Научная статья на тему 'Determination of acid dissociation constants of some new 4-{[(5-(bromo/chloro)-2-hydroxyphenyl)methylene]amino}-5- alkyl(aryl)-2,4-dihydro-3h-1,2,4-triazol-3-one derivatives and evaluation of their antioxidant activity'

Determination of acid dissociation constants of some new 4-{[(5-(bromo/chloro)-2-hydroxyphenyl)methylene]amino}-5- alkyl(aryl)-2,4-dihydro-3h-1,2,4-triazol-3-one derivatives and evaluation of their antioxidant activity Текст научной статьи по специальности «Фундаментальная медицина»

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Ключевые слова
triazole / acid dissociation constants / antioxidant activity / potentiometric titration / триазол / постоянные кислотной диссоциации / антиоксидантная активность / потен- циометрическое титрование

Аннотация научной статьи по фундаментальной медицине, автор научной работы — Fatih İslamoglu, Emre Menteshe, Derya Bal Altuntash, Zeynep Levent

Acid dissociation constants of some new 4-{[(5-bromo-2-hydroxyphenyl)methylene]amino}-5alkyl(aryl)-2,4-dihydro-3H-1,2,4-triazol-3-one derivatives were determined experimentally with potentiometric titration method and theoretically with SPARC computer program. The effect of solvents composition on the acid dissociation constants is discussed and experimental and theoretical values are compared. In the DPPH, free radical scavenging assay was achieved. The compounds have shown hydrogen-donating ability in the reaction with DPPH (1,1-diphenyl-2-picrylhydrazyl) radical.

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ОПРЕДЕЛЕНИЕ ПОСТОЯННЫХ КИСЛОТНОЙ ДИССОЦИАЦИИ НЕКОТОРЫХ НОВЫХ ПРОИЗВОДНЫХ4-{[5-БРОМ/ХЛОР)-2-ГИДРОКСИФЕНИЛ)МЕТИЛЕН]АМИН}-5- АЛКИЛ(АРИЛ)-2,4-ДИГИДРО-3Н-1,2,4-ТРИАЗОЛ-3-ОНА И ОЦЕНКА ИХ АНТИОКСИДАНТНОЙ АКТИВНОСТИ

Постоянные кислотной диссоциации некоторых новых производных 4-{[5-бром/хлор)-2-гидроксифенил)метилен]амин}-5-алкил(арил)-2,4-дигидро-3Н-1,2,4-триазол-3-она были определены экспериментально методом потенциометрического титрования и теоретически компьютерной программой SPARC. Обсуждается воздействие составов растворителей и сравниваются экспериментальные и теоретические оценки. В ДФПГ достигнут свободный радикал пробы продувки. Соединения проявили способность отдачи водорода в реакции с радикалом ДФПГ (1,1-дифенил-2-пикрилгидразил).

Текст научной работы на тему «Determination of acid dissociation constants of some new 4-{[(5-(bromo/chloro)-2-hydroxyphenyl)methylene]amino}-5- alkyl(aryl)-2,4-dihydro-3h-1,2,4-triazol-3-one derivatives and evaluation of their antioxidant activity»

UDC 547.543.63

DETERMINATION OF ACID DISSOCIATION CONSTANTS OF SOME NEW 4-{[(5-(BROMO/CHLORO)-2-HYDROXYPHENYL)METHYLENE]AMINO}-5-ALKYL(ARYL)-2,4-DIHYDRO-3#-1,2,4-TRIAZOL-3-ONE DERIVATIVES AND EVALUATION OF THEIR ANTIOXIDANT ACTIVITY

Fatih Islamoglu, Emre Menteshe, Derya Bal Altuntash*, Zeynep Levent

Department of Chemistry, Art and Science Faculty, Rejep Tayyip Erdogan University,

Rize, 53100, Turkey

Department of Bioengineering, Faculty of Engineering, Rejep Tayyip Erdogan University,

Rize, 53100, Turkey

fatih.islamoglu@erdogan.edu.tr

Received 27.04.2015

Acid dissociation constants of some new 4-{[(5-bromo-2-hydroxyphenyl)methylene]amino}-5-alkyl(aryl)-2,4-dihydro-3^-1,2,4-triazol-3-one derivatives were determined experimentally with poten-tiometric titration method and theoretically with SPARC computer program. The effect of solvents composition on the acid dissociation constants is discussed and experimental and theoretical values are compared. In the DPPH, free radical scavenging assay was achieved. The compounds have shown hydrogen-donating ability in the reaction with DPPH (1,1-diphenyl-2-picrylhydrazyl) radical.

