Synthesis, characterization and acute toxicity of new Schiff base derived from phenylethyl amine and 2-hydroxy naphthaldehyde European Journal of Chemistry 10 (1) (2019) 26-29 European Journal of Chemistry View Journal Online View Article Online Synthesis, characterization and acute toxicity of new Schiff base derived from phenylethyl amine and 2-hydroxy naphthaldehyde Ibtihal Hassan Hatim , Wasfi Aboud Al-Masoudi * and Rashad Fadhil Ghadhban Department of Physiology, Pharmacology and Chemistry, College of Veterinary Medicine, University of Basrah, Basrah, 61001, Iraq ibtihalhassan9191@gmail.com (I.H.H.), almasoudi59@yahoo.com (W.A.A.-M.), rashadfadhil@gmail.com (R.F.G.) * Corresponding author at: Department of Physiology, Pharmacology and Chemistry, College of Veterinary Medicine, University of Basrah, Basrah, 61001, Iraq. Tel: +964.40.7809830756 Fax: +964.40.412714 e-mail: almasoudi59@yahoo.com (W. A. Al-Masoudi). 10.5155/eurjchem.10.1.26-29.1790 Received: 16September 2018 Received in revised form: 01 November 2018 Accepted: 10 November 2018 Published online: 31 March 2019 Printed: 31 March 2019 There is an urgent need for the design and development of new and safer drugs, this has attracted organic chemists to synthesize new compounds with potential of biological and chemotherapeutic activities. Here we report, the condensation of phenylethylamine with 2- hydroxy naphthaldehyde yielded Schiff base derivative in good yield. Characterization of synthesized compound was carried by elemental analysis, IR, 1H-, 13C- and HSQC-NMR spectroscopy. The toxicity of the synthesized compound was determined using Balb/c mice model. Dixon’s up and down method was found to have an LD50 of 827.2 mg/kg of body weight, moderate toxicity. Schiff base HSQC-NMR Acute toxicity IR spectroscopy Phenylethylamine 2-Hydroxy naphthaldehyde Cite this: Eur. J. Chem. 2019, 10(1), 26-29 Journal website: www.eurjchem.com 1. Introduction Phenylethylamine or β-phenethylamine, is an organic compound and a natural mono amine alkaloid, a trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects [1]. Phenylethylamine functions as a neuromodulator or neuro- transmitter in the mammalian central nervous system [2]. The chemistry of the carbon-nitrogen double bond plays a vital role in progresses of chemistry science. Schiff base exhibit a plethora of bioactivities viz, antitubercular, anticancer, anti- bacterial, antifungal, analgesic, CNS depressant, anti-inflam- matory, anticonvulsant, insecticidal, plant growth inhibitors, antimouse hepititis virus (MHV), inhibition of herpes simplex virus type 1 (HSV-1) and adenovirus type 5 (Ad5), antimosqito larvae and herbicidal activities [3,4]. Schiff bases include industrial synthesis of high value lifesaving beta lactam antibiotics from class of penicillin’s and cephalosporin’s. Schiff bases are used as starting material for the synthesis of various bioactive heterocyclic compounds like 4-thiazolidinones, 2-azetidinones, benzoxazines and forma- zans. Schiff-base compounds have been used as fine chemicals and medical substrates [5]. El-Ajaily et al. were prepared Schiff base derived from phenylethylamine and salicyldehyde as precursor techniques in coordination chemistry [6]. The aim of present work is to synthesis and investigate the structure of the Schiff base derived from phynylethylamine and 2-hydroxy naphthaldehyde and characterized by using physical and spectral techniques, including elemental analysis, IR and NMR. Acute toxicity of synthesized compound was performed. 2. Experimental 2.1. Instrumentation The IR spectra were recorded in the range 4000-200 cm-1 on a Pye-Unicam SP3-300 spectrometer using KBr discs at Department of Chemistry, College of Education for Pure Sciences, University of Basrah, Basrah, Iraq. 1H, 13C-NMR and 2D HSQC-NMR spectra were measured on a Bruker at 600 MHz, with TMS as internal reference at Konstanz University, Germany. Melting point was measured by a Philip Harris melting point apparatus at College of Veterinary Medicine, University of Basrah, Basrah, Iraq. ABSTRACT RESEARCH ARTICLE KEYWORDS European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2019 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. http://dx.doi.org/10.5155/eurjchem.10.1.26-29.1790 http://dx.doi.org/10.5155/eurjchem.10.1.26-29.1790 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.1.26-29.1790&domain=pdf&date_stamp=2019-03-31 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.10.1.26-29.1790 mailto:ibtihalhassan9191@gmail.com mailto:almasoudi59@yahoo.com mailto:rashadfadhil@gmail.com mailto:almasoudi59@yahoo.