropyrimidine in 50 mL of methanol +5 mL of triethylamine. After the mixture was stirred under reflux for 60 h the solvent was removed by evaporation in a rotary evaporator and the residue was recrystallized in (methanol + water). The resulting 4 had a melting point of (369 to 371) K. Compound 5 (PH22-41), Benzaldehyde Pyridin-2-ylhydrazone. A 2.1 g sample of benzaldehyde in 50 mL of methanol was combined with 2.2 g of 2-hydrazinopyridine in 30 mL of methanol. After 3 h at ambient temperature the mixture was warmed to 333 K for 1 h and then cooled to ∼295 K. The precipitated product was filtered by suction, washed with small amounts of methanol, dried, and recrystallized in (methanol + water). Yield, 3.2 g; melting point, (424 to 426) K. Compound 6 (PH22-43), Pyridine-2-aldehyde Phenylhydrazone. A 3 g sample of phenylhydrazine in 15 mL of methanol was combined with 3 g of pyridine-2-aldehyde in 15 mL of methanol. The product precipitated after a short time and was left standing for 2 h to complete the reaction. The precipitated product was filtered by suction, washed with small amounts of methanol, and dried. Yield, 3.8 g; melting point, (447 to 449) K. Compound 7 (PH22-44), Pyridine-3-aldehyde Pyridin-2′ylhydrazone. A 3.23 g sample of pyridine-3-aldehyde in 15 mL of methanol was combined with 3.4 g of 2-hydrazinopyridine in 15 mL of methanol. The product precipitated after a short time

and was left standing overnight to complete the reaction. The precipitated product was filtered by suction, washed with small amounts of methanol, and dried. Melting point, (448 to 451) K. Compound 14 (PH22-45), 2-Benzoylpyridine 6′-Chloro-3′pyridazinylhydrazone. A 5 g sample of 3,6-dichloropyridazine was dissolved in 100 mL of methanol. The solution was boiled under reflux, 4 mL of hydrazine hydrate (80 %) in 50 mL of methanol was added dropwise, and the mixture was boiled under reflux for 10 h. The solution was evaporated to dryness in a rotary evaporator. As the product could not be recrystallized the remaining substance was dissolved in methanol. Activated carbon was added to the solution which was stirred and filtered and evaporated to dryness in a rotary evaporator. A 4.5 g sample of crude 6-chloro-3-hydrazinopyridazine was obtained. A 1.44 g sample of this substance were dissolved in 50 mL of methanol, and 1.83 g of 2-benzoylpyridine in methanol was added. After the addition of 1 mL of glacial acetic acid, the mixture was stirred for 48 h at ambient temperature. The resulting crystalline precipitate was filtered by suction and washed with methanol. A 0.3 g of 14 with a melting point of (438 to 441) K was obtained. Compound 15 (PH22-46), 2-Benzoylpyridine 6′-Chloro-4′pyrimidinylhydrazone. A 1.83 g sample of 2-benzoylpyridine in 30 mL of methanol was combined with 1.44 g of 6-chloro-4hydrazinopyrimidine (see 3) in 30 mL of methanol. After the addition of 1 mL of glacial acetic acid the mixture was left to stand at ∼295 K for 4 days. The precipitated product was filtered by suction, washed with methanol, and dried. Yield, 0.9 g; melting point, (455 to 458) K. Compound 16 (PH22-50), 5-Benzyloxypyridine-2-aldehyde 6′-Chloro-4′-pyrimidinylhydrazone. By the same method described for 15, 5-benzyloxypyridine-2-aldehyde (see 10) was reacted with 6-chloro-4-hydrazinopyrimidine to result in 16 (melting point, (471 to 472) K). Compound 17 (PH22-53), 2-Propanoylpyridine 6′-Chloro4′-pyrimidinylhydrazone. By the same method described for 15, 2-propanoylpyridine (see 12, 18) was reacted with 6chloro-4-hydrazinopyrimidine to result in 17 (melting point, (394 to 395) K). Compound 18 (PH22-54), 2-Butanoylpyridine 6′-Chloro4′-pyrimidinylhydrazone. For the synthesis of 2-butanoylpyridine the general procedure (alkylation and hydrolysis of 2cyanopyridine) described in reference 42 has been applied: 30 g of 1-bromopropane were dissolved in 30 mL of dry diethyl ether and with slight warming slowly added to a suspension of 6.2 g of magnesium turnings in 100 mL of dry diethyl ether. After the addition of a further 50 mL of dry diethyl ether the mixture was heated under reflux for 1 h and then cooled to about (273 to 278) K. Subsequently 20 g of 2-cyanopyridine in 30 mL of dry diethyl ether was slowly added, and the solution was heated under reflux for 1 h to 2 h. Finally the mixture was poured on ice and adjusted to pH ∼5 by H2SO4. The ether phase was separated and dried by Na2SO4, and the solvent was removed by evaporation in a rotary evaporator to yield 2butanoylpyridine which was reacted with 6-chloro-4-hydrazinopyrimidine (see 3, 15) to result in 18 (melting point, (384 to 385) K). The same procedure can also be used for the synthesis of 2-propanoylpyridine (see 12, 17). Compound 19 (PH22-49), 5-Benzyloxypyridine-2-aldehyde 2′-Pyridinylhydrazone. A 1.8 g sample of 5-benzyloxypyridine-2-aldehyde (see 10) in 50 mL of methanol was added to 1.03 g of 2-hydrazinopyridine in 30 mL of methanol. After 2661



