научная статья по теме SYNTHESIS OF SOME NEW HYBRIDE MOLECULES CONTAINING SEVERAL AZOLE MOIETIES AND INVESTIGATION OF THEIR BIOLOGICAL ACTIVITIES Химия

Текст научной статьи на тему «SYNTHESIS OF SOME NEW HYBRIDE MOLECULES CONTAINING SEVERAL AZOLE MOIETIES AND INVESTIGATION OF THEIR BIOLOGICAL ACTIVITIES»

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EHOOPrÁHH^ECRAa XHMH3, 2014, moM 40, № 3, c. 341-356

SYNTHESIS OF SOME NEW HYBRIDE MOLECULES CONTAINING SEVERAL AZOLE MOIETIES AND INVESTIGATION OF THEIR BIOLOGICAL ACTIVITIES

© 2014 Sule Ceylan*, Hacer Bayrak**, Ahmet Demirbas**, Serdar Ulker***, Sengul Alpay-Karaoglu***, Neslihan Demirbas**, #

*Artvin Qoruh University, Department of Forest Industrial Engineering, Artvin, 08000 Turkey **Karadeniz Technical University Department of Chemistry, Trabzon, 61080 Turkey ***Recep Tayyip Erdogan University, Department of Biology, Rize, 5300 Turkey Received November 7, 2013; in final form, December 5, 2013

1,2,4-Triazole-3-one prepared from tryptamine was converted to the corresponding carbotioamides by several steps. Their treatment with ethyl bromoacetate or 4-chlorophenacyl bromide produced the corresponding 5-oxo-1,3-thiazolidine or 3-(4-chlorophenyl)-1,3-thiazole derivatives. Acetohydrazide derivative that was obtained starting from tryptamine, was converted to the corresponding Schiff basis and sulfonamide by the treatment with suitable aldehydes and benzensulphonyl chloride, respectively. 2-[(4-Amino-5-thioxo-4,5-di-hydro-1^-1,2,4-triazole-3-yl)methyl]-4-[2-(1^-indole-3-yl)ethyl]-5-methyl-2,4-dihydro-3^-1,2,4-triazole-3-one was synthesized starting from hydrazide via the formation of the corresponding 1,3,4-oxadiazole compound, while the other bitriazole compounds were obtained by intramolecular cyclisation of carbothioamides in basic media. The treatment of 1,2,4-triazole or 1,3,4-oxadiazole compound with several amines generated the corresponding Mannich bases. Ethyl (2-amino-1,3-thiazole-4-yl)acetate was converted to the corresponding 1,3,4-oxadiazole derivative, arylidenehydrazides, 1,2,4-triazole-3-one and 5-oxo-1,3-oxazolidine derivatives by several steps. The structural assignments of new compounds were based on their elemental analysis and spectral (FT IR, 1H NMR, 13C NMR and LC-MS) data. The antimicrobial, antilipase and antiurease activity studies revealed that some of the synthesized compounds showed antimicrobial, antilipase and/or an-tiurease activity.

Keywords: 1,2,4-triazole, 1,3,4-oxadiazole, 1,3-thiazolidinone, 1,3,4-thiadiazole, piperazine, biological activity

DOI: 10.7868/S0132342314030142

INTRODUCTION

The rising prevalence of multi-drug resistant bacteria continues to serve of medicinal chemists to search and discovery novel antimicrobial agents effective against pathogenic microorganisms resistant to current treatment. Furthermore, treatment of infectious diseases is more difficult for patients infected with human immunodeficiency virus (HIV) [1—4]. Beside this, the newly synthesized agents should display low as possible side effects on human body. Because, in some cases, especially in case of patients with impaired liver or kidney functions, the use of antimicrobial drugs causes several problems [5—8]. Recent studies have showed that the application of appropriate dosage regimen with highly potent antimicrobial agents not only eradicates bacterial growth but also minimizes the probability of resistance formation [1].

# Corresponding author (phone: +90 462 377425; fax: +90 462 325-31-96; e-mail: neslihan@ktu.edu.tr).

Triazoles have been shown to possess a number of desirable features in the context of medicinal chemistry. They are stable to acidic/basic hydrolysis and also reductive/oxidative conditions, indicative of a high aromatic stabilization. This moiety is relatively resistant to metabolic degradation. Tazobactam, a P-lactamase inhibitor, is the best known examples of triazole containing structures with the broad spectrum antibiotic piperacillin [9]. 4-Oxo-thiazolidine derivatives were also reported to have antibacterial, antitubercular, antiviral and anticancer properties [10—12].

