234 © 2025 The Author(s). Published by College of Education for Pure Science (Ibn Al-Haitham), University of Baghdad. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License New Boric Acid Derivative with Some of Its Complexes and Study the Biological and Anticancer Activity Alaa Abdullah Majeed1* and Asmaa Mohammed Noori2 1,2 Department of Chemistry, College of Sciences, University of Baghdad, Baghdad, Iraq *Corresponding Author. Received: 16 April 2023 Accepted: 23 July 2023 Published:20 January 2025 doi.org/ 10.30526/38.1.3418 Abstract Background Spectral methods such as Fourier transform infrared spectroscopy, ultraviolet- visible spectroscopy, and proton nuclear magnetic resonance (1H-NMR) spectra, along with thermal analysis (TG/DTA), elemental analysis (CHN), and melting point, were used to characterize the synthesized compounds. This study conducted additional examinations for metal complexes, including molar conductivity, magnetic susceptibility, chloride, and metal content. Objectives This study aims to synthesize and characterize a novel ligand and its metal complexes with cobalt, nickel, and platinum complexes and to evaluate their potential biological activities through focusing on their antibacterial, antifungal and anticancer properties. Materials and Methods A new ligand (5-(2-benzamido-N-methylacetamido)-4-((3,4,5- trimethoxycyclohexa-1,3-dien-1-yl) methyl) pyrimidine-2-yl)amino)boric acid was synthesized by the reaction of trimethoprim amide derivative with boric acid, as well as its metal complexes with cobalt, nickel, and platinum. Results All synthesized complexes have octahedral geometry; cobalt and nickel complexes are nonelectrolytes, while platinum complexes are electrolytic. This study tested all the synthesized compounds as antibacterial and antifungal agents against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albican. Additionally, this study tested the new ligand and its platinum complexes as anticancer agents against adenocarcinoma human cells (A549). Conclusion Thus study have achieved positive outcomes for every complex's antibacterial, antifungal, and anticancer properties. Keywords: Trimethoprim, boric acid, cobalt complex, nickel complex, platinum complex. 1. Introduction Producing novel compounds with antimicrobial and anticancer activities uses trimethoprim, a crucial synthetic ligand material (1). Trimethoprim is an antibiotic combined with sulfonamide, a standard treatment for various bacterial infections. It works by inhibiting the production of folic https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://doi.org/10.30526/38.1.3501 https://orcid.org/0009-0005-4005-9896 mailto:alaaabdulla132@gmail.com https://orcid.org/0000-0002-2877-5663 mailto:asmaa.m@sc.uobaghdad.edu.iq IHJPAS. 2025, 38 (1) 235 acid, which is essential for bacterial growth. Boric acid, on the other hand, is an inorganic compound with antifungal and antiseptic properties (2). X-ray crystallography prepared and identified a trimethoprim-boric acid compound (3). Researchers have carried out investigations into the antimicrobial and anticancer properties of trimethoprim-boric acid. Researchers have also found the compound to have potent anti-proliferative activity against various cancer cells, including those of the breast, lung, and colon (4). Various studies (5, 6) have demonstrated