283 This work is licensed under a Creative Commons Attribution 4.0 International License IHJPAS. 37 (1) 2024 Ibn Al-Haitham Journal for Pure and Applied Sciences Journal homepage: jih.uobaghdad.edu.iq PISSN: 1609-4042, EISSN: 2521-3407 1Mustafa Moaied Rabea* 2Muna Ismael Khalaf 3Farouk Abdulla Kandil 1,2Department of Chemistry, College of Sciences, University of Baghdad, Baghdad, Iraq. 3Chemistry Department, College of Science, Damascus University, Damascus, Syria. *Corresponding author: mostafa.moaid1205m@sc.uobaghdad.edu.iq Abstract The research study included the synthesis of a new series of heterocyclic derivatives containing the antibiotic Levofloxacin. The first way provides for the reaction of Levofloxacin with thionyl chloride in benzene as a solvent to give an acid chloride derivative. A new class of acid hydrazide synthesized from Levofloxacin was studied. Schiff bases were produced via the reaction of acid hydrazide with substituted aromatic ketones in methanol. The next stage involved the response of Schiff bases with thioglycolic acid and mono chloroacetic acid in DMF to produce derivatives of the antibiotic levofloxacin that have five heterocyclic members, including the derivatives thiazolidine-4-one and oxazolidine-5-one. The FTIR, 1HNMR, and 13CNMR spectra methods were used to confirm the structures of newly synthesized compounds. Also, the antioxidant properties of the synthetic compounds were evaluated in vitro. According to this study, levofloxacin-derived compounds have higher antioxidant capacities than ascorbic acid (vitamin C), and the medication also acts as an anti-inflammatory for respiratory infections. Keywords: Levofloxacin, Thiazolidin-4-one, Oxazolidinone, Schiff bases, Anti-oxidant activity. Received 26 January 2023, Received 4 March 2023, Accepted 14 March 2023, Published 20 January 2024 Modification, Characterization of New Thiazolidinone and Oxazolidinone Derived from Levofloxacin and Evaluation of Anti-oxidant doi.org/10.30526/37.1.3240 https://creativecommons.org/licenses/by/4.0/ https://jih.uobaghdad.edu.iq/index.php/j/index#1609-4042 https://jih.uobaghdad.edu.iq/index.php/j/index#2521-3407 mailto:mostafa.moaid1205m@sc.uobaghdad.edu.iq https://orcid.org/0000-0002-2869-0176 mailto:alsaademustafa7@gmail.com https://orcid.org/0000-0001-6086-153X mailto:muna.i@sc.uobaghdad.edu.iq https://orcid.org/0000-0003-4021-3388 mailto:Farouk-k@windowslive.com IHJPAS. 37 (1) 2024 284 1. Introduction Levofloxacin is a fluoroquinolone antibiotic used to treat various conditions, including allergies, prostatitis, and urinary tract infections. Studies show that the antibiotic Levofloxacin kills bacteria quickly while protecting human DNA by acting as a DNA synthesis inhibitor in bacterial cells. Levofloxacin has demonstrated anticancer action against various cancer cells, including breast and lung cancer cells, with cell cycle arrest occurring most frequently in the S and G2 phases of progression [1,2]. As a result, many anticancer fluoroquinolones differ from clinical antibacterial fluoroquinolone in that they have nitrogen-containing rings on the 7-position and the 2-position, like piperazine. Additionally, alterations for the carboxylic group at the 3-position were not documented [2,3]. This group was modified with heterocyclic derivatives and showed higher antioxidants than vitamin C. The most frequent