Beside the development of completely new agents possessing different chemical properties than those of the existing ones, another approach is to combine two or more pharmacophores into a single molecule. Therefore, a single molecule containing more than one pharmacophore, each with different mode of action, could be beneficial for the treatment of microbial infectious [14—18]. These synergistic antimicrobial combinations have several major advantages, includ-

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Scheme 1. Reactions and conditions. i: 115°C, 2 h; ii: absolute ethanol, Na, ethyl bromoacetate, reflux for 14 h; iii: K-butanol, hydrazine hydrate, reflux for 6 h; iv: benzyl- (for Via) or 4-fluorophenylisothiosyanate (for VIb) in ethanol, reflux for 5 h; v: 2 N NaOH in ethanol/water (1 : 1), reflux for 6 h; vi: piperidine and formaldehyde in THF, rt, 2 h; vii: ethyl bromoacetate in absolute ethanol, dried sodium acetate, reflux for 8 h; viii: 4-chlonol, dried sodium acetate, reflux for 8 h; viii: 4-chlorophenacylbromide, sodium acetate in absolute ethanol, reflux for 8 h.

ing the potential to slow down the development of drug resistance, a broader antimicrobial spectrum, and a potential reduction in the dose and toxicity of each drug [19].

The amino alkylation of aromatic substrates by Mannich reaction has considerable importance for optimization of drug discovery processes [20—22]. Some Mannich bases derived from 1,2,4-triazole nu-

cleus have been reported to possess protozocidal and antibacterial activity [23—27].

Hydroxamic acids, phosphoramidates [31], polyphenols [32], 1,2,4-triazoles [32, 33], 1,3,4-oxadiazoles and 1,3,4-thiadiazoles [32, 33] have been reported as the compounds possessing antiurease activity. Although some Schiff base-metal complexes have been found to display urease inhibitory effects along with other metal complexes, as well, the presence of heavy-metal atoms has restricted of their applications as drugs in the human body [34, 35].

Obesity can lead to a series of serious diseases including but not limited to hypertension, hyperlipi-demia, arteriosclerosis, and type II diabetes [36]. Pancreatic lipase plays an important role in digestion of fat. Pancreatic lipase inhibitors, such as Orlistat, have been used as therapeutic agent for curing obesity [37]. However, some side effects including fecal incontinence, flatulence, and steatorrhea have been reported for Orlistat [38, 39]. The compounds possessing anti-lipase activity can be the alternatives of Orlistat.

In the present study, as a part of our ongoing study on the synthesis of bioactive hybrid molecules, we aimed to obtain new molecules containing two or more azole moieties.

RESULTS AND DISCUSSION

The synthetic strategies adopted to obtain the target compounds are depicted in Schemes 1—3. Primary amines are useful and widely-used building blocks in the synthesis of nitrogen containing heterocycles, dies, pigments, pharmaceutical and industrial products. In the present study, the synthesis of compound (III) has been performed by cyclocondensation of tryptamine [2-(1#-indol-3-yl)ethanamine, (I)] with ethyl 2-(1-ethox-yethylidene) hydrazinecarboxylate (II) [At Scheme 1 this compound is depicted as ...propoxyethylidene...] and and then compound (III) was converted to the corresponding hydrazide (V) via the formation of ester (IV). With the introduction of hydrazide function in the molecule, two signals appeared at 4.23 and 9.20 ppm as D2O exchangeable singlets in the 1H NMR spectrum of compound (V). Compounds (VIa) and (VIb) were obtained by the reaction of compound (V) with benzyl- (for (VIa)) or 4-fluorophenylisothiocyanate (for (VIb)) in ethanolic solution in good yields, and their structures were confirmed with FT IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis. The intramolecular cyclisation of compound (VIa) and (VIb) in basic media resulted in the conversion of carbothioamide side change to 5-mercapto-1,2,4-triazole ring, thus, compounds (VIIa) and (VIIb) were obtained. These compounds were characterized by the presence of a signal at 14.04 or 14.09 ppm in the 1H NMR spectra as D2O exchangeable singlet confirming the existence of a —SH function. The stretching band derived from this group appeared at 2593 (for (VIIa)) or 2516 (for (VIIb)) cm-1,

in the FT-IR spectra of these compounds. Moreover, these compounds gave Mass spectral data and elemental analysis results consistent with the assigned structures.

The treatment of compound (VIIb) with piperidine in tetrahydrofurane at the room temperature in the presence of formaldehyde generated the corresponding Mannich base (VIII) with 74% yield. In the 1H and 13C NMR spectra ofcompound (VIII), additional signals originated from piperidine moiety were observed at the related chemical shift values. In the EI MS spectrum of compound (VIII), the presence of[M + 1], [M + 2] and [M + K] ion peaks confirmed its molecular mass. Furthermore, this compound gave elemental analysis consistent with the assigned structure.

The synthesis of compounds (IX), (Xa) and (Xb) was carried out by the treatment of compounds (VIa), (VIb) with ethyl bromoacetate and 4-chlorophenacyl bromide, respectively, and the structures of these compounds were elucidated by spectroscopic techniques such as 1H NMR, 13C NMR, FT IR, EI MS and elemental analysis.

The attempts to convert compound (V) to arylidene-hydrazides allowed the isolation of the corresponding products ((XIa) and (XIb)) in good yields, after 6 hours in ethanolic solution at reflux temperature. On the other hand, the reaction of compound (V) with benzenesulfo-nylchloride in tetrahydrofurane afforded ^"-(phenylsul-phonyl)acetohydrazide derivative (XII) in moderate yield. As different from compound (V), th

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