Keywords: triazole, acid dissociation constants, antioxidant activity, potentiometric titration.

Introduction

1,2,4-Triazoles are pharmaceutically important compounds due to their antimicrobial [1], antifungal [2], anticancer [3], antioxidant [4], antihypertensive, and antiviral activities [5]. Compounds with 1,2,4-triazole moiety have been demonstrated to have anticonvulsant activity [6, 7]. Shalini et al. [6] demonstrated that cyclization of aryl semicarbazones leads to the formation of 1,2,4-triazoles with high anticonvulsant activity [8-11]. Rufinamide, a compound with triazole ring, is a third-generation antiepileptic drug [12]. Loreclazole is a member of (alkyl/aryl)azole antiepileptic drugs, and has been tested in clinical trials in humans [13, 14]. In addition, triazole derivatives such as vorozol (and anastrozol) and fluconazole are currently in clinical use as anticancer and antifungal agents, respectively [3, 15].

In recent years, there has been an increasing interest in the synthesis of antioxidant compounds. Among the number of synthetic compounds, triazole derivatives were reported to have stronger substantial scavenger effects on DPPH radical [16, 17].

Acidity measurements of organic compounds have a long history dating back to the end of the 19th century, when the pKa was

measured for the first time. Since then, a vast body of data on acidities in various solvents has been collected [18]. Acid dissociation constants are very important parameters, which can provide critical information about chemical properties such as acidity [19-21]. Hence, the relationship between the acid dissociation constants and structure in molecules is important [20, 21, 24]. Acid dissociation constants are also important parameters for the selection of the optimum conditions in the development of analytical methods [23, 25] and provide information about the stereo chemical and conformational structures of active centers of enzymes [26]. Acid dissociation constants are determined by several methods such as potentiometric [23], spectroscopic [24], electrophoretic [20, 27] methods and theoretical [26]. Thus, the acid dissociation constants of these compounds is still of great interest.

Experimental

In this study, Orion Model 720A pH ion meter, fitted with a combined pH electrode (Ingold) was used for potentiometric titration. An Ingold pH electrode was preferred due to its advantage. A magnetic stirrer, a semi-micro burette and a 25 mL beaker were also used in

titration. All the chemicals were supplied from Merck. Before potentiometric titrations (Figure 1), the pH meter was calibrated according to the

instructions supplied by the manufactures of the pH meter. In this section, the pH electrode calibrated with 4, 7, 10 and 12 pH tampon solution.

Figure 1. System of potentiometric titration cell used in study.

In this study, ten new 4-{[5-(R2-2-hydro-xyphenyl)methylene]amino}-5-Ri-2,4-dihydro-3#-1,2,4-triazol-3-one derivatives (Schemel)

were synthesized in Rejep Tayyip Erdogan University Organic Chemistry Research Laboratory and published [28].

Molecule Ri R2

1 Methyl Bromine

2 Ethyl Bromine

3 Phenyl Bromine

4 Benzyl Bromine

5 4-Chlorobenzyl Bromine

6 Methyl Chlorine

7 Ethyl Chlorine

8 Phenyl Chlorine

9 Benzyl Chlorine

10 4-Chlorobenzyl Chlorine

Scheme 1

For each compound that would be titrated, the 0.001 M solution was separately prepared in each non-aqueous solvent (isopropyl alcohol, N,N-dimethylformamide, tert-butyl alcohol and acetonitrile). While titrating, a titrant was added to increments of 0.05 mL after each stable reading, and mV values were recorded. After purification, isopropyl alcohol was used to prepare 0.05 N tetrabutylammonium hydroxide (TBAH). For all potentiometric titrations, 0.05 N TBAH in isopropyl alcohol, which was prepared from 0.1 N TBAH by dilution, was used as titrant. The mV values, that were obtained in pH meter, were recorded. Graphs were drawn by obtained from

