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Design, Synthesis and Antioxidant Evaluation of Certain New Phthalazine Derivatives

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Design, Synthesis and Antioxidant Evaluation of Certain New Phthalazine Derivatives Available online a t www.derpharmachemica.com Scholars Research Library Der Pharma Chemica, 2014, 6(3):89-102 (http://derpharmachemica.com/archive.html) ISSN 0975-413X CODEN (USA): PCHHAX Design, synthesis and antioxidant evaluation of certain new phthalazine derivatives Waleed A. Bayoumi 1* , Alaa-Eldin M. Barghash 1, Magdy M. Gineinah 1,2, Mohamed A. Massoud 1 and Ali M. Abdelal 1 1Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia _____________________________________________________________________________________________ ABSTRACT In this research, certain phthalazine scaffolds were designed and synthesized. Hyperidzation with pharmacophoric moieties possessing antioxidant activityincluding glycine hydrazides and derivatives(10 , 11 and 12 ), amide derivatives ( 19 ), hydrazone ( 7, 14 and 18 ), Schiff’s base derivatives( 6a-c, 13a-c and 20a-c) and N-phtalimido derivatives(8a-c, 15a-c and 21a-c);was achieved.In addition, a synthetic comparison between O- and N-alkylation products of phthalazinone ring systemwas studied.All the newly synthesized compounds were screened for their in vitro antioxidant activity through ABTS antioxidant assay. Compound 5 showed the best activity, whereas compound 12 showed moderate activity. The rest of compounds showed weak to mild activity. Keywords: Phthalazines; ABTS; Antioxidant _____________________________________________________________________________________________ INTRODUCTION Phthalazines are unique well-known class of nitrogen-containing heterocyclic compounds, possessing versatile chemical, industrial and biological properties. Among the important pharmacological activities exhibited by phthalazine derivatives are: anti-inflammatory activity [1,3],PDE4 inhibitors [4-6], antihypertensive [7],vasodilator [8], cytotoxic [9],antitumor [10], anticancer [11],anticonvulsant [12],antiasthmatic [13], vasorelaxant [14],antibacterial [15], and antifungal activity [16]. In general, little efforts has been directed to evaluation of the effect of the 2,3-disubstituted-1-phthalazinones or 2,3- disubstituted-1,4-phthalazinediones on alteration of the pharmacological activity. Considerably less effort has been devoted to the modification of the benzene nucleus of the phthalazine in general [17-19].A library model for phthalazine essential skeleton for a variety of pharmacological activity is illustrated ( Figure 1 ). 89 89 www.scholarsresearchlibrary.com Waleed A. Bayoumi et al Der Pharma Chemica, 2014, 6 (3):89-102 ___________________ __________________________________________________________ Figure 1.A library model for phthalazine scaffold Antioxidants are molecules, natural, or synthetic, capable to interact with free radicals and stop their chain reactions before essential vital molecules are damaged. Owing to the contribution and implication of oxidative stress in many human diseases, antioxidants are intensively studied in medicinal chemistry and pharmacology. Their main use is for treatment, prevention, or protection against many disease conditions [20,21]. Diverse biological and pharmacological activities of phthalazines were reported by many workers. To the best of our knowledge, literature survey did not reveal antioxidant evaluation. Therefore, the first objective of this work to investigate and evaluate the potential antioxidant activity of this class of compounds via design, synthesis, and in vitro antioxidant screening of selective representatives of phthalazine derivatives bearing pharmacophoric moieties. In this research, Introduction of a phenyl ring instead of R 1 in the library model in order to increase the lipophilicity, steric effect, and planarity, Modification of R by OR in 3 and by its isosteric NHR in 18 because of their polarity and their important crucial role in varying the pharmacological activity of such derivatives [22]. In addition, hybridization of the synthesized phthalazines scaffolds with potential pharmacophoric moieties possessing antioxidant activity, e.g. glycine and derivativesrs [23,24](10 , 11 and 12 ), Amide derivatives [25,26](19 ), Hydrazone [27,28](7, 14 and 18 ), Schiff’s base derivatives [29-31](6a-c, 13a-c and 20a-c), and N-Phtalimido derivatives [32]through ring expansion of N-phenylphthalimide into phthalazinedione derivative in 12 by incorporation of the glycine moiety, offering some flexibility to the heterocyclic ring (8a-c, 15a-c and 21a-c) was achieved to afford the designed target compounds. Figure 2.O- and N-Alkylation products of phthalazine From a chemical point of view, some of the synthesized compounds were designed for the aim of comparison between O-alkylation and N-Alkylation products of phthalazine. Alkylation of 4-hydroxyphthalazin-1(2 H)-one and its derivatives was studied sporadically, like