heteroatoms are (N, O, and sulfur S) [4,15]. Heterocyclic compounds are organic compounds with at least one hetero atom and are cyclic. Heterocyclic compounds are among the most influential families of organic chemicals used in various biological disciplines because of their activity in multiple diseases. It has been used to create anticancer pharmaceuticals [5], anti-fungal [6], antioxidants [7] and anti-microbial [8]. Hugo Schiff was the first to report Schiff's bases in 1864. In principle, it is produced when an aldehyde or ketone is combined with the primary amine [9]. These compounds are also known as imine and azomethine; numerous heterocyclic compounds have been investigated to develop drug-like molecules. Thiazolidin-4-one and Oxazolidin-4-one [10,18] derivatives, among others, have been playing a significant role in pharmaceutical chemistry. 2. Materials and Methods The melting points of the prepared compounds were obtained using open glass capillaries by SMP10 digital. Shimadzu FTIR-8400 Fourier Transform Infrared (FTIR) Spectrophotometer was used to record the FTIR spectra as a KBr disc, and Bruker Bio Spin instrument was used to record the 1H-NMR MHz and 13C-NMR spectra at the University of Basra in Iraq. 2.1 Synthesis of acid chloride derivative (1) [11] Levofloxacin (0.5 g,1.3 mmol) was taken with (0.5 mL) of thionyl chloride in the presence of dry benzene (15 mL) and was refluxed for 4 hours evaporated the solvent and washed with diethyl ether. The products were collected as crystals. Physiochemical properties are shown in Table 1. 2.2 Synthesis of acid hydrazide derivative (2) [12,19] In a round bottom flask, Acid chloride derivative (1) (0.5 g,1.3 mmol) was dissolved in 10 mL of methanol as a solvent. An excess of hydrazine hydrate (1.5 mL, 99%) was added to the reaction mixture and refluxed for 8 hours. The solvent was evaporated, and the product was washed with Diethyl ether and collected as crystals. Physiochemical properties as shown in Table 1. 2.3 Synthesis of Schiff bases derivatives (3-5) [13,20-22] A mixture of acid hydrazide (0.5 g, 0.0013 mmol) and various aromatic ketones [p-bromo Acetophenone, p-Chloro Acetophenone, p-amino Acetophenone] (0.0013 mol) in methanol (20 mL) and few drops of GAA was refluxed for 8 hours; the precipitate was filtered, washed with diethyl ether to give the final product. The physical properties are listed in Table 1. IHJPAS. 37 (1) 2024 285 2.4 Synthesis of oxazolidine-4-one derivatives (6-8) [10,23] To a well-stirred mixture of chloroacetic acid (0.0013 mmol) and drops of Et3N as a catalyst, Schiff bases [3-5] (0.0013 mmol) in DMF (10 mL) were added. After 35 hours of refluxing, the mixture was put into freezing water to produce the final result. The physical properties are listed in Table 2. 2.5 Synthesis of thiazolidine-4-one derivatives (9-11) [10,17,24] A mixture of Schiff bases [3-5] (0.0013 mmol) and an excess of 2-mercapto acetic acid (0.0026 mmol) in DMF was refluxed for 35 hours. The solvent was evaporated, and the residue was neutralized with 5% Na2CO3 solution to remove excess 2-mercapto acetic acid. The reaction mixture was poured into ice water to give the final product. The physical properties are listed in Table 3. Table 1. The physical characteristics and FT-IR data of the compounds 1-5 No. Physical properties Major FTIR Absorption cm-1 Structure M.P Yield % Color (N-H) (C-H) Arom. (C-H) Aliph (C=O) (C=N) (C=C) Other bands 1 236- 238 76 Yellow _ 3041 2975 2856 1768 1718 _ 1590 (C-O) 1294 2 280- 282 66 Green 3280 3080 2977 2839 1701 1683 _ 1556 (NH2) 3434 3298 3 250- 252 81 Yellow 3155 3050 2960 2856 1704 1662 1639 1560 / 4 298- 300 88 Off- white 3280 3160 2977 2962 1710 1689 1640 1575 5 295- 296 80 Pale Yellow 3218 3043 2948 2902 1697 1658 1641 1542 (NH2) 3431 3325 IHJPAS. 