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Synthesis, identification, antibacterial activity and QSAR study of some new cinnamoyl thiouredio-amino acid derivatives.

Introduction

Thioure as derivatives have been used in applications in a wide range of medicinal chemistry due to their diverse biological activities, such as anti-HIV activity [1], anticancer [2], antimicrobial [3, 4], antibacterial [5], antifungal [6] and antimalarial [7]. Itis also may be applied in electrochemistry, as corrosion inhibitors and in agriculture [8-10]. On the other hand, the synthesis of biologically active amino acid coupled derivatives were considered to be of a major interesting [11]. In addition, cinnamic acids play vital role in the synthesis of other important compounds. For example, cinnamic acid derivatives, are used as sources for pharmaceuticals [12].

QSARs (Quantitative) Structure-Activity relationships) are based on the assumption that the structure of a molecule (i.e. its geometric, steric and electronic properties) must contain the features responsible for its physical, chemical, and biological properties, and on the ability to represent the chemical by one, or more, numerical descriptor(s). By QSAR models, the biological activity (or property, reactivity, etc.) of a new or untested chemical can be inferred from the molecular structure of similar compounds whose activities (properties, reactivities, etc.) have already been assessed [13, 14]

In this study, three new compounds of thioure as bearing amino acids were synthesized and their use ability as antibacterial agents, and made quantitative structure activity relationship parameters (QSAR) study on it.

Experimental

Physical Measurement

Melting point are uncorrected and were measured on a Gallen-Kamp melting point apparatus. IR spectra were recorded with a FT-IR 8400S spectrophotometer model (2000) from SHIMADZU Japan. The [sup.1]H NMR spectra were obtained in deutrated solation DMSO + 2 drops TFA by using Bruker 300MHZ, type advance Mltrasheild instrument in central laboratories of the Institute of earth and environment science of the university of Al al-Bayt, Jordan.

General Procedure of Preparation

Three new compounds 4-6 were synthesized in this study based on the solution of cinnamoyl chloride (0.54gm, 3.4mmol) in acetone (20ml) was heated under reflux for 1h. After cooling and filtration, a solution of the desired free amino acid (3.4mmol) in dry acetone (15ml) was added and the mixture was heated under reflux for 6h. After cooling, an excess of crushed ice was pouted on the mixture with vigroue stirring. The result was collected, washed with acetone and recrystallized from DMF-ether[15].

(E)-2-(3-cinnamoyl thiouredio)-3-(1H-indol-3-yl)propanoic acid (4). From L-tryptophane (0.69 g). Yield: (0.83 g, 62%), mp(224-226[degrees]C). IR (KBr pellet, [cm.sup.-1]):u(C=[O.sub.carboxylic]) 1662.52, [upsilon] (C=[O.sub.amide]) 1638.31, [upsilon](N-H) 3051.18, u(C-N) 1238.21, [upsilon] (C=S) 742.54. [sup.1]H NMR(DMSO-2 drops TFA) ([delta] ppm): 13.58 (s, 1H, C[O.sub.2]H), 11.03 (s, 1H, NHindole), 8.25 (s, 1H, CONH), 2.50 (s, 1H, CSNH), 7.32 (s, 1H, CH indole), 7.60 (s, 1H, CH indole), 7.10 (d, 2H, 2CH indole), 7.18 (s, 1H, CH indole), 7.56 (d, 2H, Ar-H), 7.36 (d, 2H, Ar-H), 7.33 (s, 1H, Ar-H), 7.37 (s, 1H, ethylene), 6.89 (s, 1H, ethylene), 4.16 (s, 1H, methane), 3.27 (s, 1H, methylene), 3.16 (s, 1H, methylene).