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Table 1. Experimental Solubility Values of the Compounds Studied (Crystals) in Water (SW), 1-Octanol (SO) and Hexane (SH) →O →H and Transfer Coefficients from Water to 1-Octanol (KW ), from Water to Hexane (KW ) and from Hexane to 1-Octanol tr tr H→O 0 (Ktr ) at 298 K (p = 0.1 MPa) SWa N

compound PQ22 PH22 PH22-26 PH22-38 PH22-41 PH22-43 PH22-44 PH22-56 PH22-4 PH22-6 PH22-15 PH22-25 PH22-34 PH22-45 PH22-46 PH22-50 PH22-53 PH22-54 PH22-49 PH22-52

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 a

SOa

mol·kg−1 −5

1.14·10 1.07·10−3 3.62·10−5 6.25·10−4 8.30·10−5 8.04·10−5 7.00·10−4 nsb 3.04·10−5 1.10·10−5 5.82·10−5 3.26·10−5 2.34·10−4 1.27·10−5 2.66·10−5 3.39·10−6 1.72·10−4 5.29·10−5 1.17·10−5 2.28·10−5

SHa

log SW

mol·kg−1

−4.94 −2.97 −4.44 −3.20 −4.08 −4.09 −3.15 nsb −4.52 −4.96 −4.24 −4.49 −3.63 −4.90 −4.58 −5.47 −3.76 −4.28 −4.93 −4.64

−2

4.35·10 2.62·10−1 2.00·10−3 1.34·10−1 1.42·10−1 1.38·10−1 8.72·10−2 nsb 7.64·10−2 2.45·10−2 4.86·10−2 6.42·10−2 4.77·10−2 1.28·10−2 1.27·10−2 1.14·10−2 7.98·10−2 1.44·10−1 2.32·10−2 3.08·10−2

log SO

mol·kg−1

log SH

→O log(KW ) tr

−1.36 −0.58 −2.70 −0.87 −0.85 −0.86 −1.06 nsb −1.12 −1.61 −1.31 −1.19 −1.32 −1.89 −1.90 −1.94 −1.10 −0.84 −1.63 −1.51

−4

−3.39 −2.69 −3.01 −1.46 −2.19 nsb −3.47 nsb −3.17 −3.60 −2.68 −2.13 −3.45 −3.41 −2.71 −3.91 −2.32 −2.09 −3.33 −3.34