37 (1) 2024 286 Table 2. The physical characteristics and FT-IR data of the compounds 6-8 Table 3. The physical characteristics and FT-IR spectrum of the compounds 9-11 No. Physical properties Major FTIR Absorption cm-1 Structure M.P Yield % Color (N-H) (C-H) Arom (C-H) Aliph (C=O) (C=C) (C-S) Other bands 9 287-289 65 Brown 3112 3058 2954 2896 1620 1733 1566 655 10 257-259 63 Dark Brown 3180 3089 2981 2846 1683 1703 1590 713 11 277-278 70 Dark Yellow 3150 3037 2989 2813 1672 1712 1602 690 (NH2) 3425 3375 Anti-oxidant: [14,25-26] No. Physical properties Major FTIR Absorption cm-1 Structure M.P Yield % Color (N-H) (C-H) Arom (C-H) Aliph (C=O) (C=C) (C-O) Other bands 6 213-215 66 White 3170 3099 2972 2845 1620 1749 1580 1245 7 246-248 65 White 3113 3083 2952 2866 1697 1710 1588 1230 8 233-235 68 Off- White 3201 3037 2983 2833 1670 1716 1600 1280 (NH2) 3390 3444 IHJPAS. 37 (1) 2024 287 2.6 Preparation of the solutions of DPPH and the samples For each prepared compound, a stock solution was produced by dissolving 1 mg of the compound in 10 mL of methanol to create (100) ppm. This stock solution was diluted to make the other concentrations (100, 50, 25) ppm. The (2,2-diphenyl-1-picrylhydrazyl) (2 mg) was dissolved in 50 mL of methanol, and the solution was kept shielded from light by covering the test tubes with aluminum foil. Additionally, identical vitamin C concentrations (ascorbic acid) were generated. 3. Results and Discussion [27,28] Thiazolidin-4-one and Oxazolidin-5-one derivatives were synthesized from Schiff bases derived from Levofloxacin, including new five-member heterocyclic rings. The synthesis steps are summarized in Scheme 1. Scheme 1. Synthesis steps of new heterocyclic compounds derived from Levofloxacin drug Levofloxacin reaction with thionyl chloride (SOCl2) in Benzene as solvent. The FT-IR spectrum showed the appearance of ν(C=O) acid chloride and ketone at (1768) cm-1 and (1718) cm-1. It showed ν(C=C) at (1590) cm-1, FT-IR spectrum of this compound (2) indicates that (CO-Cl) at (1768) cm-1 was disappeared from the spectrum while the appearance of the asymmetric and symmetric stretching bands of (NH2) absorption bands at (3434) cm-1 asym., (3298) cm-1 sym., also the presence of a sharp band of ʋ (N-H) at (3280) cm-1, ʋ (C-H) aromatic at (3080) cm-1, ʋ (C- H) aliphatic at (2977, 2839) cm-1 and ʋ(C=O) at (1701, 1683) cm-1,1H-NMR and 13C-NMR are shown in Table 4 and 5. Figure 2-5. Schiff bases derivatives [3-5] are synthesized by the reaction of acid hydrazide derived from levofloxacin with substituted aromatic ketones in Me-OH as a solvent. The FT-IR spectra of IHJPAS. 