all data and end point is determined by AE/AV (TBAH, mL), A2E/AV2 (TBAH, mL) and AV/AE (TBAH, mL) graphics. Finally, the half-neutralization potential (HNP) values were determined by drawing these graphic and pKa values according to half-neutralization method. The pH of the weak acids are given by the follow equation:

pH = pKa + log[A-] / [HA],

pH = pKa occurs when [A] is equal to [HA] at the half-neutralization point. Therefore, the pH values can be regarded as pKa at the half-neutralization points.

The computer program SPARC (SPARC Performs Automated Reasoning in Chemistry) was developed to predict numerous physical properties such as vapor pressure, distribution coefficient, and GC retention time as well as chemical reactivity parameters like pKa and electron affinity. SPARC predicts both macro-

AGi

AHCg) -

AH(S) AG

Calculation of pKa were made using the free energy changes in the thermodynamic cycle. Respectively AG1, AG2, AG3 and AG4 are calculated to find the AG. Then, pKa is calculated using the equation with calculated AG. In this paper, we describe the details of the SPARC reactivity computational methods and its performance on predicting the pKa values of 4-{[(5-(bromo/chloro)-2-hydroxyphenyl)methylene]ami-no}-5-alkyl(aryl)-2,4-dihydro-3#-1,2,4-triazol-3-one derivatives in comparison with experimental values.

The DPPH radical scavenging activity of the complex was determined according to the methods described by [30] with some modifications. Different concentrations (1, 2, 4, 8, 12, 16, 20 mM) compound dissolved in DMF were added to 2 mL of freshly prepared (0.1 mM) DPPH in methanol. After being shaken vigorously and kept for 30 min at room temperature the absorption was measured at 517 nm against the blank (methanol). Vitamin C was used as a standard and the results were compared with as a standard antioxidant Vitamin C. All the tests were run in triplicate and the percentage of radical scavenging activity (RSA%) was calculated according to the following equation:

RSA% = ~ A ^ 100 ,

A

scopic and microscopic pKa values strictly from molecular structure using relatively simple reactivity models [28]. The operating mechanism of this program are shown in Scheme 2.

The ionization of weak acid (HA) is given for the gas and liquid phase in Scheme 2.

A (g) + H (g)

where, A0 is the absorbance of the control and Ai is the absorbance of the complex/standard.

The half maximum inhibitory concentration (IC50) is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. It is commonly used as a measure of antagonist drug potency in pharmacological research. According to the FDA, IC50 represents the concentration of a drug that is required for 50% inhibition in vitro. It is comparable to an EC50 for agonist drugs. EC50 also represents the plasma concentration required for obtaining 50% of a maximum effect in vivo. The IC50 value was determined as the concentration of compound that gives 50% inhibition of maximum activity.

Results and discussion

In this study, all compounds were titrated potentiometrically with TBAH in isopropyl alcohol, N,N-dimethylformamide, tert-butyl alcohol and acetonitrile. The mV values read in each titration were drawn against TBAH volumes (mL) added and potentiometric titration curves were formed for all the cases. Experiments were repeated 3 times for each experiment. Standard deviations were calculated for these three ex-

= [((AG3 + AG4) -AG2) + AGi] AG = -2.303 RT logKa

Scheme 2

periments. Calculations were performed within 95% confidence interval. From the titration curves Figure 2, the HNP values were measured

and the corresponding pKa values were calculated.

d

a

b

e

2500

^Isopropyl alcohol

2000 -»-Tert-Butyl —Aceto nitri

I

1500 > <¡

1000

500

0 \

0 0, 0 mL 0,8 (TBAH) 1 1 2

Figure 2. (a) pH-mL (TBAH), (b) mV-mL (TBAH), (c) AE/AV-mL (TBAH), (d) A2E/AV2-mL (TBAH) and (e) AV/AE-mL (TBAH) potentiometric titration curves of 0.001 M solutions of compound 4 titrated with 0.05 M TBAH in isopropyl alcohol, N,N-dimethylformamide, ieri-butyl alcohol and acetonitrile at 250C.

c

The HNP values and the corresponding pKa values of all triazole derivatives, obtained from the potentiometric titrations with 0.05 M TBAH in isopropyl alcohol, N,N-dimethylfor-

Theoretical and experimental pKa values were comparisoned as an example of the compound 4 in Figure 3.