borate's anticancer and antibacterial benefits with ligands and metal trimethoprim. The studies reported that to fight the growing threat of widespread antibiotic resistance, there is a need for innovative antimicrobial medications (7,8). Furthermore, recent studies have shown platinum complexes also have anticancer solid properties, which are cytotoxic to various cell types (9, 10). The current research synthesized a new boric acid derivative ligand from a trimethoprim amide derivative to enhance its medicinal and biological properties. This study also makes metal complexes of this amide ligand with cobalt (II), nickel (II), and platinum (IV) [Co (II), Ni (II), and Pt (IV), respectively] metal ions to make it more biologically active. A physicochemical and spectral inspection of all produced compounds has been conducted to support the proposed structures. This study evaluated the biological and anticancer activity of the synthetic compound. This study aims to synthesize and characterize a novel ligand, 5(2-benzamido-N- methylacetamido)-4-((3,4,5-trimethoxycyclohexa-1,3-dien-1yl) methyl) pyrimidine-2-yl) amino) boric acid, and its metal complexes with Co (II), Ni (II), and Pt (IV) also to investigate the biological activity of the ligand and its complexes. 2. Materials and Methods 2.1. Synthesis of ((5-(2-benzamido-N-methylacetamido)-4-((3,4,5-trimethoxy-cyclohexa-1,3- dien-1-yl) methyl) pyrimidin-2-yl) amino) boric acid The ligand Figure 1 was synthesized by adding boric acid (0.1 g, 1.6 mmol) to a warm solution of N-(2-((2-amino-4-((3,4,5-trimethoxycyclohexa-1,3-dien-1-yl) methyl) pyrimidine-5-yl) (methyl)amino)-2-oxoethyl) benzamide (previous work) (11). In 6 mL H2O, a mixture was heated under reflux with stirring for 15 hours (the reaction was terminated after TLC tested the solution). The off-white powder was obtained after cooling the solution in an ice bath; it was washed with ice water and dried in the oven at 80 ⁰C (12,13). Figure 1. The suggested structure of the prepared ligand. IHJPAS. 2025, 38 (1) 236 2.2. Synthesis of Co (II) , Ni (II) and Pt (IV) complexes (C1,C2 and C3) The mixture of ligand (0.1 g, 0.194 mmol) in 6 mL water and metal salts (2:1, L: M) in 4 mL water (Table 1) was heated under reflux for 5 hrs. with stirring. Heating evaporates a portion of the solvent. The product was collected by crushing it in an ice bath, washing it with ice water, and drying it in an oven at 80 ⁰C. Figures 2- 4 display the suggested structures of the complexes. Figure 2. The structure of Ni(II) complex. Figure 3. The structure of Pt(IV) complex. Figure 4. The structure of CO(II) complex. Table 1. The optimization conditions for synthesis of complexes. No Ligand (wt(g),mmol) in 6 mL H2O Metal salts (wt(g),mmol) in 4 mL H2O Color of precipitate Color of solution C1 Co(II) L (0.1 g,0.194 mmol) [CoCl2.6H2O] (0.023g ,0.097 mmol) Pale blue Reddish pink C2 Ni(II) L (0.1 g,0.194 mmol) [NiCl2.6H2O] (0.023g,0.097 mmole) Light green Green C3 Pt(IV) L (0.1 g,0.194 mmol) [K2PtCl6] (0.047g,0.097 mmol) Brown Yellow 2.3. Anticancer For anticancer detection, each of the 96 flat-well microtiter plates held 1x104–1x106 cells/mL of tumor cell culture media. The microplate was wrapped with Parafilm to prevent contamination and gently shaken before use. After removing the incubation media and incubating the plates at IHJPAS. 