3.58 2.39 1.74 2.33 3.23 3.24 2.10

1.55 0.28 1.43 1.75 1.89

2.03 2.11 0.32 0.58 1.34

−0.31

2.41

3.40 3.35 2.92 3.29 2.31 3.00 2.68 3.53 2.67 3.43 3.30 3.13

1.35 1.36 1.56 2.36 0.18 1.49 1.86 1.56 1.44 2.19 1.60 1.30

2.05 1.99 1.37 0.93 2.12 1.52 0.81 1.96 1.22 1.25 1.70 1.83

4.03·10 2.05·10−3 9.69·10−4 3.50·10−2 6.51·10−3 nsb 3.43·10−4 nsb 6.81·10−4 2.50·10−4 2.09·10−3 7.49·10−3 3.58·10−4 3.90·10−4 1.94·10−3 1.24·10−4 4.78·10−3 8.10·10−3 4.63·10−4 4.58·10−4

→H log(KW ) tr

log(KHtr → O)

Relative standard uncertainty for solubility values ur(S) = 0.04. bNot soluble.

0 Table 2. Experimental Values of Melting points (Tm) and Fusion Enthalpies (ΔHTm fus ) (p = 0.1 MPa) of the Compounds Studied and Some HYBOT Physicochemical Descriptors

N

compound

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

PQ22 PH22 PH22-26 PH22-38 PH22-41 PH22-43 PH22-44 PH22-56 PH22-4 PH22-6 PH22-15 PH22-25 PH22-34 PH22-45 PH22-46 PH22-50 PH22-53 PH22-54 PH22-49 PH22-52

−1 ΔHTm fus /kJ·mol

Tm/K 475.4 455.3 525.6 370.5 424.6 448.0 449.0

± ± ± ± ± ± ±

0.5 0.5 0.5 0.5 0.5 0.5 0.5

38 28 50 29 29 34 34

± ± ± ± ± ± ±

1 1 1 1 1 1 1

416.6 433.2 416.8 415.0 484.7 440.3 456.3 471.9 394.9 384.4 433.7 458.3

± ± ± ± ± ± ± ± ± ± ± ±

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

31 40 35 34 42 35 34 41 35 37 38 41

± ± ± ± ± ± ± ± ± ± ± ±

1 1 1 1 1 1 1 1 1 1 1 1

Σ(Ca)/αa/Ǻ −3

ΣCadb

Σ(Ca)c

0.171 0.218 0.242 0.251 0.159 0.134 0.237 0.221 0.157 0.187 0.137 0.189 0.194 0.187 0.181 0.199 0.205 0.192 0.182 0.182

7.75 7.57 8.41 6.2 6.33 5.75 8.01 13.12 7.62 10.3 8.04 8.86 8.64 8.89 8.7 9.73 8.28 8.28 8.88 10.09

5.16 4.97 5.82 6.2 3.74 3.16 5.41 7.94 5.03 7.71 5.45 6.27 6.05 6.3 6.11 7.13 5.69 5.69 6.28 7.5

Σ(Ca)/α is the sum of H-bond acceptor factors normalized to polarizability.38 bΣCad is the sum of H-bond acceptor−donor factors.38 cΣ(Ca) is the sum of H-bond acceptor factors.38

a

(see 10) was performed in analogy to the synthesis of 19. Melting point, (458 to 459). Purity of the hydrazones was 0.98 (mass fraction). All solvents were of AR grade. 2.2. Solubility Experiments. All the experiments were carried out by the isothermal saturation method at (298 ± 0.1) K in water. The solid phase was removed by isothermal filtration (Acrodisc CR syringe filter, PTFE, 0.2 μm pore size)

the addition of 1 mL of glacial acetic acid the mixture was left to stand at ∼295 K for 1 day. The precipitated product was filtered by suction, washed with methanol, and dried. Melting point, (433 to 434) K. Compound 20 (PH22-52), 5-Benzyloxypyridine-2-aldehyde 4′-Quinazolinylhydrazone. The reaction of 4-hydrazinoquinazoline (see 13) with 5-benzyloxypyridine-2-aldehyde 2662



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Figure 2. Dependence of solubility values in logarithmic scale (log S) versus melting points (Tm) in water (a), 1-octanol (b), and hexane (c).

