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Synthesis, characterization and biological activity studies on amide derivatives.


Amides are multifunctional groups found in many molecules. Not only are they used as prodrugs (e.g. salicylamide), but also they possess diverse biological activities such as anticancer (Jung et al. 2009; Xu et al. 2010; Yurttas et al. 2014; Wang et al. 2014; Huczynski et al. 2015; Mathew et al. 2017), antimalarial (Delarue-Cochin et al. 2008; Kumar et al. 2011), insecticidal (Deng et al. 2016; Yang et al. 2016; Lv et al. 2018); antimicrobial (Huczynski et al. 2012; Soni and Soman 2014; Swapnaja et al. 2016; Wei et al. 2018), anti-inflammatory (Bai et al. 2018), antioxidant (Narender et al. 2011), antinociceptive (Czopek et al. 2016) and antithrombotic (Sashidhara et al. 2012), depending on their substituents. Moreover, amide carrying compounds were noted for their remarkable antibacterial (Mishra et al. 2008; Cui et al. 2017; Bi et al. 2018) and antifungal (Li et al. 2012; Sun et al. 2015; Yu et al. 2018) activities. It should be added that they have also attracted a great deal of attention for their significant anti-biofilm (Ballard et al. 2008; Richards et al. 2009; Rogers et al. 2010; Rane et al. 2012) and antiviral (Hao et al. 2012; Lan et al. 2017) activities.

As is known, the discovery of antibiotics made it possible to treat the infectious diseases that were once untreatable and enabled to save millions of lives by taking many dangerous bacterial infections under control. However, with the occurence of bacterial resistance and in regard to the increasing incidence of multidrug resistance in pathogenic bacteria, the identification of alternative antimicrobial drug targets to develop novel treatment strategies have become a necessity. Recently, it has been regarded that inactivating the quorum sensing (QS) system in bacteria by the use of QS inhibitors holds great promise for the treatment of infectious diseases. QS is a cell-to-cell communication system utilized by a wide variety of Gram (-) and Gram (+) bacteria to control the expression of virulence factors like elastase, extracellular protease, swarming, swimming motility and biofilm formation (de Kievit et al. 2000). Various types of screening have been carried out to find QS inhibitory molecules. Furanone derivatives, AHL analogs, synthetic compounds and some natural substances have been reported to possess QS inhibitory activity (Bosgelmez-Tinaz et al 2007; Galloway et al. 2011; Miandji et al. 2012).

Viruses have a simple structure and wholly depend on the host cells for almost all their vital functions. This situation makes it difficult to develop antiviral agents which are non-toxic for host cell metabolic systems. Antiviral agents that can be used against influenza A viruses (which pose great risks for human health), are also limited with NA inhibitors. These viruses belong to the Orthomixoviridae family and at times cause recurrent epidemics and pandemics within the global human population (Oxford 2000). Recurrent infections of influenza viruses in the human population are largely due to the continual changes occurring in the antigenic properties of virus surface glycoproteins (Laver 1984; Jimenez-Alberto et al. 2013). In particular, the changes of the viral surface antigens enable the virus to avoid the immunological defense of the host organism (Govorkova, 2000). Consequently, the control of influenza by vaccination is not completely effective. Therefore, a considerable effort is being made to develop new drugs and vaccines to combat influenza A viruses.

Hence, in this study, we synthesized a group of amide molecules with reference to p-aminophenylacetic acid and investigated their effects on biofilm formation and swarming motility in P. aeruginosa. Furthermore, the antiviral activities of these molecules were examined.



All of the chemicals, reagents and solvents were purchased from Sigma Aldrich (St. Louis, MO, USA) and Merck (Darmstadt, Germany). Melting points were determined using Schmelzpunktbestimmer SMP II apparatus. For HPLC studies, an Agilent 1100 series system with a G1311A quaternary HPLC pump, a G1315A DAD detector, a G1379A vacuum degasser and a Kromasil 100 C18 5[micro]m, 250 x 4.6 mm column was used. The Rt (retention time) values were determined by an isocratic HPLC grade acetonitrile/water (60:40 v/v) mobile phase at a flow rate of 1 ml/min with DAD detector set at 254 nm. The IR spectra were recorded on a Schimadzu FTIR 8400 S Spectrometer. The NMR spectra were recorded (in DMSO-[d.sub.6]) with a Bruker spectrometer (Billerica, MA, USA) (300 MHz for [.sup.1]H-NMR and 75 MHz for [.sup.13]C-NMR, decoupled). The chemical shift values were expressed in ppm ([delta] scale) using tetramethylsilane as an internal standard. The mass spectral measurements were carried out by Electron Spray Ionization (ES) method on LC-MS-Agilent 1100. Elemental analysis was performed on Leco 215 CHNS-932 analyzer.