When the dielectric permittivity of solvents is taken into consideration, the acidic arrangement can be expected as follows: N,N-dimethyl-formamide (e=36.7) > acetonitrile (e=36.0) > iso-

mamide, tert-butyl alcohol and acetonitrile and pKa for all compounds were calculated theoretically with SPARC computer program. All pKa and HNP values are presented in Table 1.

propyl alcohol (e=19.4) > tert-butyl alcohol (e=12.0). But, in this study that it is observed: isopropyl alcohol > N,N-dimethylformamide > tert-butyl alcohol > acetonitrile for compound 2, 3, 5, 6, 7, 8, 9 and 10 and isopropyl alcohol > tert-butyl alcohol > N,N-dimethylformamide > acetonitrile for compound 1 and 4.

Table 1. HNP, experimental and theoretical corresponding pKa values for all molecules

Comp. Solvent pKa (experimental) HNP (mV) pKa (theoretical) Relative error, %

1 isopropyl alcohol 11.48 ± 0.11 -265.4 ± 7.5 12.13 -5.66

N,N-dimethylformamide 12.64 ± 0.15 -333.4 ± 5.6 12.86 -1.74

tert-butyl alcohol 12.47 ± 0.09 -324.0 ± 8.1 12.97 -4.01

acetonitrile 16.39 ± 0.10 -555.5 ± 4.9 15.18 7.38

2 2-propanol 11.46 ± 0.13 -263.4 ± 6.3 12.24 -6.81

DMF 12.86 ± 0.08 -346.6 ± 8.3 13.05 -1.48

tert-butanol 13.85 ± 0.12 -404.9 ± 7.6 14.11 -1.88

acetonitrile 15.41 ± 0.11 -497.3 ± 8.2 15.86 -2.92

3 isopropyl alcohol 11.74 ± 0.10 -280.2 ± 7.4 12.03 -2.47

N,N-dimethylformamide 12.76 ± 0.08 -340.7 ± 6.1 12.93 -1.33

tert-butyl alcohol 14.47 ± 0.12 -441.6 ± 8.5 14.74 -1.87

acetonitrile 15.73 ± 0.13 -516.8 ± 4.7 15.96 -1.46

4 isopropyl alcohol 11.45 ± 0.07 -263.0 ± 7.6 11.86 -3.58

N,N-dimethylformamide 12.77 ± 0.12 -341.0 ± 8.1 12.98 -1.64

tert-butyl alcohol 12.71 ± 0.11 -337.8 ± 5.5 13.02 -2.44

acetonitrile 16.10 ± 0.09 -538.1 ± 7.8 16.31 -1.30

5 isopropyl alcohol 11.62 ± 0.10 -273.3 ± 9.2 11.94 -2.75

N,N-dimethylformamide 12.43 ± 0.06 -320.5 ± 8.6 12.79 -2.90

tert-butyl alcohol 14.73 ± 0.09 -450.3 ± 5.7 15.17 -2.99

acetonitrile 15.90 ± 0.12 -526.1 ± 6.9 16.28 -2.39

6 isopropyl alcohol 11.94 ± 0.08 -292.1 ± 7.2 12.19 -2.09

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N,N-dimethylformamide 13.01 ± 0.13 -355.1 ± 9.1 13.24 -1.77