The comparison of compounds 2 and 1 shows that removing the condensed benzo fragment at position 5′,6′ (numbering of Scheme 1) leads to an essential increase of solubility in the studied solvents. The following is observed: solubility increase in water by 94 times, in 1-octanol by 6 times, and in hexane by 5 times. A comparison of compounds 1, 9, and 11 (variation of substituent at position R1-) leads to the following solubility trend. Introducing the phenyl substituent (11) increases water solubility by almost 6 times in comparison with the unsubstituted substance (1). In contrast, the solubility of 11 in 1-octanol is slightly higher than the SO of 1 (1.1 times), whereas in hexane it is 5 times higher. The solubility values of the considered hydrazones in 1-octanol can be arranged as: SO(9) > SO(11) > SO(1). A comparison of the solubility data of other R1-substituted derivatives demonstrates the following regularities. Astonishingly in comparison with the unsubstituted compound (3) the ethyl and propyl derivatives (17, 18) show improved solubility not only in the organic solvents but also in water (possibly due to the much lower melting points and fusion enthalpies of 17, 18). However, the water solubility of the propyl derivative (18) is more than 3 times lower than the SW of the ethyl derivative (17). In contrast, as expected the solubility values of 18 in 1octanol and hexane are higher than those of 17. For the discussed compounds (17, 18) the following sequence is observed: SW < SH < SO. The phenyl derivative (15) has a solubility in water a little bit lower than that of the unsubstituted one (3), however in 1-octanol its solubility is 6 times higher. By introduction of the 5-PhCH2O substituent (see 16) into the parent compound (3) the water solubility decreases by one decimal order, moreover its solubility in 1octanol improves by almost 6 times. The results of DSC experiments with melting points (Tm/K) −1 and fusion enthalpies at melting temperature (ΔHTm fus /kJ·mol ) are shown in Table 2. To investigate correlations between the solubility values in the considered solvents and the melting points of the hydrazones the observed log S values were plotted against the experimental Tm data (Figure 2). It is not difficult to recognize that there is a slight correlation only for hexane (Figure 2c):

or centrifugation (Biofuge pico). The experimental results are reported as an average value of at least three replicated experiments. The molar solubilities of drugs were measured spectrophotometrically with an accuracy of (2 to 3) % using a protocol described previously.37 2.3. Differential Scanning Calorimetry. The thermal analysis experiment was carried out by DSC 204 F1 Phoenix differential scanning heat flux calorimeter (NETZSCH, Germany) with a high sensitivity μ-sensor. A sample was heated at 10 K·min−1 in argon and cooled by gaseous nitrogen. The DSC temperature calibration was performed against six high-purity substances: cyclohexane (purity 0.9996 mass fraction), mercury (0.9999), biphenyl (0.995), indium (0.99999), tin (0.99999), and bismuth (0.999995). The accuracy of the weighing procedure was 0.01 mg. 2.4. Calculation Methods. Physicochemical descriptors applied in the analysis of transfer coefficients were estimated by means of the program HYBOT (hydrogen bond thermodynamics).38 Statistical analyses were performed by Origin version 7.0.40 Transfer coefficients from phase (1) to phase (2) have been calculated using solubility values S(phase1) and S(phase2) obtained from the solubility experiments by equation: K trphase1 → phase2 = S(phase2)/S(phase1)