Synthesis of amide derivatives (1-6)

Firstly to obtain compound 1, p-aminophenylacetic acid (0.012 mol) was reacted with the equivalent moles of p-fluorobenzoylchloride in a chloroform media, while stirred at room temperature. Secondly, for compounds 2 and 3, the amide derivative (0.010 mol) was dissolved in concentrated sulphuric acid/methanol or ethanol media and refluxed. The precipitate was obtained through the neutralization reaction with sodium bicarbonate. Thirdly, to obtain compound 4 the methyl ester derivative was refluxed with hydrazine hydrate in an ethanol media. Fourthly, compound 5 was obtained through the reaction of hydrazide with ethyl isothiocyanate in an ethanol media. Finally, the thiosemicarbazide was reacted with concentrated sulphuric acid while stirring at room temperature for 45 minutes to obtain the compound 6 (Kucukguzel et al. 2006; Karakus et al. 2010). All of the compounds were purified with hot ethanol.

{4-[(4-Fluorobenzoyl)amino]phenyl}acetic acid (1): Cream solid. Yield 75%; m.p. 152 [degrees]C; MW: 273.2591 g/mol; Rt value: 7.69 min. FT-IR [u.sub.max]. ([cm.sup.-1]): 3323 (O-H and N-H), 1726 (amide C=O), 1645 (carboxylic acid C=O), 1223 (Ar-F). (CAS Number: 907947-59-5).

Methyl {4-[(4-fluorobenzoyl)amino]phenyl}acetate (2): Cream solid. Yield 79%; m.p. 148 [degrees]C; MW: 287.2857 g/mol; Rt value: 6.00 min. FT-IR [u.sub.max]. ([cm.sup.-1]): 3329 (N-H), 1742 (ester C=O), 1651 (amide C=O), 1221 (Ar-F). [.sup.1]H-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 3.62 ([.sup.3]H, s, -C[H.sub.3]), 3.65 (2H, s, -C[H.sub.2]-), 7.26 (2H, d, J: 8.40 Hz, Ar-H), 7.37 (2H, t, Ar-H), 7.68 (2H, d, J: 8.40 Hz, Ar-H), 8.04 (2H, t, Ar-H), 10.27 (1H, s, -CONH-). [.sup.13]C-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 39.57, 51.62, 115.12, 115.41, 120.39, 129.48, 129.60, 130.27, 130.39, 131.29, 131.33, 137.79, 162.37, 164.31 (amide C=O), 165.67, 171.67 (C=O). MS (ES m/z): 310 (M++Na), 180, 179, 101. Elemental analysis for [C.sub.16][H.sub.14] FN[O.sub.3] Calculated/Found (%): C: 66.89/66.28, H: 4.91/4.89, N: 4.88/4.72. (CAS Number: 2204929-37-1).

Ethyl {4-[(4-fluorobenzoyl)amino]phenyl}acetate (3): White solid. Yield 65%; m.p. 154-155 [degrees]C; MW: 301.3122 g/mol; FT-IR [u.sub.max]. ([cm.sup.-1]): 3337, 3298 (N-H), 1722 (ester C=O), 1647 (amide C=O), 1229 (Ar-F). [.sup.1]H-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 1.19 ([.sup.3]H, t, -C[H.sub.2]-C[H.sub.3]), 3.63 (2H, s, -C[H.sub.2]-), 4.05-4.12 (2H, q, - C[H.sub.2]-C[H.sub.3]), 7.26 (2H, d, J: 8.40 Hz, Ar-H), 7.34-7.40 (2H, m, Ar-H), 7.69 (2H, d, J: 8.40 Hz, Ar-H), 8.01-8.06 (2H, m, Ar-H), 10.26 (1H, s, -CONH-). [.sup.13]C-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 14.53, 40.26, 60.73, 115.65, 115.94, 120.89, 129.97, 130.23, 130.76, 130.88, 131.74, 131.78, 138.19, 162.87, 164.88 (amide C=O), 166.17, 171.75 (C=O). Elemental analysis for [C.sub.17][H.sub.16]FN[O.sub.3] Calculated/Found (%): C: 67.76/68.05, H: 5.35/5.50, N: 4.65/4.53. (CAS Number: 2204959-86-2).