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.1.26-29.1790&domain=pdf&date_stamp=2019-03-31� Hatim et al. / European Journal of Chemistry 10 (1) (2019) 26-29 27 Table 1. Dixon values. + K represented serial tests as follows Second part of serial OOOO OOO OO O OXXX -0.154 -0.154 -0.154 -0.157 XOOO OXXO -0.860 -0.860 -0.861 -0.878 XOOX OXOX 0.741 0.741 0.747 0.701 XOXO OXOO 0.182 0.181 0.169 0.084 XOXX OOXX 0.381 0.380 0.372 0.305 XXOO OOXO -0.142 -0.144 0.169 -0.305 XXOX OOOX -1.549 1.544 1.500 1.288 XXXO OOOO 1.000 0.985 0.897 0.555 XXXX Second part of serial XXXX XXX XX X - K represented serial results as follows * LD50 = XF + K × d = Median lethal dose; XF = Last dose used in the experiment; K = Factor of change from the table; d = Difference between doses. NH2 OH O H Gla. HOAc OH NH Scheme 1. Preparation of 1-((phenethylimido)methyl)naphthalen-2-ol. 2.2. Acute toxicity (LD50) study The lethal dose (50%) of the synthesized compound in Balb/c mice was determined using up-and-down method [7]. Male and female mice aged 4-6 weeks were injected intraperitoneally with different doses of the synthesized compound after conducting series of test levels. With equal spacing between doses, a series of trails were carried out using this method: increased dose following a negative response and decreased dose following a positive response. Testing continued until chosen “nominal” sample size was reached. LD50 were determined after reading final result (response- dead (X) or non-response alive (O), then the following equation was applied LD50 = XF + Kd. The estimate of LD50 is XF + Kd, where XF is the final test level and K is the interval between dose levels. d is the tabulated value (Table 1). 2.3. Synthesis 2.3.1. Synthesis of 1-((phenethylimido)methyl)naphthalen- 2-ol Phenyl ethyl amine (3.36 mmol, 0.4 g) in 25 mL ethanol was added to hot ethanolic solution of 2-hydroxy naphthaldehyde (3.36 mmol, 0.58 g), two drops of glacial acetic acid was added and resulting solution was refluxed for 3 h and then lift overnight in refrigerator. The solid product obtained was filtered and washed with acetone and the final product was recrystallized by using chloroform: ethanol (8:2, v:v) to yield yellow-green crystals of 1-[(2-phenylethyl) carbonoimidoyl]naphthalene 2-ol. Color: Pale Yellow. Yield: 80%. M.p.: 192-194 °C. FT-IR (KBr, ν, cm-1): 3300 (OH), 3068 and 3024 (CH-Ar-H); 2929 and 2858 (CH-Aliph.), 1639-1537 (C=C, C=N). 1H NMR (600 MHz, CDCl3, δ, ppm): 2.92-2.96 (t, 2H, CH2-Ar), 3.72-3.74 (t, 2H, CH2-N), 6.81-7.57 (m, 11H, Ar-H), 8.39 (s, 1H, CH=N), 14.36 (s, 1H, OH). 13C NMR (150 MHz, CDCl3, δ, ppm), 37.40 (1C, CH2-Ar), 54.72 (1C, CH2-N), 106.48- 137.96 (15C, C-Ar), 158.01 (1C, CH=N), 176.47 (1C, C-OH). Anal. calcd. for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 83.14; H, 6.51; N, 5.26%. 3. Results and discussion 3.1. Chemistry The present work describes the synthesis of some Schiff base by reaction of ethyl phenyl amine with 2-hydroxy naphthaldehyde in 1:1 ratio to produce the Schiff base derivatives, Scheme 1, in good yield. IR spectra for compound displayed common features in certain regions and characteristic bands in the fingerprint and other regions. The IR spectra confirm the presence of the azomethine group (- CH=N) stretching with a sharp region around 1537 cm-1. 1H NMR spectra of synthesized compound show signal due to azomethine proton (CH=N) at δ 8.39 ppm, 1H NMR spectra of Schiff base show a triplet at the range δ 2.92-2.96 ppm due to CH2-Ar and triplet at range δ 3.72-3.74 ppm due to CH2-N group. The region at δ 6.81-7.57 ppm due to aromatic protons. 1H NMR spectra of synthesize compound show singlet at δ 14.36 ppm due to phenolic OH. The 13C NMR spectrum of all compounds was measured in DMSO-d6. 13C NMR spectra gave further support to the formation of these compounds. The spectra revealed the presence of –CH=N group around δ 158.01 ppm. The signal at δ 176.47 ppm due to C-OH [8]. These spectra data sports the structure of synthesized compound. The 1H, 13C HSQC NMR spectrum [9] of synthesized compound showed a cross peak at δH/δC = 14.35/178.4 ppm, belonged to Ar-OH. The cross peak at δH/δC = 8.39/158 ppm due to azomethine group (CH=N). Thus, the correlation of protons and carbon in aromatic rings such as, δH/δC = 7.57/137, 7.48/129 ppm and other positions can be assigned to the protons and carbon atoms of the aromatic rings [8], while the cross peak at δH/δC = 3.73/54.7 and δH/δC = 2.93/37.4 ppm can be attributed to methylene groups, Figures 1 and 2. 