tert-butyl alcohol 13.25 ± 0.12 -369.6 ± 8.5 13.51 -1.96

acetonitrile 16.53 ± 0.08 -563.3 ± 7.4 16.80 -1.63

7 isopropyl alcohol 11.71 ± 0.11 -278.6 ± 4.8 12.07 -3.07

N,N-dimethylformamide 12.80 ± 0.10 -344.5 ± 7.2 13.14 -2.66

tert-butyl alcohol 14.63 ± 0.08 -450.7 ± 8.5 14.81 -1.23

acetonitrile 15.75 ± 0.06 -517.3 ± 6.4 15.95 -1.27

8 isopropyl alcohol 12.88 ± 0.13 -288.4 ± 8.3 13.28 -3.11

N,N-dimethylformamide 13.32 ± 0.06 -373.3 ± 7.5 13.64 -2.40

tert-butyl alcohol 14.83 ± 0.12 -463.4 ± 9.2 15.12 -1.96

acetonitrile 16.00 ± 0.08 -532.3 ± 6.8 16.21 -1.31

9 isopropyl alcohol 12.00 ± 0.07 -296.0 ± 6.1 12.34 -2.83

N,N-dimethylformamide 13.10 ± 0.09 -360.2 ± 9.6 13.29 -1.45

tert-butyl alcohol 13.21 ± 0.12 -367.2 ± 7.5 13.62 -3.10

acetonitrile 16.50 ± 0.06 -562.1 ± 8.4 16.82 -1.94

10 isopropyl alcohol 11.46 ± 0.05 -268.0 ± 6.7 11.59 -1.13

N,N-dimethylformamide 12.84 ± 0.11 -345.9 ± 4.9 13.13 -2.26

tert-butyl alcohol 15.07 ± 0.12 -477.8 ± 8.1 15.28 -1.39

acetonitrile 15.44 ± 0.08 -499.5 ± 7.7 15.69 -1.62

Isopropyl alcohol N,N-Di methyl formamide Tert-Butyl alcohol Aceioriiirile

Medium

Figure 3. Theoretical and experimental pKa values for compound 4.

When dielectric constant is examined according to the acidity forces (amphiprotic solvents the dielectric constant of isopropyl alcohol and tert-butanol, respectively, 19.4 and 12.0). The acidity of the compounds are expected more acidic for high dielectric constant has solvent (isopropyl alcohol). In this study, it is obtained that a result of all compounds data were found to be suitable in this order. When dipolar aprotic solvents is considered, the increase in strength of the acidity is expected as N,N-dimethylformamide > acetonitrile. All compounds were observed to follow this order.

When analyzed according to autoprotoly-sis constant, weak acidic property is shown in isopropyl alcohol (pKs: 20.6), N,N-dimethyl-formamide (pKs: 18.0) and tert-butanol (pKs: 22.0) but strong acidic property is shown in acetonitrile (pKs: 33.0) for all compounds. By the time analyzed according to the functional group (-R) effect, it has showed very small effect for acidic protons due to the distance.

By the time compounds were analyzed by each solvent, acidity strength decrease, e.g., 4 >

2 = 10 > 1 > 5 > 7 > 3 > 6 > 9 > 8 in isopropyl alcohol, 5 > 1 > 3 > 4 > 7 > 10 > 2 > 6 > 9 > 8 in N,N-dimethylformamide, 1 > 4 > 9 > 6 > 2 > 3 > 7 > 5 > 8 > 10 in tert-butyl alcohol and 2 > 10 >

3 > 7 > 5 > 8 > 4 > 1 > 9 > 6 in acetonitrile was observed. Differentiation of all compounds in the studied solvents was showed when the effect of

the leveling and differentiation was investigated. When compared theoretical results with potenti-ometric results were obtained by the half-neutralization method, errors were found to be between 7.38% and -1.13%. Percentage error values between the theoretical values and the experimental ones are given in Table 1.

DPPH scavenging activity of the synthesized compounds is shown in Table 2. In the DPPH free radical scavenging assay, vitamin C with IC50 value was 17.5 ^M and compound 6 with IC50 value of 72 ^M was the most active compound of the series. The compounds have shown hydrogen-donating ability for reaction with DPPH (1,1-diphenyl-2-picrylhydrazyl) radical. The good activity of these compounds may come from the presence of salicyl moiety group.

