EHOOPrÄHH^ECRAa XHMH3, 2012, moM 38, № 5, c. 610-620
SYNTHESIS OF EPEREZOLID-LIKE MOLECULES AND EVALUATION OF THEIR ANTIMICROBIAL ACTIVITIES
© 2012 Meltem Yolal", Serap Basoglu", Hakan Bektas4, Serpil Demirci", Sengul Alpay-Karaogluc, and Ahmet Demirbas",#
aDepartment of Chemistry, Faculty of Arts and Sciences, Karadeniz Technical University, Trabzon, Turkey bGiresun University, Department of Chemistry, Giresun, Turkey cRize University, Department of Biology, Rize, Turkey Received October 3, 2011; in final form, November 20, 2011
3-Fluoro-4-(4-phenylpiperazin-1-yl)aniline (II) prepared from 3,4-difluoro nitrobenzene was converted to the corresponding Schiff bases (III) and (IV) by treatment with 4-methoxybenzaldehyde and indol-3-carbal-dehyde, respectively. Treatment of amine (II) with 4-fluorophenyl isothiocyanate afforded the corresponding thiourea derivative (V). Compound (V) was converted to thiazolidinone and thiazoline derivatives (VI) and (VII) by cyclocondensation with ethylbromoacetate or 4-chlorophenacylbromide, respectively. The synthesis of carbothioamide derivative (X) was performed starting from compound (II) by three steps. Treatment of compound (X) with sodium hydroxide, sulfuric acid, or chlorophenacyl bromide generated the corresponding 1,2,4-triazole (XI), 1,3,4-thiadiazole (XII), and 1,3-thiazolidinone (XIII) derivatives, respectively. The structural assignments of new compounds were based on their elemental analysis and spectral (IR, 'H-NMR, 13C-NMR, and LC-MS) data.
In the antimicrobial activity study all the compounds revealed high anti-Mycobacterium smegmatis activity. Keywords:piperazin, 1,3-thiazolidinone, 1,2,4-triazole, 1,3,4-thiadiazole, antimicrobial activity.
INTRODUCTION
The treatment of infectious diseases remains an important and challenging problem due to a combination of factors including emerging infectious diseases and the increasing number of multidrug resistant microbial pathogens. In spite of the wide range of antimicrobial drugs with different mechanisms of action used to treat microbial infections, either alone or in combination, and the existence of many compounds undergoing different phases of clinical trials, microbial infections are becoming a worldwide problem. The problem with clinically used drugs is not only the increasing microbial resistance; also, administration of such drugs is accompanied by toxic side effects that are often dose limiting. Although a number of synthetic and semi-synthetic antimicrobial compounds have been developed for infectious disease treatment, the alarming rates of emerging microbial threats continuen to challenge public health. Among the infections leading to death, tuberculosis (TB) has retrieved its place. As per the survey reported by Global Alliances, there are 8—10 million new active cases of TB with approximately 3 million deaths each year [1—6].
Substituted piperazines are pharmacophores of a number of important drugs such as crixivan, an HIV protease inhibitor, piperazinyl-linked ciprofloxacin
# Corresponding author (phone: +90 462 3772600; fax: +90 462 3253196; e-mail: ndemirbas651@mynet.com).
dimers, which are potent antibacterial agents, and an oxazolidinone antibiotic eperezolid [7, 8]. The drugs prazosin, lidoflazine, and urapidil, which contain a piperazine nucleus in their structures, are used as cardiovascular agents [9, 10].
Oxazolidinones are a new and promising class of synthetic antibiotics that exhibit activity against numerous multidrug-resistant Gram positive pathogens. Oxazolid-inones have been believed to be not cross resistant with other types of antibiotics due to their different mode of action which includes interaction with the bacterial ribo-some to inhibit bacterial growth [5, 11—14]. Eperezolid, that is an oxazolidinone antibiotic also containing a pip-erazine moiety, is currantly in the phase II clinical trial. Literature survey revealed that since phenyloxazolidin moiety is core of molecule, Eperezolid structure allows various modifications including the introduction of five-membered heterocyclic residues attached to the rest of the molecule by a methylene linker [15, 16].
There is a considerable interest in the chemistry of thiazolidinone ring which constitutes an important class of pharmaceuticals displaying a broad spectrum of biological activity such as anti-mycobacterial, antifungal, anticancer, antituberculosis, anticonvulsant, anti-inflammatory, and analgesic activities [17—24].
Here, we reportthe design and preparation of new heterocycles incorporating the known bioactive piper-azinyl-fluorophenyl-thiazolidinone core structure in
order to obtain novel molecules with high therapeutic index.
RESULTS AND DISCUSSION
Synthetic strategies adopted to obtain the target compounds are depicted in Schemes 1 and 2. Aromatic primary amines are widely-used building blocks in the synthesis of nitrogen-containing heterocycles, dyes, pigments, pharmaceuticals, and industrial products. In the present study, synthesis of compound (I)
was performed by condensation of 3,4-difluoro nitrobenzene with phenylpiperazine. The compound was characterized by the presence of two strong bands at 1334 and 1495 cm-1 in the IR spectrum due to the nitro group. When compound (I) was converted to compound (II) by the reduction of the nitro group, these signals disappeared, while two strong absorption bands derived from -NH2 functionality were observed at 3387 and 3487 cm-1. In the 1H-NMR spectrum the —NH2 group resonated at 5.03 ppm (exch. with D2O).