2025, 38 (1) 237 37 ⁰C with 5% carbon dioxide for 72 hours, two-fold dilutions of the target chemical (50, 100, 200, and 400 mg/mL) were added to the wells. Tests were performed in triplicate at each concentration and with the controls (cells treated with serum-free medium). The plates were exposed for the appropriate amounts of time. 2.4. Antimicrobial Activities All synthesized compounds have been evaluated for antibacterial action against Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans when tested at 10-2 M in DMSO solutions using the agar diffusion method. Inhibition radii were used to determine their efficacy against bacteria and fungi (14). 3. Results and Discussion 3.1. Physical properties and elemental microanalysis Tables 2 and 3 contain information on the metal concentration (atomic absorption), (C.H.N.), physical characteristics, and the name of the ligand and its metal complexes. Based on (C.H.N.), atomic absorption analysis, chloride content, spectral data, magnetic measurement, and thermal analysis, the molecular formulas of the investigated compounds were proposed. Table 2. Elemental analysis and physicochemical characteristics of ligand and metal complexes. Comp. The molecular formulae Color m.p (°C) Yield % M.wt g.mol-1 Elemental Micro Analysis (Found) Calc. Metal content % Chloride content % C% H% N% L C23H28N5O8B Off white 194-196 84-90 513.282 56.87 (56.02) 6.14 (5.64) 15.62 (14.89) _ _ C1Co(II) [C46H56N10O16B2Co.Cl2] Pale blue 184-188 83-87 1156.494 50.24 (49.53) 5.27 (4.84) 15.22 (14.08) 5.09 (5.4) 6.13 (6.5) C2Ni(II) [C46H56N10O16B2Ni.Cl2] Light green 188-190 86-91 1156.254 50.90 (50.14) 5.34 (4.84) 14.81 (14.08) 5.07 (4.1) 6.14 (5.74) C3Pt(IV) [C46H56N10O16B2Pt.Cl2] 6H2O.2Cl Brown 228-230 90-94 1471.654 36.38 (37.25) 3.91 (4.42) 11.72 (11.01) _ 9.64 (8.5) Table 3. ligand and its metal ion complex by their respective names and formulas. Comp. The molecular formula Name L2 C23H28N5O8B ((5-(2-benzamido-N-methylacetamido)-4-((3,4,5-trimethoxycyclohexa1,3- dien-1-yl)methyl)pyrimidin-2-yl)amino)boric acid C1 Co(II) [C46H56N10O16B2Co.Cl2] DiChloro[bis((5-(2-benzamido-N-methylacetamido)-4-((3,4,5- trimethoxycyclohexa-1,3-dien-1-yl)methyl)pyrimidin-2-yl)amino)boric acid cobalt(II)] C2 Ni(II) [C46H56N10O16B2Ni.Cl2] DiChloro[bis((5-(2-benzamido-N-methylacetamido)-4-((3,4,5- trimethoxycyclohexa-1,3-dien-1-yl)methyl)pyrimidin-2-yl)amino)boric acid Nickle(II)] C3 Pt(IV) [C46H56N10O16B2Pt. Cl2].6H2O .2Cl Di chloro [bis ((5-(2-benzamido-N-methylacetamido)-4-((3,4,5- trimethoxycyclohexa-1,3-dien-1-yl)methyl)pyrimidin-2-yl)amino)boric acid platinum(IV)] chloride hexa hydrate. IHJPAS. 2025, 38 (1) 238 3.2. The FT-IR spectroscopy It has been revealed that the FTIR spectra of Co, Ni, and Pt complexes changed in the way the ω (C=O) amide and ω (C=N) groups stretched, which was caused by the ligand interacting with metal ions through the ω (C=O) amide and ω (C=N) group (15,16). Figures 5-8 display the ligand and complex spectra. The spectra of the ligand and its complexes showed the appearance of a new band at 1338 cm-1 due to the υ (B-O) and 1375 cm-1 due to the υ (B-N) (17). A new band appeared at low frequency, which was attributed to (υ M-N), (υ M-O), and (υ M-Cl) (18). There is no change in O-H and NH2 stretching vibrations, as shown in Table 4. Figure 5. Fourier transform infrared spectrum of the ligand. Figure 6. Fourier transform infrared spectrum of a platinum complex. IHJPAS. 2025, 38 (1) 239 Figure 7. Fourier transform infrared spectrum of a nickel complex. Figure 8. Fourier transform infrared spectrum of a cobalt complex. IHJPAS. 2025, 38 (1) 240 Table 4. The FT-IR data of ligand and it complexes. N o C o m p . O-H υ NH2 υ N-H amide υ C=O amide C=N B-O υ B-N M-O υM-N υM-Cl 1 L 3409 3282asy 3195sy 3317 1668 1575 1338 1375 _ _ _ 2 C1 Co(II) 3409 3290asy 3209sy 3315 1674 1602 1344 1388 582 455 343 3 C2 Ni(II) 3411 3286asy 3195sy 3319 1656 1589 1338 1388 520 445 337 4 C3 Pt(IV) 3417 3226asy 3070sy 3317 1633 1602 1342 1380 576 447 343 3.3. The 1HNMR spectra The ligand (L) was characterized using 1H-NMR in d6-DMSO, as shown in Figure 10. In the ligand's 1H-NMR spectrum, there was a singlet peak at ε (2.5) ppm, which was caused by the chemical shift of the solvent d6-DMSO. The other peak at ε (3.2) ppm was caused by H2O protons in DMSO as impurities (19). Ligand's spectra revealed a new peak at approximately 8.64 ppm, attributed to B-OH (20), with additional peaks in Table 5, Figure 9 depicts the ligand's structure. Figure 9. Structure of the ligand. Table 5. The 1H-NMR data of the ligand. Assignments in d6 -DMSO Mark Chemical shifts δ (ppm) Methylene protons 10 (3.58), 2H ,s Methyl protons 9 (3.64), 3H ,s Methyl protons 8 (3.87), 6H ,s Aromatic protons 7 (6.61), 2H ,d Amine protons 5 (7.08), 2H ,m Piperazinyl protons 6 (7.48), H ,m Aromatic protons 1, 2 (7.55)3H, d BOH protons 11 8.64, 3H ,s Amide protons 3 (8.92), 2H ,d IHJPAS. 2025, 38 (1) 241 Figure 10. The 1HNMR spectrum of the ligand. 3.4. Thermal analysis of the ligand and its metal complexes Thermogravimetric (TG) and DTA were measured in argon gas at 25 to 800 °C (10 °C/min). Table 6 contains thermal dissociation data; Figures 11–14 display thermographs of ligands and their metal complexes. Table 6. Thermal decomposition data of the ligand and its complexes. C o m p . Molecular formula and molecular weight g/mole Steps Temp. rang of the decomposition °C Suggested formula of loss Mass loss% Cal. (Found) DTA °C L 2 C23H28N5O8B 513.282 1 0-33 CH3 1.881(2.928) _ 2 33-162 O+2(OCH3)+OH 17.74(18.521) 115 (EXO) 3 162-300 B(OH)2+NH2+C6H2+CH2+C4N2H+NH 47.07(46.957) 210 (EXO) 4 300-581 C6H5+CO+H2 21.85(20.870) 435 (EXO) residue 581-800 NH+C+CO 11.64(10.722) 575 (EXO) C 1 C o (II) [C46H56N10O16B2Co.Cl2] 1156.494 1 0–38 2CL+6(OCH3)+2OH 24.84(25.16) 75 (EXO) 2 38–314 4(OH)+2B+2NH2+2C6H2+4CH2+3CO+2NH 51.07(51.32) _ 3 314–562 CO+2NH+C4HN2+C2H 13.88(13.083) 375 (EXO) residue 562–800 Co+ CN 10.21(9.59) 555 (EXO) C 2 N i(II) [C46H56N10O16B2Ni.Cl2] 1156.254 1 0 – 33 2CL+4(OCH3) 16.19(16.86) _ 2 33–297 2(OCH3)+2(C6H2)+4CH2+2B+6OH+4CO2NH2 +NH 62.75(62.06) _ 3 297–619 2NH+C3HN 6.898(7.005) 200 (EXO) residue 619-800 C4HN2+Ni+CN 14.16(13.98) 300 (EXO) C 3 P t(I V ) [C46H56N10O16B2Pt. 1 0–33 6(H2O)+4CL+3(OCH3) 22.82(23.31) _ IHJPAS. 2025, 38 (1) 242 C o m p . Molecular formula and molecular weight g/mole Steps Temp. rang of the decomposition °C Suggested formula of loss Mass loss% Cal. (Found) DTA °C 2Cl].6H2O+2Cl 1471.654 2 33 –362 3(OCH3)+6OH+2B+2NH2+ 2C6H2+2CH2+C3H 31.41(31.39) 180 (EXO) 3 362–533 NCN+2(C6H5)+2CO+2NH 18.74(19.04) 510 (EXO) residue 533-800 2CH2+2CO+Pt+2NH+N2HC4 27.03(26.24) _ 3.5. Electronic spectra The electronic spectra of synthetic compounds were performed at ambient temperature in methanol (10-3M). Table 5 is a list of all the information about electronic spectra. Figure 11. Thermogram of the ligand. Figure 12. Thermogram of cobalt complex. IHJPAS. 