O Shyvka - Synthesis and predicted biological activity of alkyl 2-(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl-3-arylpropanoates - страница 1

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ВІСНИК ЛЬВІВ. УН-ТУ

Серія хім. 2010. Bun. 51. С. 203-210

VISNYKLVIV UNIV. Ser. Chem. 2010. Is. 51. P. 203-210

УДК 547.794.3

SYNTHESIS AND PREDICTED BIOLOGICAL ACTIVITY OF ALKYL 2-[(5-AMINO-1,3,4-THIADIAZOL-2-YL)SULFANYL]-3-ARYLPROPANOATES

O. Shyyka, N. Pokhodylo

Ivan Franko National University of Lviv, Kyryla & Mephodiya Str., 6, 79005 Lviv, Ukraine e-mail: pokhodylo@gmail.com

New 1,3,4-thiadiazole derivatives were synthesized by the reaction of 5-amino-1,3,4-thiadiazole-2-thiol and alkyl 2-bromo-3-arylpropanoates. Biological activities of these compounds were predicted. The correlation between structure and reactivity of the target products was discussed.

Key words: 1,3,4-thiadiazole, alkyl 2-bromo-3-arylpropanoates, PASS, Hammett

equation.

A large number of 1,3,4-thiadiazole derivates shows a broad spectrum of biological activity - antimicrobial, antibacterial, antimycobacterial [1-4], anti-trypanosomal [5, 6], analgestic [7, 8], anti-inflammatory [7-10], antifungal [11, 12], antituberculosis [13-15], anticancer [16, 17], antihypertensive [18, 19], local anesthetic [20], and anticonvulsant one [21-23]. The biological activity of these compounds induced us to investigate methods of the synthesis of new 2,5-disubstituted 1,3,4-thiadiazole derivates and study their properties. Therefore, we prepared starting compounds (3a-g, 4) according to the methods developed recently [23, 24]. 2-Bromo-3-arylpropanoic acid esters (3a-g) were synthesized via the Meerwein reaction between arenediazonium bromides (1a-g) and esters of acrylic acid (2a-c). 5-Amino-1,3,4-thiadiazole-2-thiol (4) was obtained by the reaction of thiosemicarbazide and carbon disulfide.

CuBr

Br

*R1

1a-g

O

2a-c

H2N

Y

S

If

3a-g O

R1

HS

N-N 4

NH2

Ar = Ph (a), 3-MeC6H4 (b), 2-ClC6H4 (c), 4-ClC6H4 (d), 4-BuC6H4 (e), 2,4-Cl2C6H3 (f), 2-Me, 3,5,-Cl2C6H2 (g) R1 = Et (a,b,c), Me (d,e,f), Bu (g)

Scheme 1

The series of the target compounds (5a-g) were synthesized in a single step by addition of different 2-bromo-3-arylpropanoic acid esters (3a-g) to 5-amino-1,3,4-thiadiazole-2-thiol (4) in KOH ethanol solution.

ArN2+Br-

+

S

C

+

S

© Shyyka O., Pokhodylo N., 2010

R

EtOH

О

3a-g  O 4

О

L2

N-N

KOH

S

NH

Ar

S

2

Ar = Ph (a), 3-MeC6H4 (b), 2-ClC6H4 (c), 4-ClC6H4 (d), 4-BuC6H4 (e), 2,4-Cl2C6H3 (f), 2-Me, 3,5,-Cl2C6H2 (g) R1 = Et (a,b,c), Me (d,e,f), Bu (g)

5a-g

Scheme 2

The obtained products (5a-g) were investigated for biological activity using the program PASS (Prediction of Activity Spectra for Substances) [25]. The computer system PASS predicts several hundreds of biological activities (main and side pharmacological effects, mechanisms of action, mutagenicity, carcinogenicity, teratogenicity, and embryo-toxicity). The majority of biologically active compounds often reveal a wide spectrum of different effects. Some of them are useful in treatment of definite diseases; others cause various side and toxic effects. The whole complex of activities caused by the compound in biological entities is called the "biological activity spectrum of the substance", i.e. the property of a compound dependent only on its structure and physicochemical charac­teristics. This spectrum can be predicted by PASS. The result of prediction is presented as the list of activities with appropriate Pa and Pi. Pa and Pi are the estimates of probability for the compound to be active and inactive respectively for each type of activity from the biolo­gical activity spectrum. It is reasonably that only those types of activities may be revealed by the compound, which Pa > Pi. If Pa > 0.7 the compound is very likely to reveal this activity in experiments, but in this case the chance of being the analogue of the known pharmaceutical agents for this compound is also high.

Target compounds exhibit antidiabetic and cutinase inhibitor activities with a high value of probability to be active. Change of Pa values for these activities is shown on the diagram (Fig. 1). Furthermore, (-)-(4S)-limonene synthase inhibitor activity is found with high values of Pa in products (5a-c). Such results seem to be quite suitable and thus such compounds are worth to be tested in experiments to confirm these activities. Only activities with Pa > 0,6 are shown in Table 1.