37 (1) 2024 288 compounds [3-5] shown disappearance of amine absorption bands of acid hydrazide, while appearance of new bands of azomethine (C=N) at (1639-1641) cm-1, FTIR spectral data showed absorption at (C-H) aromatic bands at (3160-3043) cm-1, ν (C=O) amide absorption bands at (1689- 1658) cm-1 and (C=C) aromatic bands at (1575-1542) cm-1 spectrum. While the 1H- NMR spectral data for compound [5] appeared doublet signal at δ= 1.22 ppm (3H, -CH3-CH, CH3 in oxazine ring); singlet signal at δ= 2.23 ppm (3H, -CH3-N-); triplet signal at δ= 2.50-3.11 ppm (2H,-N-CH2-CH2-N-, 2CH2 in piperazine ring); multiplet signal at δ= 4.38 ppm (1H, -O-CH2-CH- ); singlet signal at δ= 4.94 ppm (1H, -NH2); while appeared multiplet signal at δ= 6.51-7.59 ppm (m, 5H, Ar-H); singlet signal at δ=8.92 ppm (1H, -CO-NH); at δ= 9.11 ppm (s, 1H, -N-CH=C(CO)2 and 13C-NMR spectral data are listed in Table 5 and Figure 6,7. Table 4. Compounds were characterized by 1H-NMR No. Structures Spectral data (1H-NMR) (ᵟppm) 1 1.39 (d, 3H, -CH3-CH- , CH3 in oxazine ring) ; 2.51 (s, 3H, CH3_N) ; 3-4(t, 2H, - NCH2CH2-N- , 2CH2 in piperazine ring ) ; 4.42 (d, 2H, -CH2-O) ; 7.60 ( s, 1H, Ar- H) ; 9:00 ( s, 1H, -N-CH=C(CO)2 ) 2 1.42 (d, 3H, -CH3-CH-, CH3 in oxazine ring) ; 2.21 (s, 3H, CH3_N) ; 3.27-3.56(t, 2H, -NCH2CH2N- , 2CH2 in piperazine ring) 4.42 (d, 2H, -CH2-O) ; 4.90 (s, 1H, -NH2) ; 7.49 ( s, 1H, Ar-H) ; 8:91 ( s, 1H, -N-CH=C(CO)2 ) ; 10.61 (s, 1H, -CO-NH) 5 1.22 ( d, 3H, -CH3-CH, CH3 in oxazine ring) ; 2.23 (s, 3H, -CH3-N-) ; 2.50-3.11 (t, 2H, -N-CH2-CH2-N- , 2CH2 in piperazine ring) ; 4.38 (m, 1H, -O-CH2-CH-) ; 4.94 (s, 1H, -NH2) ; 6.51_7.59 (m, 5H, Ar-H) ; 8.92 (s, 1H, -CO-NH) ; 9.11 (s, 1H, -N- CH=C(CO)2) 6 1.14 (d, 3H, -CH3-CH, CH3 in oxazine ring) ; 2.83 (s, 3H, -CH3-N-) ; 3.13-3.26 (t, 2H, -N-CH2-CH2-N- , 2CH2 in piperazine ring) ; 4.11 (s , 2H ,oxazolidin-4-one ring) ; 4.11-4.45 (m, 1H, -O-CH2-CH-) ;7.09-8.34 (m, 5H, Ar-H) ; 8.40 ( s, 1H, -N- CH=C(CO)2 ) ; 9.61 (s, 1H, -CO-NH) 10 1.44 (d, 3H, -CH3-CH , CH3 in oxazine ring) ; 2.27 (s, 3H, -CH3-N-) ; 3.37-3.44 (t, 2H, -N-CH2-CH2-N-, 2CH2 in piperazine ring) ; 4.13 (s , 2H ,thiazolidin-4-one ring) ; 4.37-4.60 (m, 1H, -O-CH2-CH-) ; 7.45-7.96 (m, 5H, Ar-H) ; 8.80 ( s, 1H, -N- CH=C(CO)2 ) ; 8.99 (s, 1H, -CO-NH) The Thiazolidin-4-one derivative was synthesized by cyclization reaction of Schiff base [3-5] with thioglycolic acid in DMF as a solvent, as shown in Scheme (1), to produce compounds [9-11]. These compounds' FTIR spectra showed the disappearance of azomethine group absorption bands at range (1639-1641) cm-1, show the bands of (C-S) thiazolidine ring absorption at range (655- IHJPAS. 37 (1) 2024 289 713) cm-1, while showed absorption band for (C-H) aromatic at (3037-3089) cm-1, ν (CO-NH) at (1620-1680) cm-1 and ν (C=O) at (1703-1733) cm-1 for thiazolidine ring, and ν (C=C) at (1566- 1602) cm-1 for aromatic bands. The 1H-NMR spectrum data for compound [10] as shown in fig-8, appeared doublet signal at δ= 1.44 ppm (3H, CH3-CH, CH3 in oxazine ring); singlet signal at δ= 2.27 ppm (3H, -CH3-N-); triplet signal at δ= 3.37-3.44 ppm (2H, -N-CH2- CH2-N-, 2CH2 in piperazine ring); singlet signal at δ= 4.13 ppm (2H, thiazolidin-4-one ring); while appeared multiplet signal at δ= 7.45-7.96 ppm (5H, Ar-H); singlet signal at δ= 8.80 ppm (1H,-N- CH=C(CO)2); 8.99 ppm (s, 1H, -CO-NH). Schiff bases [3-5] were reacted with Chloroacetic acid to synthesize the oxazolidin-5-one derivatives [6-8]. These compounds' FTIR spectra showed the disappearance of azomethine group absorption bands at (1639-1641) cm-1, with bands of (C=O oxazolidinone ring) at range (1230-1280) cm-1, absorption bands for (C-H Arom.) at (3037-3099) cm-1, ν (CO-NH) absorption bands at (1620-1680) cm-1 and ν (C=C Arom.) bands at (1566-1602) cm-1 spectrum. The 1H-NMR spectral data for compound [6] as shown in Figure 9, appeared doublet signal at δ= 1.44 ppm (3H, -CH3-CH , CH3 in oxazine ring); at singlet signal δ= 2.27 ppm (3H,-CH3-N-); triplet signal at δ= 3.37-3.44 ppm (2H, -N-CH2-CH2-N-, 2CH2 in piperazine ring); singlet signal at δ= 4.13 ppm (2H ,oxazolidin-4-one ring); while appeared multiplet signal at δ= 7.45-7.96 ppm (5H, Ar-H); at δ= 8.80 ppm (1H, -N-CH=C(CO)2) and signals at δ= 8.99 ppm (1H, -CO-NH). Table 5. Compounds were characterized by 13C-NMR [29,30] No. Structures Spectral data (13C-NMR) (ᵟppm) 1 C1/18.42 C2/40.35 C3/51.75 C4/55.75 C5/68.75 C6/103.79 C7/107.28 C8/120.92 C9/125.22 C10/130.99 C11/141.06 C12/146.58 C13/157.00 C14/176.85 C15/166.44 2 C1/20.37 C2/39.88 C3/46.49 C4/50.52 C6/55.20 C7/68.49 C8/103.59 C9/109.95 C10/120.09 C11/124.69 C12/131.24 C13/140.51 C14/144.80 C15/154.38 C16/166.69 C17/174.68 5 C1/18.37 C2/39.29 C3/48.10 C4/54.01 C5/55.33 C6/107.30 C7/113.64 C8/125.24 C9/128.12 C10/140.00 C11/146.84 C12/150.51 C13/160.78 C14/166.50 C15/176.89 In vitro antioxidant activity (DPPH. 2,2-diphenyl-1-picrylhydrazyl) [14,16] The activity of all the compounds [3–10] and the beginning drug levofloxacin was comparable to or slightly higher than the standard (ascorbic acid). The DPPH (2,2-diphenyl-1-picrylhydrazyl) assay method predestines it at different concentrations (25, 50 and 100) g/mL. The outcome is IHJPAS. 37 (1) 2024 290 determined by the reaction of and is defined by change. The amount of electrons caught determines the stoichiometry of the deep violet color (DPPH) or decolorization. Among all chemicals,compounds [3,4,5,6,9,10] showed the most outstanding performance. When compared to some compounds that include amino groups, some compounds [4,7,10] bearing a Chloro group (electron-withdrawing group) at the para position demonstrated high antioxidant activity (electron donating group). Intense antioxidant action is shown by compounds [5,8,10] modified with halogen groups -Cl (electron-withdrawing group). As shown in Table 6 and Figure 1. Table 6. Antioxidant for compounds (3-10) Comp No. 25(mg/ml) 50(mg/ml) 100(mg/ml) 3 96.03 90.19 89.07 4 93.03 98.19 91.07 5 92.78 87.82 95.17 6 88.13 99.15 94.57 7 75.53 87.82 95.53 8 88.31 86.93 80.89 9 92.11 82.13 92.50 10 81.44 88.38 91.11 Ascorbic acid 80.95 86.25 90.54 Figure 1. The compounds and their effectiveness with ascorbic acid 0 20 40 60 80 100 120 Comp No. 3 4 5 6 7 8 9 10 Ascorbic acidComp No. 3 4 5 6 7 8 9 10 Ascprbic acid IHJPAS. 37 (1) 2024 291 Figure 2. The 1H-NMR spectrum of compound [1] Figure 3. The 13C-NMR spectrum of compound [1] IHJPAS. 37 (1) 2024 292 Figure 4. The 1H-NMR spectrum of compound [2] Figure 5. The 13C-NMR spectrum of compound [2] IHJPAS. 37 (1) 2024 293 Figure 6. The 1H-NMR spectrum of compound [5] Figure 7. The 13C-NMR spectrum of compound [5] IHJPAS. 37 (1) 2024 294 Figure 8. The 1H-NMR spectrum of compound Thiazolidinone derivative Figure 9. The 1H-NMR spectrum of compound Oxazolidinone derivative 4. Conclusion The levofloxacin drug was fused to new five-membered rings of oxazolidinone and thiazolidinone. Several novel derivatives were found by using the FTIR, 1H-NMR, and 13CNMR spectra. The antioxidant activity of compounds 3 through 10 was then assessed. 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