4-Fluoro-N-[4-(2-hydrazinyl-2-oxoethyl)phenyl]benza-mide (4): White solid. Yield 86%; m.p. 352 [degrees]C (decomposed); MW: 287.2890 g/mol; Rt value: 2.70 min. FT-IR [u.sub.max] ([cm.sup.-1]): 3352, 3295, 3210 (N-H), 1645 (C=O), 1233 (Ar-F). [.sup.1]H-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 3.22 (2H, s, -C[H.sub.2]-), 4.22 (2H, b.s, -NH-N[H.sub.2]), 7.25 (2H, d, J: 8.70 Hz, Ar-H), 7.36 (2H, t, Ar-H), 7.65 (2H, d, J: 8.40 Hz, Ar-H), 8.02 (2H, t, Ar-H), 9.21 ([.sup.1]H, b.s, -NH-N[H.sub.2]), 10.23 (1H, s, -CONH-). [.sup.13]C-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 39.87, 115.11, 115.40, 120.34, 129.04, 130.24, 130.36, 131.28, 131.32, 131.59, 137.17, 162.35, 164.26 (amide C=O), 165.65, 169.66 (C=O). MS (ES m/z): 310 ( [M.sup.+]+Na), 180, 179, 101. Elemental analysis for [C15][H.sub.14]F[N.sub.3][O.sub.2] Calculated/Found (%): C: 62.71/63.37, H: 4.91/4.97, N: 14.63/14.21. (CAS Number: 2214835-31-9).

N-(4-{2-[2-(ethylcarbamothioyl)hydrazinyl]-2-oxoethyl} phenyl)-4-fluorobenzamide (5): White solid. Yield 79%; m.p. 226 [degrees]C; MW: 374.4325 g/mol; Rt value: 3.63 min. FT-IR [u.sub.max] ([cm.sup.-1]): 3314, 3196 (N-H), 1674, 1645 (C=O), 1219 (C=S), 1159 (Ar-F). [.sup.1]H-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 1.07 ([.sup.3]H, t, -C[H.sub.2]-C[H.sub.3]), 3.45 (4H, s, -C[H.sub.2]-C[H.sub.3] and -C[H.sub.2]-), 7.28 (2H, d, J: 8.70 Hz, Ar-H), 7.37 (2H, t, Ar-H), 7.67 (2H, d, J: 8.40 Hz, Ar-H); 7.93 (1H, t, [N.sub.4]H), 8.01-8.06 (2H, m, Ar-H), 9.17 (1H, b.s, N2H), 9.91 (1H, b.s, [N.sub.1]H), 10.24 (1H, s, -CONH-). [.sup.13]C-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 14.44, 37.13, 115.13, 115.42, 120.27, 129.40, 130.26, 130.38, 130.79, 131.27, 131.31, 137.49, 162.36, 164.27 (amide C=O), 165.66, 169.95 (C=O), 181.25 (C=S). Elemental analysis for [C.sub.18][H.sub.19]F[N.sub.4][O.sub.2]S Calculated/Found (%): C: 57.74/58.31, H: 5.11/5.27, N: 14.96/14.94, S: 8.56/7.90.

N-(4-{[5-(ethylamino)-1,3,4-thiadiazol-2-yl]methyl} phenyl)-4-fluorobenzamide (6): Light brown solid. Yield 40%; m.p. 310-311 [degrees]C; MW: 365.4248 g/mol; Rt value: 4.20 min. FT-IR [u.sub.max] ([cm.sup.-1]): 3310, 3188 (OH and N-H), 1651 (C=O), 1231 (Ar-F), 760 (C-S-C). [.sup.1]H-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 1.13 ([.sup.3]H, t, -C[H.sub.2]-C[H.sub.3]), 3.18-3.27 (2H, m, -C[H.sub.2]-C[H.sub.3]), 4.13 (2H, s, -C[H.sub.2]-), 7.27 (2H, d J: 8.70 Hz, Ar-H), 7.37 (2H, t, Ar-H), 7.57 ([.sup.1]H, t, -NH-), 7.70 (2H, d, J: 8.40 Hz, Ar-H), 8.03 (2H, t, Ar-H), 10.27 (1H, s, -CONH-). [.sup.13]C-NMR (DMSO-[d.sub.6]/TMS) d (ppm): 14.24, 34.99, 115.13, 115.42, 120.61, 128.82, 130.27, 130.39, 131.27, 131.30, 133.24, 137.82, 157.09, 162.37, 164.32, 165.67, 168.78 (amide C=O), 169.69. MS (ES m/z): 357 ([M.sup.+]+1), 189, 182, 179, 101. Elemental analysis for [C.sub.18][H.sub.17]F[N.sub.4]OS.1/2[H.sub.2]O Calculated/Found (%): C: 59.16/59.34, H: 4.96/4.87, N: 15.33/15.18, S: 8.77/8.74.