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3. RESULTS AND DISCUSSION 3.1. Solubility Processes. The results of solubility experiments and transfer characteristics are presented in Table 1. The solubility values of compounds 5 and 6 (differing only in the location of the nitrogen atom at 1- and 1′-positions) in water and 1-octanol are virtually identical. As a consequence, →O the transfer coefficients KW coincide with each other. The tr solubility of both compounds in 1-octanol is higher by a factor of 1.7·103 in comparison with water. Unfortunately, the solubility of 6 in hexane could not be obtained due to poor solubility; however, the solubility of 5 in this solvent is 80 times higher than in water. Introducing an additional nitrogen atom at the second phenyl ring (2 and 5) and (2 and 6) leads to an increase in the water solubility by 13 times, whereas in 1octanol only by 2 times. The solubility in hexane decreases by 3 times. Shifting the nitrogen atom from position 1 (compound 2) to position 6 (7) leads to solubility reduction in water by 1.5 times, in 1-octanol by 3 times, and in hexane by 6 times. This fact confirms that the crystal lattice energy of substance 7 increases (in absolute value) in comparison with 2 (see also fusion enthalpies in Table 2).

log(SH/mol·kg −1) = (2.0 ± 1.4) − (0.0116 ± 0.0032) ·Tm/K R = 0.666; σ = 0.51; F = 12.8; n = 18 2663

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where n is the number of compounds, σ is the standard deviation, and R is the correlation coefficient, F is Fisher’s criterion (ratio of explained and unexplained variance). For water there is no correlation at all (Figure 2a). Finally, the solubility data in 1-octanol represent an intermediate case (Figure 2b). Probably, the poor correlation in water is connected with the fact that for the solubility process in this solvent the hydrophobic hydration plays an essential role. Because a relatively poor correlation is observed between the melting points and the hydrazone solubility in hexane, we tried to find correlation equations that include as independent variables also the HYBOT physicochemical descriptors.38 The statistical analysis of the experimental data shows that the descriptor (ΣCad), characterizing the sum of H-bond acceptor− donor factors, fits best in comparison with all other descriptors. The observed regularity can be described by the following correlation equation:

another can be considered as a pure partitioning process (i.e., solute association effects can be neglected). It is well-known that the pairs of (almost) immiscible solvents (1-octanol + water) and (hexane + water) are model systems for characterization of partitioning/distribution and drug delivery processes at the gastrointestinal tract and blood-brain barrier, respectively. On the other hand, the transfer characteristics from hexane to 1-octanol are often used for analysis and description of transfer processes of drugs from blood plasma across the blood-brain barrier.39 Moreover, this transfer describes the Gibbs energy of specific interactions of a solute molecule with 1-octanol. (The interaction between solute and hexane may be considered to be nonspecific, whereas the interaction with octanol corresponds to the sum of specific and nonspecific interactions. Thus the difference corresponds to the isolated specific interaction). →O →H In this section the transfer coefficients KW and KW tr tr are analyzed. In QSAR-related drug design frequently the log P(octanol+water) partition coefficient (P = CO/CW) is used which describes the partitioning between water-saturated (i.e., wet) octanol (containing about 2.3 M/L of H2O in octanol) and octanol-saturated water phase (here the octanol content in water (0.5 M/L) may be neglected). In this paper the solubility-based transfer coefficient is investigated which in →O →O the case of KW (KW = SO/SW) corresponds to the tr tr “partitioning” between pure (i.e., dry) octanol and pure water. →O An inspection of KW values (Table 1) shows that the tr values of the hydrazones vary on the logarithmic scale within the limits 1.66 (3) and 3.5 (1). On the basis of this dispersion, we tried to find correlations/regularities between the discussed coefficients and HYBOT physicochemical descriptors.38 A test using 32 different single HYBOT descriptors demonstrated that →O the log(KW ) function can be described by two descriptors tr indicating the sum of H-bond acceptor factors (ΣCa) and polarizability (α) of the molecule. The discussed regularity can be described by the following correlation equation:

log(S H/mol·kg −1) = (3.3 ± 1.3) − (0.0087 ± 0.0029) · Tm/K − (0.28 ± 0.10) ·ΣCad R = 0.800; σ = 0.42; F = 13.2; n = 18

(3)