In addition, the structure-reactivity relationship of compounds (5a-g) were studied. Such a relationship is usually discussed within a context of the linear free energy relationship (LFER). The Hammett equation is the most frequently used LFER correlation in organic chemistry [26].

The Hammett equation is widely applied in the form  logk - logk0 = op or

logk/ = op , where k and k0 are rates or equilibrium constants for reactions of m- and

^-substituted and unsubstituted benzene derivatives, respectively, о is a parameter dependent only on a substituent and its position, and p is a parameter dependent upon the nature of a derivative and conditions under which the reaction occurs. The constant p measures the susceptibility of the reaction to the influence of a substituents.

Table 1

Biological activities and <r-values for alkyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-

3-arylpropanoates 5a-g

Entry

Structure            o=£oomp                  Predicted activities (Pa)

5a

O

0

0.931 (0.004) Cutinase inhibitor

0.801 (0.068) (-)-(4S)-limonene synthase inhibitor

0.710 (0.00б) Antidiabetic

0.689 (0.047) Convulsant

0.680 (0.073) 2-Haloacid dehalogenase

(configuration-inverting) inhibitor

0.660 (0.032) Laccase inhibitor

0.660 (0.039) Oxidoreductase inhibitor

0.645 (0.041) Teratogen

0.625 (0.014) Ophthalmic drug

0.615 (0.050) Lipid metabolism regulator

5b

O

-0.069

0.916 (0.005) Cutinase inhibitor

0.737 (0.096) (-)-(4S)-limonene synthase inhibitor 0.688 (0.007) Antidiabetic

0.669 (0.036) Oxidoreductase inhibitor 0.672 (0.053) Convulsant

0.642 (0.040) Laccase inhibitor

0.606 (0.050) Teratogen

5c

O

0.227

0.920 (0.005) Cutinase inhibitor

0.717 (0.105) (-)-(4S)-limonene synthase inhibitor

0.683 (0.007) Antidiabetic

0.669 (0.036) Teratogen

0.630 (0.045) Laccase inhibitor 0.628 (0.077) Convulsant

0.625 (0.056) Oxidoreductase inhibitor

5d

h3c     jf    s s о

0.227

0.902 (0.005) Cutinase inhibitor 0.711 (0.006) Antidiabetic 0.671 (0.054) Convulsant 0.644 (0.042) Teratogen

5e

BuY^

О

-0.161

0.908 (0.005) Cutinase inhibitor

0.687 (0.007) Antidiabetic

0.666 (0.056) Convulsant 0.614 (0.015) Ophthalmic drug 0.610 (0.063) Oxidoreductase inhibitor 0.576 (0.058) Teratogen

5f

h3c               s s о

0.454

0.905 (0.005) Cutinase inhibitor 0.694 (0.006) Antidiabetic 0.667 (0.036) Teratogen

0.621 (0.082) Convulsant

5g

О Bu

_/=\_ s   \ 1

Cl    \\    //    Cl        S NH2

0.43

0.906 (0.007) Cutinase inhibitor

0.676 (0.007) Antidiabetic

0.651 (0.041) Teratogen

0.628 (0.047) Oxidoreductase inhibitor

5a 5b 5c 5d 5e 5f 5g

compound

Fig. 1. Predicted biological activity of alkyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl] -3 -arylpropanoates

The Hammett equation was successful in the treatment of the effects of groups in the meta and para positions and attempts to apply it to ortho positions were made (ortho-effects). The Hammett equation is directly applicable to ortho-substituted benzene reaction series, in which the reaction site and benzene ring are separated by some group Z, apparently due to the absence of steric effects in these series. The side-chain Z must consist of at least two atoms for satisfactory correlation. In this case, ortho-substituted benzene reaction series can be correlated directly by the Hammett equation using the op substituent constants. In such reaction series ortho substituents have the same type and magnitude of electrical effects as para substituents [27]. Thus, using values of о constants and values of the three predicted highest activities, we obtained the relationship between them. As we can see it is in good linear correlation (Fig. 2). In such a way we analyzed the influence of substituents on reactivity.

Experimental

All melting points are uncorrected. The 1H-NMR spectra were measured on a Mercury 400 MHz spectrometer for DMSO-d6 solutions using TMS as internal reference. Compounds (3a-g) were obtained using methods described in the literature [23], 5-amino-1,3,4-thiadiazole-2-thiol (4) was prepared according to the literature procedure [24] in good yields.

Synthesis of compounds 5 a-g

Compound 4 (10 mmol) was refluxed with 2-bromo-3-arylpropanoic acid esters 3a-g (10 mmol) in EtOH (10 mL) solution of KOH (10 mmol) during 2 h. The reaction mixture was cooled at room temperature. The solid was filtered, washed with EtOH and dried.

Ethyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-3-phenylpropanoate (5a); yield 78 %; Found: C 50.46; H 4.89; N 13.58; О 10.34; S 20.73 %; C13H15N3O2S2 requires 50.46; H 4.89; N 13.58; О 10.34; S 20.73 %; 1H-NMR 5: 1.08 (3H, t, 7=6.8 Hz, CH3CH2); 3.05­3.2 (2H, d.d., CH2); 4.0 (2H, q, 7=7.6 Hz, CH3CH2); 4.19-4.23 (1H, t, 7=6.8 Hz, CH); 7.21-7.33 (5H, m, C6H5); 7.51 (2H, s, NH2).

Fig. 2. Relationship between Pa and о values

Ethyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-3-(3-methylphenyl)propanoate (5b); yield 86 %; Found: C 51.99; H 5.30; N 12.99; О 9.89; S 19.83 %; C14H17N3O2S2 requires C 51.99; H 5.30; N 12.99; О 9.89; S 19.83 %; [1]H-NMR 5: 1.08 (3H, t, 7=6.8 Hz, CHsCH2); 2.27 (3H, s, CH3); 3.0-3.13 (2H, d.d., CH2); 3.99-4.05 (2H, m, CH3CH2); 4.19 (1H, t, 7=6.8 Hz, CH); 7.04-7.07 (3H, m, 2,4,6-H3 C6H4); 7.18 (1H, t, 7=7.6 Hz, 5-H

C6H4); 7.51 (2H, s, NH2).

Ethyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-3-(2-chlorophenyl)propanoate

(5c); yield 81 %; Found: C 45.41; H 4.10; Cl 10.31; N 12.22; О 9.31; S 18.65 %; C13H14ClN3O2S2 requires C 45.41; H 4.10; Cl 10.31; N 12.22; О 9.31; S 18.65 %; [2]H-NMR 5: 1.09 (3H, t, 7=6.8 Hz, CH3CH2); 3.17-3.33 (2H, d.d., CH2); 4.04 (2H, q, CH3CH2); 4.21 (1H, t, 7=7.2 Hz, CH); 7.28-7.46 (4H, m, 3,4,5,6-H4 C6H4); 7.54 (2H, s, NH2).

Methyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-3-(4-chlorophenyl)propano-ate (5d); yield 74 %; Found: C 43.70; H 3.67; Cl 10.75; N 12.74; О 9.70; S 19.44 %; C12H12ClN3O2S2 requires C 43,70; H 3,67; Cl 10,75; N 12,74; О 9,70; S 19,44 %; [3]H-NMR 5: 3.05-3.15 (2H, d.d., CH2); 3.60 (3H, s, CJH3); 4.26 (1H, t, 7=7.6 Hz, CH); 7.30-7.32 (2H, d., 7=7.6 Hz, 2,6-H2 C6H4); 7.36-7.38 (2H, d., 7=7.6 Hz, 3,5-H2 C6H4); 7.54 (2H, s, NH2).

Methyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-3-(4-butylphenyl)propanoate (5e); yield 76 %; Found: C 54.67; H 6.02; N 11.95; О 9.10; S 18.25 %; C16H21N3O2S2 requires C 54.67; H 6.02; N 11.95; О 9.10; S 18.25 %; [4]H-NMR 5: 0.88 (3H, t, 7=7.6 Hz, CHsCH2CH2CH2); 1.3 (2H, m, CH3CH2CH2CH2); 1.53 (2H, m, CH3CH2CH2CH2); 2.50 (2H, m, CH3CH2CH2CH2), 2.9-3.15 (2H, d.d., CH2); 3.58 (3H, s, CH3); 4.20 (1H, t, 7=7.6 Hz, CH); 7.10-7.20 (4H, m, C6H4); 7.50 (2H, s, NH2).

Methyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-3-(2,4-dichlorophenyl)propa-noate (5f); yield 81 %; Found: C 39.57; H 3.04; Cl 19.47; N 11.54; О 8.78; S 17.61 %; C12H11Cl2N3O2S2 requires C 39.57; H 3.04; Cl 19.47; N 11.54; О 8.78; S 17.61 %; 1H-NMR 5: 3.14-3.34 (2H, m, CH2); 3.63 (3H, s, CH3); 4.26 (1H, t, 7=7.6 Hz, CH); 7.40­7.46 (2H, m, 3,6-H2 C6H3); 7.54 (2H, s, NH2); 7.62 (1H, d, 7=7,6 Hz, 5-H C6H3).

Butyl 2-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanyl]-3-(3,6-dichloro-2-methylphe-nyl)-propanoate (5g); yield 90 %; Found: C 45.71; H 4.56; Cl 16.87; N 10.00; О 7.61; S 15.26 %; C16H19Cl2N3O2S2 requires C 45.71; H 4.56; Cl 16.87; N 10.00; О 7.61;

S 15.26 %.

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