Anti-biofilm activity

The anti-biofilm capacities of the substituted-amide derivatives were examined using the biofilm assay. The overnight culture of P. aeruginosa PA01 strain was diluted to an O[D.sub.600] of 0.02. 1mL aliquots of the diluted cultures were allocated in polystyrene tubes and incubated at 32[degrees]C for 10 h. Nonadherent cells were removed. The biofilms were dyed with 1 ml of crystal violet (0.3%) and the absorbance was measured at 570 nm using a spectrophotometer (Truchado et al. 2009).

Swarming motility assay

The swarming motility was measured as described by Rashid et al. (2000). Five microliters of PA01 cultures were inoculated onto the surface of swarm plates containing Bacto Agar (0.5%), Nutrient Broth and glucose (1%). This was completed both in the presence and absence of the test compounds and then incubated overnight at 37[degrees]C for 24 h.

Cells and viruses

Madin-Darby canine kidney (MDCK) cells were used for plaque inhibition assays. The cells were grown in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal calf serum (Gibco), penicillin G (100 U/mL) and streptomycin (100 [micro]g/mL), and maintained in a humidified atmosphere containing 5% C[O.sub.2] at 37 [degrees]C. The antiviral activities of the synthesized compounds were investigated on influenza A virus, strain A/WSN/33 (H1N1). The viruses were grown in the allantoic cavity of 10 day-old chick embryos at 35.5 [degrees]C for 48 h. The allantoic fluid was clarified by centrifugation at 3,000g for 10 minutes, passed through 0.45 [micro]m sterile filter, and the filtrate was stored in small aliquots at 80 [degrees]C

Plaque inhibition assay

For the plaque inhibition assay, confluent monolayer cultures of MDCK cells in 12-well plate were washed twice with DMEM (-), and infected with influenza viruses at the appropriate multiplicity of infection (moi). After adsorption for 30 min at 37 [degrees]C, virus inoculums were completely removed, and the cell monolayers were overlaid with a maintenance medium (DMEM containing 0.6% agarose, 0.2% Bovine Serum Albumin and 4 mg/mL TPCK-treated trypsin). In test conditions, synthesized compounds were added to a maintenance medium at defined concentrations. The plates were incubated at 34 [degrees]C for 2-3 days, and plaques were visualized by staining the cells with amido black (Turan et al. 1996; Guveli et al 2018).


In the present study, six amide derivatives (compounds 1-6) were synthesized from p-aminophenylacetic acid. The synthetic route of compounds is represented in Scheme 1.

Their purity was proven by TLC, HPLC and elemental analyses. Also, their structures were elucidated by FT-IR, [.sup.1]H-NMR, [.sup.13]C-NMR and MS spectral methods. IR absorption bands due to amide C=O and aromatic C-F stretching bands were recorded at 1726-1645 and 1233- 1159 [cm.sup.-1], respectively. According to the [.sup.1]H-NMR spectra, the -C[H.sub.2]- and amide N-H peaks were observed at 3.22-4.13 and 10.23-10.27 ppm as singlets, in turn. In addition, the [.sup.13]C-NMR spectra exhibited resonances at 164.26-168.78 assigned for amide C=O. Aside from these, the elemental analysis and MS spectral data results were in accordance with the compounds structures.

The synthesized compounds' anti-biofilm capacities were confirmed by the biofilm assay Biofilm formation causes serious problems in both medicine and industry Biofilm-associated bacteria are more resistant to antimicrobials than planktonic cells. We tested the effects of compounds 1-6 on biofilm formation of P. aeruginosa PA01. According to the results these molecules inhibited biofilm formation by 8.7-25.6% at 200 [micro]M concentration. Among the tested compounds, compound 3 was found to be the most active one, reducing the biofilm formation by 25.6% in P. aeruginosa PA01 at a concentration of 200 [micro]M. We also performed a swarming motility assay. Swarming motility plays an important role in the early stages of biofilm development and antibiotic resistance. The swarming motility of P. aeruginosa PAO1 was assayed both in the presence and absence of test compounds. Swarming plates were supplemented with 200 [micro]M synthesized compounds. The treatment of P. aeruginosa PAO1 with these compounds resulted in reductions in swarming motility by 18.3-33.8% (Table 1, Figure 1).