To describe the solubility of the hydrazones in water first the general solubility equation (GSE) proposed Yalkowsky and Valvani41 was applied, which estimates log(SW) using the compounds melting point (tm/°C) and their octanol−water partition coefficient logPow. In our case Pow = Co/Cw was expressed by the experimentally determined solubility ratio SO/ →O SW = KW . Equation 4 presents the GSE result obtained: tr log(S W /mol·kg −1) = (− 0.1 ± 0.7) − (0.0088 ± 0.0027)· (tm/°C − 25) − (1.04 ± 0.17)· log(K trW → O) R = 0.850; σ = 0.41; F = 20.8; n = 19

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W

Unfortunately for prediction of log(S ) this equation requires experimental melting points and experimental water−octanol transfer coefficients. Furthermore the latter coefficients intrinsically contain log(SW). A search for a replacement of the →O log(KW ) term in eq 4 by HYBOT descriptors indicating the tr sum of H-bond acceptor factors (ΣCa) and polarizability (α) of the molecule results in the following best, but unsatisfactory, correlation: log(SW /mol·kg −1) = (0.21 ± 1.55) − (0.12 ± 0.03)α /Å

log(K trW → O) = (2.0 ± 0.5) + (0.11 ± 0.02) ·α /A3 − (0.45 ± 0.11) ·ΣCa R = 0.803; σ = 0.38; F = 14.48; n = 19

This equation is similar to eq 5 obtained previously for n = 38 sulfonamides. Here it is easy to recognize that with increasing ΣCa-parameter (i.e., increasing acceptor hydrogen →O bond ability) the transfer from water to octanol log(KW ) tr W→O decreases, whereas the log(Ktr )-function increases with increasing polarizability value. →H The analysis of KW values (Table 1) shows that for tr compound 7 the (hexane+water) partition coefficient is smaller than 1. This fact indicates that this substance with an exposed N-atom might prefer water-rich drug delivery pathways. On the →H other hand, the KW values for 2 and 13 are close to unity tr (nonlogarithmic scale), whereas for the remaining hydrazones partition coefficients are found between 1.1 and 2.4 (logarithmic scale). Also in this case a search for correlations →H between log(KW ) and HYBOT physicochemical descriptors tr was performed. Unfortunately all derived equations showed significances below the 90 % level. However, if we arbitrarily divide the hydrazones into two groups (Cl-containing derivatives and the rest), then the following regularities may be found: The transfer coefficients for Cl-derivatives (7 compounds) lie within the quite narrow window from 1.25 up to 2.0 (logarithmic scale). For the rest of the compounds the

3

+ (0.25 ± 0.15)ΣCa − (0.0053 ± 0.0032)Tm/K R = 0.787; σ = 0.50; F = 8.11; n = 19

(5)

The best correlation obtained for the solubility in octanol is presented in eq 6: log(SO/mol·kg −1) = (1.17 ± 0.53) − (0.21 ± 0.07)ΣCa − (0.0083 ± 0.0021)tm/°C R = 0.786; σ = 0.62; F = 12.9; n = 19

(7)

44

(6)

If the α term is neglected in eq 6 then it can be stated that this equation is virtually identical with the eq 643 obtained previously for n = 217 diverse compounds. 3.2. Transfer Processes. Because of the rather low solubility of most of the hydrazones in the selected solvents, the hypothetical transfer of a compound from one solvent to 2664



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→H Figure 3. Dependence of the coefficients of transfer from water to hexane in logarithmic scale log(KW ) versus descriptor indicating the sum of tr H-bond acceptor factors normalized to polarizability (Σ(Ca)/α).