F
(I)
F
\
« O
(III)
F
(II)
S
F
UTT
N H
F
(IV)
(V)
F
(VI)
F
(VII)
Scheme 1. Reactions and conditions for the syntheses of compounds (I)—(VII). i: Pd-C, H2NNH2, ii: 4-methoxybenzaldehyde, iii: indol 3-carbaldehyde, iv: 4-fluorophenylisothiocyanate, v: ethyl bromoacetate, vi: 4-chlorophenacyl bromide.
The treatment of compound (II) with anisaldehyde or indol-3-carbaldehyde has yielded 3-fluoro-^-[(4-methoxyphenyl)methylidene]-4-(4-phenylpiperazin-
1-yl)aniline (III) and 3-fluoro-N-[(1#-indol-3-yl))methylidene]-4-(4-phenylpiperazin-1-yl)aniline (IV), respectively. The IR spectra of derivatives (III)
and (IV) both contained an absorption band at 1501 (for III) or 1496 cm-1 (for IV) indicating the presence of C=N bond in the ring, while no signal derived from NH2 group was present. Moreover, additional signals derived from the aldehyde moiety were observed at the related chemical shift values in the 1H- and 13C-NMR
spectra of compounds (III) and (IV). In addition, a singlet characteristic for the N=CH group was observed at 8.32 (for III) and 8.38 (for IV) ppm in the 1H-NMR spectra of compounds (III) and (IV). This group was recorded at 165.42 (for III) or 166.68 ppm (for IV), in the 13C-NMR spectra.
(II)
i
Scheme 2. Reactions and conditions for the syntheses of compounds (VIII)—(XIII). i: BrCH2CO2Et, ii: H2NNH2,
iii: (4-)FC6H4CNS, iv: H2SO4, v: NaOH, vi: ClC6H4CH2Br.
The compounds having imine bonding can exist as E/Z isomers for C=N double bond [25—33]. According to the literature [27], in dimethyl-d6 sulfoxide solution, imines are present preferably as E isomer. The Z isomer can be stabilized in less polar solvents by an intramolecular hydrogen bond. In the present study, the XH and 13C NMR spectra of compounds (III) and (IV) have been obtained in dimethyl-d6 sulfoxide solution and showed the presence of only one isomer. It can be concluded that compounds (III) and (IV) exist as their E geometrical isomers considering bulky arylidene substituent, which is in accordance with the literature data [28, 29, 34-38].
Isothiocyanates are other useful tools for synthesis of nitrogen, sulfur, or oxygen containing compounds. The intermediates (V) and (X), which have been synthesized by the reaction of compounds (II) and (IX) with 4-fluorophenylisothiocyanate, represent versatile building blocks for the synthesis of several heterocycles such as 1,2,4-triazoles, 1,3,4-thiadiazoles, and 1,3-thiazoles. The IR and 'H-NMR spectra of compounds (V) and (IX) displayed signals derived from two NH (for V) or four NH (for IX) protons (exchangeable with D2O). Moreover, the signals originated from 4-fluorophenyl moiety have been recorded at the aromatic region in the XH- and 13C-NMR spectra. The synthesis of 2-{[3-fluoro-4-(4-phenylpiperazin-1-yl)phenyl]imino}-3-(4-fluorophenyl)-1,3-thiazolidin-4-one (VI) was carried out by refluxing of compound (V) in ethanol with 4-chlorophenacyl bromide in the presence of anhydrous sodium acetate. Compound (VI) was characterized by the presence of two strong bands, at 3245 cm-1, representing NH group, and at 1726 cm-1, revealing carbonyl function in the IR spectrum. This was considered as a confirmation of thiazolidinone nucleus formation. Another piece of evidence for cyclocondensation is the appearance of a singlet signal at 4.13 ppm in the 1H NMR spectrum integrating for two protons, which apparently are the C5 protons of thia-zolidinone nucleus. This carbon has resonated at 33.51 ppm in the 13C-NMR spectrum. On the other hand, the condensation of compound (V) with 4-chlo-rophenacyl bromide afforded 5-(4-chlorophenyl)-2-[3-fluoro-4-(4-phenylpiperazin-1-yl)phenyl]imino-3-(4-fluorophenyl)-1,3-thiazolin (VII). 1H-NMR spectrum of derivative (VII) displayed only one signal due to NH group integrating one proton as a result of condensation. Similarly, compound (X) produced compound (XIII) under the same reaction conditions, as expected. In the IR spectrum of compound (XIII), carbonyl absorption has been observed at 1646 cm-1. The signals recorded at 4.39 and 10.47 ppm in the 1H NMR spectrum were attributed to the two NH functions. These groups exchanged protons with D2O. The absence of any -SH group signals from the IR and 1H NMR spectra of compound (XIII) has constituted another evidence for cyclocondenzation between compound (X) and 4-chlorophenacyl bromide.
Although several methods for preparation of 1,3-thiazoles have been d
Для дальнейшего прочтения статьи необходимо приобрести полный текст. Статьи высылаются в формате PDF на указанную при оплате почту. Время доставки составляет менее 10 минут. Стоимость одной статьи — 150 рублей.