Table 2. DPPH radical scavenging activities of the synthesized compounds_

Compound IC50 (pM)

1 183 ± 0.1

2 128 ± 0.2

3 143 ± 0.4

4 146 ± 0.4

5 116 ± 0.2

6 72 ± 0.3

7 116 ± 0.2

8 117 ± 0.4

9 115 ± 0.3

10 132 ± 0.2

Vitamin C 17.5 ± 0.2

Conclusion

In conclusion, the extent of anautoprotoly-sis constant depends both on the fundamental acidity and the fundamental basicity of the solvent. The importance of the autoprotolysis constant in titrations lies in its effect on the wholeness of a titration reaction. The acidity of a compound depends on mainly two factors, i.e. solvent effect and molecular structure. Half-neutralization potential (HNP) and corresponding pKa values obtained from the potentiometric titrations rely on the non-aqueous solvents. The compounds have shown hydrogen-donating ability in the reaction with DPPH (1,1-diphenyl-2-picrylhydrazyl) radical. The compound 6 with IC50 value of 72 ^M was the most active compound of the series.

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4-{[(5-(BROM/XLOR)-2-HÍDROKSÍFENÍL)METÍLEN]AMÍN}-5-ALKlL(ARlL)-2,4-DÍHÍDRO-3^-1,2,4-TRÍAZOL-3-ONUN BOZi YENÍ TÖROMOLORiNiN TUR§U DÍSSOSÍASÍYA SABÍTLORÍNÍN TOYiNi VO ONLARIN ANTÍOKSÍDANT AKTÍVLÍYÍNÍN QÍYMOTLONDÍRÍLMOSi

Fatih islamoglu, Emre Mente^e, Derya Bal Altunta^, Zeynep Levent

4-{[(5-(Brom/xlor)-2-hidroksifenil)metilen]amin}-5-alkil(aril)-2,4-dihidro-3^-1,2,4-triazol-3-onun bazi yeni töra-malarinin tur§u dissosiasiya sabitlari tacrübi - potensiometrik titrlama va nazari - SPARC computer proqrami ila tayin olunmuíjdur. Halledicilarin tarkibinin tasiri müzakira olunmu§, nazari va tacrübi dalillar müqayisa edilmi§dir. DFPH-da sarbast radikal alda olunmu§dur. Birla§malar DFPH (1,1-difenil-2-picrilhidrazil) radikali ila reaksiyada hidrogen verma qabiliyyati göstarmi§dir.

Agar sözlar: triazol, tur§u dissosiasiya sabitlari, antioksidant aktivlik, potensiometrik titrÍ3M3.

ОПРЕДЕЛЕНИЕ ПОСТОЯННЫХ КИСЛОТНОЙ ДИССОЦИАЦИИ НЕКОТОРЫХ НОВЫХ ПРОИЗВОДНЫХ4-{[5-БРОМ/ХЛОР)-2-ГИДРОКСИФЕНИЛ)МЕТИЛЕН]АМИН}-5-АЛКИЛ(АРИЛ)-2,4-ДИГИДРО-3#-1,2,4-ТРИАЗОЛ-3-ОНА И ОЦЕНКА ИХ АНТИОКСИДАНТНОЙ АКТИВНОСТИ

Фатих Исламоглу, Эмре Ментеше, Деря Бал Алтунташ, Зейнеб Левент

Постоянные кислотной диссоциации некоторых новых производных 4-{[5-бром/хлор)-2-гидроксифе-нил)метилен]амин}-5-алкил(арил)-2,4-дигидро-3^-1,2,4-триазол-3-она были определены экспериментально методом потенциометрического титрования и теоретически компьютерной программой SPARC. Обсуждается воздействие составов растворителей и сравниваются экспериментальные и теоретические оценки. В ДФПГ достигнут свободный радикал пробы продувки. Соединения проявили способность отдачи водорода в реакции с радикалом ДФПГ (1,1-дифенил-2-пикрилгидразил).

Ключевые слова: триазол, постоянные кислотной диссоциации, антиоксидантная активность, потен-циометрическое титрование.

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