2025, 38 (1) 243 Figure 13. Thermogram of nickel complex. Figure 14. Thermogram of platinum complex. 3.5.1. Electronic spectrum of the ligand The ligand's electronic spectrum showed strong bands at 271 nm (36900 cm-1) and 236 nm (42372 cm-1), caused by the (π -π*) transition (21). The data are shown in Table 5, and the ligand's spectrum is shown in Figure 15. Figure 15. The UV-Vis spectrum of the ligand. IHJPAS. 2025, 38 (1) 244 3.5.2. Electronic spectrum of Co (II) complex (C1) The spectrum of the (C1) in Figure 16 and the data are listed in Table 5. The Co complex exhibited three bands at 967 nm (10341 cm-1), which refers to 4T1g→4T2g transitions, and the other at (861 and 511 nm), (11614 and 19569 cm-1), relates respectively to (4T1g→4A2g and 4T1g→4T1g(P)) transitions for the octahedral geometry (22,23). The result of conductivity showed that the Co complex was nonelectrolyte and the µeff. The value in Table 5 is assigned to the Co complex's octahedral geometry (24). 3.5.3. Electronic spectrum of Ni (II) complex (C2) The spectrum of the (C2) complex is displayed in Figure 17, and the data are listed in Table 5. The Ni complex indicated two bands at (976 nm) (10245 cm-1); this band refers to3A2g→3T2g, transition and 540 nm (18518 cm-1), which refers to 3A2g→3T1g transition for the octahedral geometry (25,26). The conductivity result showed that the Ni complex was nonelectrolyte, and the µeff—value in Table 5. was assigned to the octahedral geometry of the Ni complex (27). Figure 16. The UV-Vis spectrum of cobalt complex C1. Figure 17. The UV-Vis spectrum of nickel complex C2. IHJPAS. 2025, 38 (1) 245 3.5.4. Electronic spectrum of Pt (IV) complex (C3) The spectrum of the C3 complex is shown in Figure 18, and the data are listed in Table 7. The Pt complex exhibited two bands at (737 and 914 nm) (13568 and 10940 cm-1), respectively; these bands refer to 1A1g→3T1g and 1A1g→3T1g(H) transition (28,29). The result of conductivity showed the electrolytic nature of the Pt complex. The magnetic property of the Pt (IV) complex was diamagnetic (30). Figure 18. The UV-Vis spectrum of platinum complex C3. Table 7. Electronic spectra of ligand and complexes. Comp Band positions nm (cm-1) Assignment Molar conductivity (S.cm2.mol-1 ) in H2O µeff. (B.M) Suggested geometry Ligand 271 (36900) 236(42372) π →π* π →π* ــــ ــــ C1 Co(II) 241 (41493) 273(36630) 511(19569) 861(11614) 967 (10341) π →π* π →π* 4T1g→4T2g (P) 4T1g→4A2g 4T1g→4T2g 63 5.46 Octahedral C2 Ni(II) 232 (43103) 271(36900) 540(18518) 976 (10245) π →π* π →π* 3A2 g→3T1g 3A2 g→3T2g 76 3.14 Octahedral C3 Pt(IV) 232 (43103) 290(34482) 737 (13568) 914(10940) π →π* π →π* 1A1 g→3T1g 1A1 g→3T1g(H) 123 Diamagnetic Octahedral 3.6. Biological activity (Antimicrobial activity) The antimicrobial properties of the ligand and its metal complexes were conducted utilizing the fusion method at 10-2 M in DMSO. All compounds' antibacterial and antifungal activities were tested against (Pseudomonas aeruginosa, Staph, and Candida albicans). The order of activities for ligand and its complexes was C1(Co) > C2(Ni) > C3(Pt)> L in Pseudomonas aeruginosa depending on inhibition zone (18>17>16>14) mm respectively, while in Staphylococcus aureus the order was C2Ni > C1(CO) >L > C3(Pt) at inhibition zone (31>30>25>18) mm, respectively. IHJPAS. 