Figure 4. Dependence of the coefficients of transfer from hexane to 1-octanol in logarithmic scale log (KHtr → O) versus descriptor indicating the sum of H-bond acceptor factors normalized to polarizability (Σ(Ca)/α): black points, compounds without Cl-derivatives; red points, Cl-derivatives. →H correlation between log(KW ) and the sum of H-bond tr acceptor factors normalized to polarizability (Σ(Ca)/α) shown in Figure 3 and described by eq 8 is obtained: again the →H log(KW ) value decreases with increasing descriptor value. tr

the partition coefficients and the descriptor. This fact suggests that as the number of experimental data will increase the statistical characteristics of the observed correlations will improve as well. The analysis of log(KtrH → O)-data versus the various descriptors did not show any significant correlations. However, again if we distinguish between two groups of experimental points, Cl-derivatives and the rest (as it was done above), then the “non-relationship” of Figure 4 is obtained for the descriptor Σ(Ca/α). For the compounds without Cl atom the log(KHtr → O)-function slightly increases with increasing descriptor value, whereas, for the Cl-derivatives the opposite tendency is observed. It may be assumed that the latter compounds could

log(K trW → H) = (5.9 ± 0.7) − (27 ± 4)(Σ(Ca)/α)/A−3 R = 0.911; σ = 0.36; F = 44.4; n = 11

(8)

It should be noted, that the pair correlation coefficients R of these equations are not sufficiently high. Only about 100·R2 = 44.4 % (eq 1), 64.0 % (eq 2), 72.3 % (eq 3), 62 % (eq 4,5), 64.4 % (eq 6), up to 83.0 % (eq 7) of the data variance can be described by the descriptors. Nevertheless, we have presented these results to demonstrate the existence of trends between 2665



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Kombinationen für die Therapie der Tuberkulose und der Lepra. Pharm. Unserer Zeit 1995, 24, 313−323. (9) Pellerano, C.; Savini, L.; Massarelli, P. Tridentate N-N-N chelating systems as potential antitumoral agents. Farmaco, Ed. Sci. 1985, 40, 645−654. (10) Savini, L.; Massarelli, P.; Chiasserini, L.; Sega, A.; Pellerano, C.; Barzi, A.; Nocentini, G. Chelating agents as potential antitumorals. 2Quinolylhydrazones and bis-2-quinolylhydrazones. Eur. J. Med. Chem. 1995, 30, 547−552. (11) Green, R. W.; Hallman, P. S.; Lions, F. Multidentate equilibria. I. Pyridine-2-aldehyde-2-pyridylhydrazone. Inorg. Chem. 1964, 3, 376− 381. (12) Anderegg, G. Pyridinderivate als Komplexbildner. IX. Die Stabilitätskonstanten von Komplexen mit (a) 2-aminomethyl-pyridin, (b) 6-methyl-2-aminomethyl-pyridin, (c) 2-pyridylhydrazin, (d) 2,2′dipyridylamin und (e) 1-(α-pyridylmethylen)-2-(α′-pyridyl)-hydrazin. Helv. Chim. Acta 1971, 54, 509−512. (13) Bell, C. F. Metal chelates of pyridine-2-aldehyde-2′-pyridylhydrazone and related ligands. Rev. Inorg. Chem. 1979, 1, 133−161. (14) Spingarn, N. E.; Sartorelli, A. C. Synthesis and evaluation of the thiosemicarbazone, dithiocarbazonate, and 2′-pyrazinylhydrazone of pyrazinecarboxaldehyde as agents for the treatment of iron overload. J. Med. Chem. 1979, 22, 1314−1316. (15) Mihkelson, A. E. Reactions of Pd(II) with a series of potentially tridentate nitrogen ligands. I. Ligand behaviour. J. Inorg. Nucl. Chem. 1981, 43, 123−126. (16) Case, F. H.; Schilt, A. A. Synthesis of some isoquinol-1ylhydrazones and spectrophotometric characterization of some of their transition-metal chelates. J. Chem. Eng. Data 1986, 31, 503−504. (17) Jayabalakrishnan, C.; Natarajan, K. Synthesis, characterization, and biological activities of ruthenium(II) carbonyl complexes containing bifunctional tridentate Schiff bases. Synth. React. Inorg. Metal Org. Chem. 2001, 31, 983−995. (18) Savini, L.; Chiasserini, L.; Gaeta, A.; Pellerano, C. Synthesis and anti-tubercular evaluation of 4-Quinolylhydrazones. Bioorg. Med. Chem. 2002, 10, 2193−2198. (19) Ragavendran, J. V.; Sriram, D.; Patel, S. K.; Reddy, I. V.; Bharathwajan, N.; Stables, J.; Yogeeswari, P. Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore. Eur. J. Med. Chem. 2007, 42, 146−151. (20) Abdel-Aal, T. M.; El-Sayed, W. A.; El-Ashry, E. S. H. Synthesis and antiviral evalution of some sugar arylglycinoylhydrazones and their oxadiazoline derivates. Arch. Pharm. Chem. Life Sci. 2006, 339, 656− 663. (21) Walcourt, A.; Loyevsky, M.; Lovejoy, D. B.; Gordeuk, V. R.; Richardson, D. R. Novel aroyl hydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and -sensitive parasites. Int. J. Biochem. Cell Biol. 2004, 36, 401−407. (22) Savini, L.; Chiasserini, L.; Travagli, V.; Pellerano, C.; Novellino, E.; Cosentino, S.; Pisano, M. B. New α-(N)-heterocyclic hydrazones: Evaluation of anticancer, anti-HIV and antimicrobial activity. Eur. J. Med. Chem. 2004, 39, 113−122. (23) Sahlin, M.; Gräslund, A.; Petersson, L.; Ehrenberg, A.; Sjöberg, B. M. Reduced forms of the iron-containing small subunit of ribonucleotide reductase from Escherichia coli. Biochemistry 1989, 28, 2618−2625. (24) Lammers, M.; Follmann, H. The ribonucleotide reductasesA unique group of metalloenzymes essential for cell proliferation. Struct. Bonding (Berlin) 1983, 54, 27−91. (25) Hogenkamp, H. P. C. Nature and properties of the bacterial ribonucleotide reductases. Pharm. Ther. 1984, 23, 393−405. (26) Stubbe, J. Ribonucleotide reductases: amazing and confusing. J. Biol. Chem. 1990, 265, 5329−5332. (27) Auling, G.; Thaler, M.; Diekmann, H. Parameters of unbalanced growth and reversible inhibition of deoxyribonucleic acid synthesis in Brevibacterium ammoniagenes ATCC 6872 induced by depletion of Mn2+. Inhibitor studies on the reversibility of deoxyribonucleic acid synthesis. Arch. Microbiol. 1980, 127, 105−114.