The antiviral activity of compounds 1-6 were revealed by using plaque inhibition assays on influenza A viruses. Among the synthesized compounds tested on influenza virus plaque formation, Compound 6 showed an inhibitory effect (Figure 2). Plaque formation by influenza A viruses was almost completely inhibited by this compound at concentrations of 10 [micro]g/mL. Compound 6 did not show any cytopathic effect on MDCK cells at 5-20 [micro]g/mL (Figure 2).

Influenza viruses are enveloped viruses having a negative polarity and a segmented RNA genome. Despite the simple structure, they have multi-stage complex replication strategies. Therefore, it is difficult to reach a firm conclusion about the action mechanism of compound 6 on the influenza virus replication based on the results of the plaque inhibition assay. The research will continue to elucidate the mode of action of this molecule. Compound 6 differs from the other 5 compounds in terms of thiadiazole group. This group may therefore be considered as important for antiviral activity (Gan et al. 2017).


A series of amide derivatives (1-6) were obtained from p-aminophenyl acetic acid, characterized by several spectroscopic methods (IR, NMR, MS) and elemental analysis. They were also evaluated for their anti-biofilm and antiviral effects. The results suggested that compounds 1-6 could be used as antibiofilm agents in combination with conventional antibiotics to increase the efficiency of current antimicrobials. Also, depending on antiviral activity studies, it can be said that compound 6 has potential as an anti-influenza virus agent. Further studies are in progress.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept--ST., S.K.; Design--ST., K.T., S.U., S.K., G.B.T.; Supervision--K.T., S.K., G.B.T.; Resource--ST., K.T., S.U., S.K., G.B.T.; Materials--ST., K.T., S.U., S.K., G.B.T.; Data Collection and/or Processing--ST., K.T., S.U., S.K., G.B.T.; Analysis and/or Interpretation--ST., K.T., S.U., S.K., G.B.T.; Literature Search--ST., K.T., S.K., G.B.T.; Writing--ST., K.T., S.K., G.B.T.; Critical Reviews--K.T., S.K., G.B.T.

Conflict of Interest: The authors have no conflict of interest to declare.

Financial Disclosure: This study was financially supported by the Marmara University Scientific Research Committee (Project No: SAG-C-DRP-070617-0343).


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Sevda Turk (1)[iD], Kadir Turan (2)[iD], Seyhan Ulusoy (3)[iD], Sevgi Karakus (1*)[iD], Gulgun Bosgelmez-Tinaz (2)[iD]

(1) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34668, Istanbul, Turkey

(2) Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Marmara University, 34668, Istanbul, Turkey

(3) Department of Biology, Faculty of Arts and Sciences, Suleyman Demirel University, 32260, Isparta,Turkey

Cite this article as: Turk S, Turan K, Ulusoy S, Karakus S, Bosgelmez-Tinaz G. (2018) Synthesis, Characterization and biological activity studies on amide derivatives. Istanbul J Pharm 48 (3): 76-81.

This study was presented at the "V. International Multidisciplinary Congress of Eurasia (IMCOFE'18)", "24-26 July 2018, "Barcelona-Spain".

Address for Correspondence :

Sevgi Karakus, e-mail:

Received: 12.09.2018

Accepted: 25.10.2018

DOI: 10.26650/IstanbulJPharm.2018.18007
Table 1. Effect of compound 1-6 derivatives on the biofilm formation
and swarming motility of P. aeruginosa PA01 strain. The data represents
the averages from the results of three independent experiments.

Biofilm Formation  Swarming Motility
Inhibition (%)     Inhibition (%)

1  13.9            28.9
2   8.7            22.4
3  25.6            18.3
4  13.0            31.4
5  19.0            32.2
6  17.3            33.8
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Title Annotation:Original Article
Author:Turk, Sevda; Turan, Kadir; Ulusoy, Seyhan; Karakus, Sevgi; Bosgelmez-Tinaz, Gulgun
Publication:Journal of the Faculty of Pharmacy of Istanbul University
Date:Dec 1, 2018
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