the similar analogs of pyridone and quinolinone. Literature survey revealed that, alkylation of ambident tautomeric heterocyclic lactam-lactim or amide-imidic acid forms is a complex process. The alkylation product, either, O-alkylation, N-Alkylation, or a mix of O- and N-alkylation are varied according to (but without a well-defined rule): the more favored tautomeric form, the solvent and reagent used, the spatial demand of the alkylating agent, steric and/or electronic factors, and in favoring ring aromaticity.Therefore, the second aim of this work was to synthesize both O-alkylation (Scheme 1,2 ) and N-alkylation (Scheme 3,4 ) in the phthalazinone series. O-alkylation was accomplished via a direct method, whereas, a chemical evidence for N- alkylation was carried out through an indirect method (Figure 2). 90 90 www.scholarsresearchlibrary.com Waleed A. Bayoumi et al Der Pharma Chemica, 2014, 6 (3):89-102 ___________________ __________________________________________________________ MATERIALS AND METHODS Chemistry Melting points were determined on Fisher-Johns melting point apparatus and were uncorrected. Microanalyses were performed in the Micro Analytical Center, University of Cairo. IR spectra (KBr) were recorded on Mattson 5000 FT-IR spectrometer ( ν in cm -1), Micro Analytical Center, University of Cairo. 1H NMR spectra were recorded on Bruker Ac 250 FT NMR spectrometer (250 MH Z) in DMSO-d6 or CDCl 3 using TMS as internal standard, chemical shifts in ppm were expressed in δ units, Micro Analytical Center, University of Cairo. MS analyses were performed on JEOL JMS-600H spectrometer, Micro Analytical Center, University of Cairo. Reaction times were determined by using TLC on Silica gel plates 60 F 245 E. Merck, and the spots were visualized by U.V (366, 245 nm). Compounds: 4-hydrhoxy-2-phenylphthalazin-1(2 H)-one ( 1) [33], 4-chloro-2-phenylphthalazin-1(2 H)-one ( 16 ) [34] and 4-(1-hydrazonoethyl)aniline ( 17 ) [35] were prepared according to the published data. Potassium 4-oxo-3-phenyl-3,4-dihydrophthalazin-1-olate (2) Finely powdered potassium hydroxide (2.81 g, 50 mmol) was added to isopropyl alcohol (80 mL) and vigorously stirred until a clear solution is obtained. Compound 1 (11.91 g, 50 mmol) was then added in small portions with continuous stirring for 1 h. The formed precipitate of the potassium salt was then filtered, washed with ice-cold isopropyl alcohol (20 mL), and dried to afford 12.15 g of the titled compound. White crystals, mp >300 °C, yield 88%. Analysis for C 14 H9KN 2O2 (276.33), Calc.: C, 60.85; H, 3.28; N, 10.14. Found: C, 60.73; H, 3.35; N, 10.31. 2-(4-Oxo-3-phenyl-3,4-dihydrophthalazin-1-yloxy)acetic acid (3) A mixture of 2 (2.76 g, 10 mmol), chloroacetic acid (0.95 g, 10 mmol), and absolute ethanol (25 mL) was refluxed with continuous stirring for 10 h. The reaction mixture was filtered while hot and allowed to cool to rt, and then cooled in ice-water. The precipitated solid was filtered, air-dried, and recrystallized from aqueous ethanol. White crystals, mp 153-155 °C, yield 60%. Analysis for C 16 H12 N2O4 (296.28), Calc.: C, 64.86; H, 4.08; N, 9.46. Found: C, 64.65; H, 4.33; N, 9.25. IR (KBr): 3300-2500 (-COOH), 3017 (CH, aromatic), 2980 (CH, aliphatic), 1661 (-COOH), 1 1601 (N-C=O), 1080 (O=C-O). H NMR (DMSO-d6): δ 4.62 (s, 2H, OCH 2), 7.23-8.16 (m, 9H, Ar-H). Ethyl 2-(4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yloxy)acetate (4) A mixture of 3 (2.96 g, 10 mmol), absolute ethanol (50 mL), and concentrated sulfuric acid (1 mL) was refluxed for 24 h then allowed to cool to rt and further in ice-cold water. A cold solution of sodium bicarbonate (5%) was added gradually until effervescence ceased. The solid obtained was collected by filtration, suspended in sodium bicarbonate solution (5%, 20 mL) and stirred for 10 min to remove unreacted acid. The precipitate was collected by filtration, washed thoroughly with cold water, dried, and recrystallized from ethyl acetate to give 2.43 g. white crystals, mp 90-92 °C, yield 60%. Analysis (%) for C 18 H16 N2O4 (324.33), Calc.: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.97; H, 4.58; N, 8.62. IR (KBr): 3061 (CH, aromatic), 2987 (CH, aliphatic), 1735 (O=C-O), 1660 (N-C=O), 1 1229, (O=C-O), 1180 (C-O-C). H NMR (CDCl 3): δ 1.15 (t, 3H, OCH 2CH3), 4.15 (q, 2H, OCH2CH 3), 4.82 (s, 2H, OCH 2CO), 7.25-8.36 (m, 9H, Ar-H). 2-(4-Oxo-3-phenyl-3,4-dihydrophthalazin-1-yloxy)acetohydrazide (5) A mixture of 4 (3.24 g, 10 mmol) and hydrazine hydrate (5 mL, 99%) in ethanol (25 mL) was refluxed for 8 h. The formed precipitate was collected by filtration, washed with ethanol, crystallized from isopropyl alcohol, and dried to afford 2.64 g. White crystals, mp 180-182 °C, yield 85%. Analysis for C 16 H14 N4O3 (310.31), Calc.: C, 61.93; H, 1 4.55; N, 18.06. Found: C, 62.17; H, 4.33; N, 17.79. H NMR (DMSO-d6): δ 4.44 (s, 2H, OCH 2), 7.21-8.24 (m, 9H, Ar-H), 9.50 (s, 1H, NH, D 2O exchangeable), NH 2 protons seemed to be exchanged by the solvent.
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