(E)-2-(3-cinnamoyl thiouredio)-3-(4-hydroxyphenyl) propanoic acid (5). From L-thyrosine (0.61 g). Yield: (0.70 g, 56%), mp (235-236 [degrees]C). IR(KBr pellet, [cm.sup.-1]): [upsilon](C=[O.sub.carboxylic]) 1695.02, [upsilon](C=[O.sub.amide]) 1614.02, [upsilon](N-H) 3207.40, [upsilon](C-N) 1242.07, u(C=S)740.61. [sup.1]H NMR (DMSO-2 drops TFA) ([delta] ppm): 13.32 (s, 1H, C[O.sub.2]H), 8.28 (s, 1H, Ar-C-OH), 8.25 (s, 1H, CONH), 2.50 (s, 1H, CSNH), 7.60 (d, 2H, Ar-H), 7.40 (d, 2H, Ar-H), 7.33 (s, 1H, Ar-H), 7.37 (s, 1H, ethylene), 6.89 (s, 1H, ethylene), 4.16 (s, 1H, methane), 2.99 (s, 1H, methylene), 2.97 (s, 1H, methylene).

(E)-2-(3-cinnamoyl thiouredio) pentanedioic acid (6). From L-glutamic acid (0.50 g). Yield: (0.86 g, 75%), mp (196-198[degrees]C). IR (KBr pellet, [cm.sup.-1]): [upsilon] (C=[O.sub.carboxylic]) 1650.95, [upsilon](C=[O.sub.amide]) 1612.09, [upsilon](N-H) 3058.89, [upsilon] (C-N) 1224.71, [upsilon] (C=S) 763.76. 1H NMR (DMSO-2 drops TFA) ([delta] ppm): 12.89 (s, 1H, C[O.sub.2]H), 12.57 (s, 1H, C[O.sub.2]H), 8.33 (s, 1H, CONH), 2.00 (s, 1H, CSNH), 7.60 (d, 2H, Ar-H), 7.40 (d, 2H, Ar-H), 7.33 (s, 1H, Ar-H), 7.37 (s, 1H, ethylene), 6.89 (s, 1H, ethylene), 3.93 (s, 1H, methane), 2.33 (d, 2H, methylene), 2.05 (d, 2H, methylene).

Antibacterial Screening

A filter disk assay was used to determine the antimicrobial activity of the compounds 4-6, against types of strains of gram positive and gram negative bacteria: which are (Staphylococcus aureus and Escherichia coli) that were tested using plates of Muller-Hinton agar, with the DMSO used as control. The antimicrobial activity was defined as the clear zone of growth inhibition [16].

QSAR

The three compounds 4-6are optimized by using the Restricted Hartree-Fock (RHF) method with basis set 6-31G and then re-optimized by the Density Functional Theory (B3LYP) method with basis set 6-31G [17, 18]. The ab initio calculations were performed to optimized these compounds using the Gaussian 98 program [19]. The QSAR calculations to estimate the logarithmic octanol-water partition coefficient (log P) of organic compounds using HyperChem[TM] Release 7.52 for Windows Molecular Modelling System [20].

Result and Discussion

In this work, cinnamicacid 1was converted into corresponding cinnamoyl chlorides 2 by treatment with thionyl chloride according to standard procedure. The cinnamoyl chloride 2has been used for the synthesis of cinnamoylthiocyanate derivative 3 by treating it with N[H.sub.4]SCN in acetone [15]. Compound 3 was the intermediate key for the synthesis of the compounds investigated in this work, is a highly reactive compound featuring electrophilic sites. The isothiocyanate functional groups in a conjugated system, afforded 3 which was directly with desired amino acid derivatives to give, after purification derivatives in (56-75%) yield. The synthetic reaction are summarized in scheme 1.

The structures of 4-6were indicated by their IR and [sup.1]H NMR spectra. The infrared spectra of all compounds shows the expected frequencies of u(C=[O.sub.carboxylic]), [upsilon](C=[O.sub.amide]), [upsilon](N-H), [upsilon] (CN) and [upsilon](C=S) at 1650-1695 [cm.sup.-1], 1612-1638 [cm.sup.-1], 3051-3207 [cm.sup.-1], 1224-1242 [cm.sup.-1] and 740-763 [cm.sup.-1], respectively which data comparison by several previous reports has been done [21-23]. The u(C=S)stretching vibration about 740-763[cm.sup.-1] are in close agreement with previously reported of the thiourea derivatives. [sup.1]H NMR spectra of the thiourea also looked similar. The sec. amide protons were observed between 8.25-8.33 ppm while the amine protons chemical shifts are slightly upfield between 2.00 and 2.50 ppm. The carboxylic acid protons are at 12.57-13.32 ppm, while the aromatic protons are between 7.10-7.60 ppm.