be the most suitable for transfer across the blood-brain barrier, because they have maximal values of KtrO → H (reciprocal quantity to the discussed transfer coefficients).39

4. CONCLUSION The solubility values of 20 hydrazones in water, 1-octanol, and hexane were determined by the isothermal saturation method. Thermophysical characteristics of fusion processes (melting points and fusion enthalpies) of the selected substances were measured by DSC method. The impact of structural modification of the molecules on solubility processes in the solvents was analyzed. Relationship between log(SH) and melting points and the HYBOT physicochemical descriptors ΣCad was gained. The general solubility equation (GSE) was adopted for water solubility estimation of the hydrazones. Transfer processes from water to 1-octanol, from water to hexane, and from hexane to 1-octanol were analyzed. →O Correlations of log(KW ) with the HYBOT physicochemical tr →H descriptors α and ΣCa, and of log(KW ) with Σ(Ca)/α were tr obtained. The presented correlation models give an opportunity to estimate/predict such important physicochemical characteristics as solubility and partitioning coefficients in various biologically relevant mediums just on the basis of knowledge of their structural formulas.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: (+7) 4932 533784. Fax: (+7) 4932 336237. Funding

This investigation was supported by the International Science & Technology Centre (Projects No. 888 and No. 3777). Notes

The authors declare no competing financial interest. ⊥ (K.-J.S.) Retired.

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REFERENCES

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Solubility and Transfer Processes of Some Hydrazones in Biologically

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