2025, 38 (1) 246 For Candida albicans, the order was C1(Co) > C2(Ni) > C3(Pt) >L at inhibition zone (30>28>27>22) mm, respectively. The ligand and its complexes have more activity than the original compounds (trimethoprim and hippuric acid) against Candida albicans and Staphylococcus aureus, as shown in Table 8 and Figure 19. Table 8. The biological activity for studied compounds in (10-2 M). Compounds Candida albicans Staphylococcus aureus Pseudomonas aeruginosa DMSO -ve -ve -ve Hippuric 14 15 14 Trimethoprim 13 17 18 L 22 25 14 C1(Co) 30 30 18 C2(Ni) 28 31 17 C3(Pt) 27 18 16 Figure 19. The inhibition zone for ligand and its complex against Pseudomonas aeruginosa, Staph and Candida albicans. 3.7. Anticancer Adenocarcinoma human cells (A549) were used in a 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay to test the cytotoxic effect of the ligand and its complexes. The findings showed that trimethoprim and ligand inhibited the vitality of A549 cells throughout a concentration range of (400-50) g/mL, while the same doses only slightly affected normal cells. The ligand and trimethoprim underwent a 72-hour cytotoxic study. The data shows trimethoprim has a more substantial killing effect than the ligand, as illustrated in Tables 9, 10 and Figures 20, 21. Table 9. The cytotoxic effects of trimethoprim on the A549 tumor cell line and a normal cell line HDFn. Cell line Conc. µg/mL IC50 µg/mL P value 400 200 100 50 A549 32.91 ±2.17 41.09 ±1.34 52.51 ±3.69 62.69 ±2.89 28.91 <0.0001 HDFn 61.42 ±1.69 72.84 ±2 83.99 ±1.58 91.59 ±2.68 208.9 IHJPAS. 2025, 38 (1) 247 Figure 20. The cytotoxic effect of trimethoprim on A549 cells after 72 hours of incubation at 37 degree Celsius (Log for the original concentration). Table 10. Cytotoxicity effects of ligand against A549 tumor cell line and normal cell line HDFn. Cell line Conc. µg/mL IC50 µg/mL P value 400 200 100 50 A549 63.23 ±2.68 66.98 ±6.09 79.54 ±6.71 95.1 ±0.66 88.44 <0.0001 HDFn 74.31 ±3.73 86.07 ±1.92 95.22 ±0.82 95.95 ±1.03 212.8 Figure 21. Cytotoxicity effect of ligand on A549 cells after 72hours of incubation at 37ºC (Log for the original concentration). IHJPAS. 2025, 38 (1) 248 4. Conclusion This study synthesized a new ligand by reacting the trimethoprim amide derivative with boric acid in a 1:1 mole ratio. The ligand's metal complexes were synthesized with Co(II), Ni(II), and Pt (IV) in a 2:1 (L:M) mole ratio. All synthesized compounds were characterized and confirmed the suggested structures using spectral and physicochemical methods. The results revealed the octahedral geometry of Co (II), Ni (II), and Pt (IV) complexes, which have nonelectrolyte character. The biological results showed that all the synthesized compounds possessed excellent antimicrobial activity against Pseudomonas aeruginosa, Staph, and Candida albicans. The results of the anticancer study showed that trimethoprim and the ligand have cytotoxic effects on A549 cells. Acknowledgment The authors thank the Department of Chemistry, College of Science, University of Baghdad for research approval. Conflict of Interest The authors declare that they have no conflicts of interest. Funding No founding. 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