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All the three compounds showed an activity against the two selected bacteria as shown in Table 1. The compounds show activity against Staphylococcus aureus and Escherichia coli. It is well known from literatures that thioureas compounds exhibit a wide range of biological activities. So, it was of interest to design new compounds containing that biologically active moieties.

To delineate the structural chemical requirements of the new compounds 4-6as inhibitors of Staphylococcus aureusand Escherichia coli growth, calculate other parameters such as, the descriptors Log P, [pi] [24]. Log P estimates the logarithmic octanol-water partition coefficient, therefore the Log P represents the lipophilic effects of a molecule which includes the sum of the lipophiliccontributions of the parent molecule and its substituent [25]. The difference between the substituted and unsubstitutedLog P values is condicionated by the [pi] value for the particular substituent. Hammett showed that [pi] values measure the free energy change caused by particular substituent to relate to biological activity [26].The results (Table 2) showed an increase in Log P, and the 4 compound shows the lowest toxic value. Also it is not needed any free energy change. This phenomenon is conditioned mainly, by the contribution of all substituent atoms involved in the chemical structure of the different compounds. The 5 compound shows the highest toxicity and free energy among them.some steric constants (MV and MR, i.e., the molar volume and molar refractivity) calculated [27], these options are useful tool for correlation of different properties which depend on characteristics of substituents attached to a constant reaction center. From the results are showed in table 2, there are stimulation in increases or decreases in both, MR and MV values in the 4-5compounds. These data indicate that steric impediment could affect the antibacterial activity of the studied compounds. Different molecular mechanisms and conformational preferences and internal rotation of the different compounds, can influence their antibacterial activity [28]. Whom show that the conformational differences between 4-5 compounds have some important consequences in the union to biological receptors by conformational changes.

Conclusion

The Compounds of (E)-2-(3-cinnamoyl thiouredio)-3-(1H-indol-3-yl)propanoic acid, 4, (E)-2-(3-cinnamoyl thiouredio)-3-(4-hydroxyphenyl) propanoic acid, 5, and (E)-2-(3-cinnamoyl thiouredio)pentanedioic acid, 6, was successfully synthesized and fully characterized by spectroscopic methods. All the compounds showed activity against the selected bacteria Staphylococcusaureus and Escherichia coli. The 4 compound shows the lowest toxic value. Also it is not needed any free energy change. The 5 compound shows the highest toxicity and free energy among them.

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Zainab Shakir Abdullah

Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq.

E-mail: zainab1976@yahoo.com
Table 1: Antibacterial activity of the compounds 4-6

No. of Gram positive bacteria Gram negative bacteria
comp. Zone of inhibition (mm) Zone of inhibition (mm)

 Staphylococcus aureus Escherichia coli

4 35 40
5 30 18
6 13 13

Concentration of the compounds 4-6 = 100 mg/mL.

Table 2: Physicochemical Parameters of the Compounds 4-6.
Log P, MV= molar volume, MR= molar Refractivity and [pi] = value for
Particular Substituent

No. LogP MV MR [pi]
of comp

4 0.65 1171.79 120.78 -0.37
5 1.46 1105.61 111.09 0.44
6 1.19 995.08 91.52 0.17

Scheme 1. Synthesis of (E)-2-(3-cinnamoyl
thiouredio)-3-(substituted R)carboxylic
acid derivatives.

No. of R Amino acid
comp.

4 C[H.sub.2]-3-indole L-tryptophane
5 P-cresol L-thyrosine
6 [(C[H.sub.2]).sub.2] L-glutamic acid
 C[O.sub.2]H
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Author:Abdullah, Zainab Shakir
Publication:International Journal of Applied Chemistry
Date:Jan 1, 2012
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