3.2. Determination of the 50% of lethal dose (LD50) of the synthesized Schiff base in-vivo The LD50 of synthesized new compound was detected in the mice by using the “up-and-down” procedure described by Dixon [7] in the experiment we using 10 animals of white mice 7-8 weeks in age, Graded doses of injection to each one animal, a series of concentrations (600, 650, 700, 750 mg/kg.bw) in 0.1 mL dimethyl sulfoxide (DMSO) were administered and chosen with equal spacing (concentrations) between doses [10]. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.26-29.1790 28 Hatim et al. / European Journal of Chemistry 10 (1) (2019) 26-29 Figure 1. HSQC-NMR spectrum of 1-[(2-phenylethyl)carbonoimidoyl]naphthalen-2-ol. Figure 2. HSQC-2 NMR spectrum of 1-[(2-phenylethyl)carbonoimidoyl]naphthalen-2-ol. Mortality was recorded after 24 h that each one animal treated with one dose and after 24 h was recorded as O if the animal lives and then increased the treated dose. While X recorded for the death of animal and then decreased the dose according for the result of the animal the code which formed as being (OOOX)and according for Dixon value was get and the LD50 was determined according to the formula employed by Dixon (D50 = Xf + Kd; LD50 = 750 + 1.544 × 50 = 827.2 mg/kg.bw). 4. Conclusion In conclusion a Schiff base of phenyl ethyl amine and 2- hydroxy naphthaldehyde compound was prepared by convenient method. Elemental analysis (CHN) and spectros- copic characterization of synthesized compound such as, infrared and nuclear magnetic resonance spectroscopy were supported the structure of synthesized compound. The synthesized compound appears to be safe with moderate toxicity. It’s LD50, calculated by Dixon, is 0.827 g/kg of body weight, and the safe dose was less than 0.08 g/kg. These results are promoted us to continue the study such as, physiological parameters and histopathological study to complete the pharmaceutical studies. Acknowledgements The authors are grateful to Prof. Najim Abood Al-Masoudi (Konstanz University, Germany) for providing the NMR spectroscopy. We are also grateful to Department of Physiology, Pharmacology and Chemistry, College of Veterinary Medicine, Al-Basrah University, Basrah, Iraq for providing the facilities. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered according to committee on the ethics of dealing with laboratory animals. Sample availability: Samples of the compounds are available from the author. ORCID Ibtihal Hassan Hatim http://orcid.org/0000-0001-9721-6024 Wasfi Aboud Al-Masoudi http://orcid.org/0000-0002-5932-0311 Rashad Fadhil Ghadhban http://orcid.org/0000-0003-3518-6653 References [1]. Glen, R. H.; Peter, J. V.; Annette, E. F. Drugs and society, 9th Edition, Jones & Bartlett, 2005. [2]. Sabelli, H.; Mosnaim, A.; Vazquez, A.; Giardina, W.; Borison, R.; Pedemonte, W. Biol. Psychiatry 1976, 11 (4), 481-524. [3]. Yang, H.; Neff, N. J. Pharmacol. Exp. Ther. 1973, 187(2), 365-371. [4]. Suzuki, O.; Katsumata, Y.; Oya, M. J. Neurochem. 1981, 36(3), 1298- 1301. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.26-29.1790 http://orcid.org/0000-0001-9721-6024 http://orcid.org/0000-0002-5932-0311 http://orcid.org/0000-0003-3518-6653 Hatim et al. / European Journal of Chemistry 10 (1) (2019) 26-29 29 [5]. Shah S. N.; Basser M. A. Asian J. Pharm. Clin. Res. 2012, 5(3), 228-232. [6]. El-Ajaily, M. M.; Abou-Krisha, M.; Etorki, A. M.; Alassbal F. S.; Maihub, A. A. J. Chem. Pharm. Res. 2013, 5(12), 933-938. [7]. Dixon, W. J. Ann. Rev. Toxicol. 1980, 20, 441-462. [8]. Al-Masoudi, W. A.; Rana, A. F.; Al-Asadi, R. H.; Hazim, S. J. Eur. J. Chem. 2016, 7(1), 102-106. [9]. Al-Rubaie, A. Z.; Al-Masoudi, W. A.; Al-Jadaan, S. A.; Ahmed, E. T. Int. J. Sci. Res. 2009, 18, 11-16. [10]. Al-Masoudi, W. A.; Al-Dewan, M. A.; Ishraq, J. H. Der Pharma Chem. 2015, 7(9), 1-5. Copyright © 2019 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.26-29.1790 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. Acute toxicity (LD50) study 2.3. Synthesis 2.3.1. Synthesis of 1-((phenethylimido)methyl)naphthalen-2-ol 3. Results and discussion 3.1. Chemistry 3.2. Determination of the 50% of lethal dose (LD50) of the synthesized Schiff base in-vivo Acknowledgements Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField20: PrintField21: PrintField22: PrintField23: