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Article

Synthesis, Characterization, and Antibacterial Studies of New Cu(II) and Pd(II) Complexes with 6-Methyl-2-Thiouracil and 6-Propyl-2-Thiouracil

by
Petya Marinova
1,*,
Mariyan Hristov
1,
Slava Tsoneva
2,
Nikola Burdzhiev
3,
Denica Blazheva
4,
Aleksandar Slavchev
4,
Evelina Varbanova
2 and
Plamen Penchev
2
1
Department of General and Inorganic Chemistry with Methodology of Chemistry Education, Faculty of Chemistry, “Tzar Assen” Str. 24, 4000 Plovdiv, Bulgaria
2
Department of Analytical Chemistry and Computer Chemistry, Faculty of Chemistry, University of Plovdiv, “Tzar Asen” Str. 24, 4000 Plovdiv, Bulgaria
3
Department of Organic Chemistry and Pharmacognosy, Faculty of Chemistry and Pharmacy, University of Sofia, 1, J. Bourchier Av., 1164 Sofia, Bulgaria
4
Department of Microbiology, University of Food Technologies, 26 Maritza Blvd., 4002 Plovdiv, Bulgaria
*
Author to whom correspondence should be addressed.
Appl. Sci. 2023, 13(24), 13150; https://doi.org/10.3390/app132413150
Submission received: 23 October 2023 / Revised: 7 December 2023 / Accepted: 9 December 2023 / Published: 11 December 2023
(This article belongs to the Special Issue Synthesis and Biological Activity of Novel Complexes)
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Abstract

:
The aim of the present study is to synthesize new metal complexes of 6-methyl-2-thiouracil and 6-propyl-2-thiouracil, elucidate their structures, and investigate their biological properties. All metal complexes were obtained after mixing water solutions of the corresponding metal salts and the ligand dissolved in DMSO and water solutions of NaOH in a metal-to-ligand ratio of 1:4:2. The structures of the new compounds are discussed based on melting point analysis (MP-AES) for Cu and Pd, UV-Vis, IR, ATR, 1H NMR, 13C NMR, and Raman spectroscopy. The interpretation of complex spectra is assisted by the data for 6-methyl-2-thiouracil and 6-propyl-2-thiouracil obtained from 1H-1H COSY, DEPT-135, HMBC and HMQC spectra. In addition, the antimicrobial activity of these complexes and the free ligands are assessed against both Gram-positive and Gram-negative bacteria, as well as yeasts. In general, the addition of metal ions improved the antimicrobial activity of both 6-methyl-2-thiouracil and 6-propyl-2-thiouracil. The Cu(II) complex with 6-methyl-2-thiouracil and the Pd(II) complex with 6-propyl-2-thiouracil exhibited the highest activity against the test microorganisms.

1. Introduction

Pyrimidine derivatives possess a wide range of biological activities, such as antineoplastic [1], antiviral [2], antimicrobial [3], free radical scavenging [4], anti-inflammatory [5], pain-relieving [6], and anxiety-reducing [7] properties. Thionamides, a class of relatively simple molecules, serve as antithyroid drugs, featuring a sulfhydryl group and a thiourea moiety within a heterocyclic framework. In the United States, the antithyroid drugs in use are Propylthiouracil (also known as 6-propyl-2-thiouracil) and Methimazole (also referred to as 1-methyl-2-mercaptoimidazole or Tapazole).
Oladipo and Isola provided a comprehensive review of the coordination possibilities of uracil and the practical applications of some of its complexes [8].
Shaban et al. synthesized metal complexes involving pyrimidine, which encompass Cd- and Zn-barbiturate, as well as Cd- and Hg-thiouracil compounds [9]. The reaction of 5-bromouracil led to the preparation of novel complexes involving Mn(II), Cd(II), Co(II), Ni(II), Cu(II), and Ag(I) [10]. The data obtained demonstrated that these complexes exhibited greater antimicrobial potency compared to the free ligand.
The interest in platinum and palladium complexes stems from their pronounced cytostatic activity. Recently, cis-dihalogeno complexes of Pt(II) and Pd(II) were synthesized in conjunction with 6-tert-butyl-2-thiouracil [11]. Furthermore, a series of complexes were synthesized using Rh(III), Ir(III), Pt(II), and Pd(II) in combination with the ligand 6-methyl-2-thiouracil [12]. Bomfim et al. conducted a synthesis of Ru(II) complexes involving 6-methyl-2-thiouracil, showing promise for novel antileukemic drug candidates [13]. Paizanos et al. successfully synthesized new Cu(I) complexes featuring the antithyroid drug 6-propyl-thiouracil [14].
To date, a multitude of metal complexes have been synthesized using uracil and thiouracil derivatives, involving various metals such as Cu, Fe, Co, Ni, Zn, Mn, Cd, and V [15,16,17], as well as Pd, Pt, and Au, with evaluations of their composition and structure [18].
In vitro screening of the antimicrobial activity of numerous metal complexes derived from thiouracil derivatives was conducted against Gram-positive and Gram-negative bacteria, filamentous fungi, and yeast [9,19,20,21].
Furthermore, the cytotoxic effects of various metal complexes of thiouracil derivatives were investigated against different tumor cell lines [13,22,23,24,25,26].
In Scheme 1 (top), the chemical structures of 6-methyl-2-thiouracil and 6-propyl-2-thiouracil are shown. Various metal complexes exhibit a monodentate coordination mode with 2-thiouracil derivatives, binding through different atoms, such as N1 (e.g., Cu(I) complex) [27], N3 (e.g., Pd(II) complex) [28], S (e.g., Ru(II), Cu(I), Sn(IV), Pt(II), and Pd(II) complexes) [11,14,23,29], or O (e.g., Co(II), Ni(II), Mn(II), and Zn(II) complexes) [30,31,32].
At the bottom of Scheme 1, the bidentate coordination modes of these ligands are highlighted. There are at least four potential bidentate coordination possibilities (A–D) for both ligands. Some of these modes were examined by Lusty and colleagues [12], who discussed coordination modes represented in (A) and (B) in the presence of platinum and rhodium centers, respectively. These were the most common coordination modes for this ligand class. Complexes with Pt(II), Pd(II), Ru(II), and Zn(II) also display coordination mode (A) [12,13,28,33], while coordination mode (B) was observed in Cd(II), Hg(II), and Co(II) complexes and peroxo complexes of vanadium [9,34]. To date, possibility (C) has not been observed for thiouracil derivatives, except in an osmium/uracil complex [35] and Mn(II), Co(II), Ni(II), Cu(II), Cd(II), and Ag(I) with 5-bromo-uracil [10] and similar ligand [36]. Coordination mode (D) was observed in a Ru(II) complex with 2,2′-bipyridine (bipy) [37], tin(IV) complexes [38], and Pt(II) with 5,6-diamino-4-hydroxy-2-mercaptopyrimidine [18]. Tridentate coordination mode with the participation of S2, N3, and O4 atoms of the free ligands [9,15,20] was also reported.
Recently, Ahmed et al. reported new 2-thiouracil-5-sulfonamide derivatives and their biological properties [39].
This paper presents the synthesis of novel metal complexes involving 6-methyl-2-thiouracil (L1) and 6-propyl-2-thiouracil (L2). The characterization of these compounds was conducted through various techniques, including melting point determination, UV-Vis, IR, 1H NMR, 13C NMR, and Raman spectroscopy. The assignment of NMR signals of the ligands was obtained from 1H-1H COSY, DEPT-135, HMBC, and HMQC spectra. Furthermore, the antimicrobial activity against both Gram-positive and Gram-negative bacteria, as well as yeasts, is evaluated.

2. Materials and Methods

2.1. Spectra Measurements

The free ligands 6-methyl-2-thiouracil and 6-propyl-2-thiouracil were purchased from Aldrich Chem. The metal salts Cu(CH3COO)2.H2O and Pd(NO3)2.H2O (Aldrich Chem) and solvents used for the synthesis of the complexes had a high purity that was generally equal to A.C.S. grade and were suitable for use in many laboratory and analytical applications. Absorption spectra were registered on a UV-30 SCAN ONDA UV/Vis/NIR Spectrophotometer from 200 to 1000 nm. The IR spectra of L1, L2, and their complexes were registered in KBr pellet on a Bruker FT-IR VERTEX 70 Spectrometer from 4000 cm−1 to 400 cm−1 at a resolution of 2 cm−1 with 25 scans. The stirred crystals were placed in an aluminum disc and the Raman spectra of the compounds were measured on a RAM II (Bruker Optics) with a focused laser beam of Nd:YAG laser (1064 nm) from 4000 to 100 cm−1 at a resolution of 2 cm−1 with 25 scans. Additionally, ATR spectra of the complexes were measured (MIRacle Single reflection, PIKE technology) to check if the coordination water was present in them. The NMR spectra of the ligand were registered on a Bruker Avance II NMR spectrometer operating at 600.130 and 150.903 MHz for 1H and 13C, respectively, using the standard Bruker software v3.6.3. The NMR spectra of the metal complexes were measured on a Bruker Avance III HD spectrometer operating at 500.130 and 125.76 MHz for 1H and 13C, respectively, using the standard Bruker software v3.6.5. Solid-state NMR spectra were acquired on a Bruker Avance III HD 500 MHz spectrometer equipped with a 2.5 mm Cross-Polarization Magic Angle Spinning (CPMAS) probe head. CP MAS and Cross-Polarization with Polarization Inversion (CPPI) MAS spectra were recorded at a MAS speed of 15 kHz and α-glycine was used as an external reference (α-glycine carbonyl C-176.03 ppm). Measurements were carried out at ambient temperature.

2.2. Microwave Plasma-Atomic Emission Spectrometry (MP-AES) Determination of Cu and Pd in the Complexes

A total of 0.0200 g of sample was weighed on an analytical balance and dissolved with 65% nitric acid, p.a. (Chem-Lab NV, Zedelgem, Belgium) for Cu-complexes, nitric acid, and 37% hydrochloric acid, and p.a. (Fluka AG, Buchs, Switzerland) for Pd-complexes. Blank solutions were prepared as well. After dilution, the concentration of Cu and Pd was determined via MP-AES 4200 (Agilent technologies, Santa Clara, CA, USA). Calibration standards were prepared from monoelemental standard solutions −1000 mg L−1 Cu (Merck, Darmstadt, Germany) and 1000 mg L−1 Pd (High-purity standards, Charlestone, UK). Conventional MP-AES operating conditions were used. Analytes were measured on three emission lines for estimation of potential spectral interferences, i.e., 324.754 nm, 327.395 nm, and 510.554 nm for Cu and 340.458 nm, 360.955 nm, and 363.470 nm for Pd. Five replicates and 5 s measurements were applied for all lines.

2.3. General Procedure for the Synthesis of Cu(II) and Pd(II) Complexes of 6-Methyl-2-Thiouracil (L1) and 6-Propyl-2-Thiouracil (L2)

All metal complexes were obtained after mixing water solutions of the corresponding metal salts and the ligands dissolved in DMSO and water solutions of NaOH, in a metal-to-ligand ratio of 1:4:2. Non-charged complexes were formed as precipitates, which were further filtrated, repeatedly washed with water, and dried over CaCl2 for 2 weeks.

2.3.1. Synthesis of CuL1

0.0008 mol Cu(CH3COO)2.H2O (0.1597 g) in 10 mL H2O;
0.0032 mol (0.4550 g) of 6-methyl-2-thiouracil (L1) in 10 mL DMSO;
0.0016 mol (0.0640 g) NaOH in 5 mL H2O.

2.3.2. Synthesis of PdL1

0.002 mol (0.4609 g) Pd(NO3)2.H2O in 10 mL H2O;
0.008 mol (1.1374 g) of 6-methyl-2-thiouracil (L1) in 10 mL DMSO;
0.004 mol (0.1600 g) of NaOH in 5 mL H2O.

2.3.3. Synthesis of CuL2

0.0008 mol Cu(CH3COO)2.H2O (0.1597 g) in 10 mL H2O;
0.0032 mol (0.5447 g) of of 6-propyl-2-thiouracil (L2) in 10 mL DMSO;
0.0016 mol (0.0640 g) NaOH in 5 mL H2O.

2.3.4. Synthesis of PdL2

0.002 mol (0.4609 g) Pd(NO3)2.H2O in 10 mL H2O;
0.008 mol (1.1318 g) of 6-propyl-2-thiouracil (L2) in 10 mL DMSO;
0.004 mol (0.1600 g) of NaOH in 5 mL H2O.
All the metal complexes were synthesized according to a previously described procedure [40], with a modification in the duration of procedures (24 h for palladium(II) complexes) and/or solvents [9,10,11,12,13].
Figure 1 and Figure 2 demonstrate the synthesis of transition metal complexes with two free ligands.
The synthetic scheme that is shown in Figure 1 and Figure 2 is similar to that reported by other authors [41,42].

2.4. Spectral Data of the Free Ligands and Their Metal Complexes

UV-Vis (DMSO) of L1: λmax = 258, 294 nm.
IR (cm−1) of L1: 3115 (NH), 3080 (NH), 3014 (=CH), 2932 (CH3), 2890 (CH3), 2580, 2407, 1920, 1893, 1863, 1754, 1698, 1676 (C=O), 1637, 1560, 1423, 1384, 1349, 1242 (C=S), 1200, 1194, 1167, 1043, 1032, 993, 962, 933, 874, 838, 808, 729, 656, 598, 580, 553, 548, 513, 457, and 416.
IR (cm−1) of CuL1: 3115 (NH), 3080 (NH), 3003 (=CH), 2931 (CH3), 2888 (CH3), 1753, 1637 (C=O), 1578, 1559, 1426, 1385, 1350, 1284, 1241(C=S), 1207, 1199, 1167, 1033, 962, 933, 906, 872, 837, 809, 755, 656, 621, 597, 553, 512, and 457.
ATR (cm−1) of CuL1: 3111 (NH), 3088 (NH), 3001 (=CH), 2934 (CH3), 2882 (CH3), 1752, 1699, 1633 (C=O), 1575, 1541, 1424, 1386, 1349, 1283, 1241 (C=S), 1207, 1195, 1164, 1032, 962, 932, 908, 872, 834, 806, 755, 656, 628, and 621.
Raman (cm−1) of L1: 3085 (NH), 2921, 1635 (C=O), 1558, 1419, 1382, 1353, 1245 (C=S), 1199, 1177, 1043, 985, 961, 931, 834, 789, 657, 597, 554, 512, 458, 258, and 214.
Raman (cm−1) of CuL1: 3084 (NH), 2916, 1636 (C=O), 1578, 1549, 1418, 1382, 1281, 1244 (C=S), 1207, 1170, 1043, 986, 961, 650, 622, 596, 573, 553, 512, 473, 456, 257, and 218.
UV-Vis (DMSO) of Pd(II)L1: λmax = 258, 318 nm.
IR (cm−1) of PdL1: 3442 (H2O), 3111 (NH), 3071 (NH), 3052 (=CH), 2993, 2930 (CH3), 2892, 2855 (CH3), 2750, 2697, 1678 (C=O), 1559, 1521, 1466, 1419, 1400, 1366, 1352, 1284, 1244 (C=S), 1193, 1168, 1064, 954, 830, 656, 614, 598, 576, 553, 513, and 459.
ATR (cm−1) of PdL1: 3400 (H2O), 3105 (NH), 3080 (NH), 3049 (=CH), 2889, 2747, 2694, 1673 (C=O), 1636, 1559, 1515, 1465, 1417, 1399, 1365, 1351, 1285, 1242 (C=S), 1232, 1192, 1166, 1064, 953, 872, 826, 655, and 613.
IR (cm−1) of L2: 3112 (NH), 3093 (NH), 3042 (=CH), 2958 (CH3), 2931 (CH2), 2873, 2607, 1877, 1777, 1703, 1656 (C=O), 1628, 1557, 1445, 1393, 1336, 1314, 1281, 1243 (C=S), 1193, 1165, 1100, 1039, 1014, 965, 940, 888, 821, 790, 743, 641, 558, 538, 508, 465, 422, and 416.
Raman (cm−1) of L2: 3110 (NH), 2929 (CH2), 2871, 1661 (C=O), 1630, 1548, 1433, 1337, 1243 (C=S), 1184, 1164, 1099, 1039, 1015, 970, 938, 643, 562, 534, 459, 352, 322, 257, and 230.
ATR (cm−1) of L2: 3088 (NH), 3038 (=CH), 2957 (CH3), 2928 (CH2), 2872, 1702, 1653 (C=O), 1627, 1554, 1445, 1392, 1336, 1313, 1281, 1242 (C=S), 1191, 1164, 1100, 1039, 1014, 965, 940, 887, 816, 787, 743, and 640.
IR (cm−1) of CuL2: 3451 (OH), 3093 (NH), 3042 (=CH), 2962 (CH3), 2914 (CH2), 2873, 1694, 1651 (C=O), 1553, 1497, 1453,1403, 1381, 1346, 1313, 1275, 1232 (C=S), 1210, 1191, 1166, 1008, 1021, 954, 876, 832, 754, 741, 703, 669, 658, 589, 571, 559, 549, 528, 468, 414, and 403.
Raman (cm−1) of CuL2: 3000, 2967, 2914, 2876, 1685, 1660 (C=O), 1631, 1595, 1500, 1438, 1416, 1381, 1276, 1230 (sh., C=S) 1212, 1165, 1089, 1021, 975, 878, 704, 670, 593, 581, 563, 531, 473, 438, 337, 307, 247, and 219.
ATR (cm−1) of CuL2: 3416 (OH), 3093 (NH), 3037 (=CH), 2959 (CH3), 2913 (CH2), 2871, 1692, 1642 (C=O), 1551, 1494, 1452, 1401, 1381, 1345, 1310, 1275, 1231 (C=S), 1210, 1190, 1165, 1105, 1015, 966, 953, 875, 831, 787, 754, 738, 703, 657, and 644.
IR (cm−1) of PdL2: 3437 (H2O), 3200, 3158, 3117 (NH), 3080 (NH), 2962 (CH3), 2872, 1657 (C=O), 1595, 1545, 1467, 1428, 1379, 1338, 1320, 1261 (C=S), 1202, 1175, 1091, 1023, 972, 916, 882, 832, 789, 748, 697, 643, 606, 548, and 468.
ATR (cm−1) of PdL2: 3402 (H2O), 3081 (NH), 2944 (CH3), 2917 (CH2), 2867, 2829, 1703, 1643 (C=O), 1616, 1564, 1516, 1445, 1425, 1386, 1329, 1286, 1223 (C=S), 1184, 1169, 1100, 997, 965, 908, 887, 860, 819, 787, 763, 745, 680, 643, and 607.
Raman spectra of PdL1 and PdL2 could not be measured; the samples burned at 1 mW.

2.5. Antimicrobial Assay

Antimicrobial activity of 6-methyl-2-thiouracil, 6-propyl-2-thiouracil and their complexes against Gram-positive bacteria—Enterococcus faecalis ATCC 19433, Staphylococcus aureus ATCC 25923, Listeria monocytogenes ATCC 8787, Bacillus subtilis ATCC 6633, and Bacillus cereus ATCC 11778, Gram-negative bacteria—Escherichia coli ATCC 8739, Salmonella enterica subsp. enterica ser. Enetritidis ATCC 13076, Pseudomonas aeruginosa ATCC 9027, Proteus vulgaris G, and Klebsiella pneumoniae ATCC 13883, and yeasts—Candida albicans ATCC 10231 and Saccharomyces cerevisiae, was tested using the agar diffusion method. A suspension of each test microorganism (106 cfu/cm3) was spread on the surface of a PCA (Scharlau) nutrient medium for C. albicans and the bacteria and Wort agar (Sharlau) was used for S. cerevisiae. Wells of 7 mm diameter were made in the inoculated agar medium. Then, 50 μL of the tested substance solution (10 mg/cm3 in DMSO) was pipetted into the wells. The Petri dishes were incubated at 37 °C (for the bacteria and C. albicans) and 30 °C (for S. cerevisiae) for 24–48 h. The inhibition zones were measured. Zones with a diameter more than 7 mm were considered as zones of inhibition. Each test was carried out in triplicate, and the data are presented as mean values.

3. Results and Discussion

3.1. Synthesis of the Metal Complexes

The interaction of metal ions with L1 and L2 in a molar ratio of metal:ligand:base (1:4:2) resulted in the formation of the complexes with suggested formulas shown in Table 1. The results of the elemental analysis for the metal ions were determined by Microwave Plasma-Atomic Emission Spectrometry. They can be used to determine the tentative average composition of different complexes.
All the complexes were stable in air and moisture and their solubility was limited. We found that the reaction of L1 and L2 with the transition metal ions afforded a 40–72% yield of a stable solid compound. The complexes obtained had a yellow-green or brown color and limited solubility in DMSO and DMF, except CuL2 (soluble in DMSO only); the complexes were insoluble in water, THF, C2H5OH, EtOAc, and cyclohexane. The analytical data including the yield percentage of the complexes are presented in Table 2.
IR Verification of the structures of the metal complexes can be easily achieved by comparing the IR spectra of the free ligands with that of their metal complexes. The selected experimental data from the IR spectra of the complexes CuL1 and PdL1 and of the free ligand (in cm−1) is shown in Table 3.
In the IR spectra of the free ligand L1, the bands at 3115 cm−1 and 3080 cm−1 were observed, which may refer to the stretching vibrations of N-H groups. In the spectrum of the Cu(II) complex, the same bands were observed at the same frequencies. In the IR spectrum of the Pd(II)L1, these bands were shifted to the lower frequencies compared to the free ligand bands with 4 cm−1 and 9 cm−1, respectively. This shows that the two N-H groups of the ligand participate in the coordination of the palladium complex. The L1 IR bands at 1676 and 1242 cm−1 can be attributed to the stretching vibration of C4=O and C2=S groups, respectively. The stretching vibration of C4=O in the CuL1 complex was shifted to the lower frequency with 39 cm−1 compared to this stretching in the free ligand. The same bands in the IR spectrum of the PdL1 complex did not change. In the ATR spectrum of PdL1 complex, the band at 3400 cm−1 may refer to the stretching vibrations of molecular H2O. This band was missing in the spectrum of the CuL1 complex.
In the IR spectrum of the free ligand L2, the bands at 3112 cm−1 and 3093 cm−1 were observed, which may refer to the stretching vibrations of N-H groups. In the spectrum of the copper complex, the same bands were observed at the same frequencies. In the IR spectrum of the PdL2 complex, these bands were shifted; the first with +5 cm−1 and the second with −13 cm−1 compared to those in the free ligand spectrum. This shows that the two N-H groups of the ligand participate in the coordination of PdL2. In the IR spectrum of L2, the bands at 1656 and 1243 cm−1 can be attributed to the stretching vibrations of C4=O and C2=S groups, respectively. The band for the C2=S group was shifted to the lower frequencies compared to the free ligand spectrum with 11 cm−1 and to the higher frequencies with 18 cm−1 for the CuL2 and PdL2 complexes, respectively. The band at 3451 and 3437 cm−1 in the IR spectrum of the two complexes may refer to the stretching vibrations of OH− (CuL2) and molecular H2O (PdL2), shown in Table 4. The solid-state ATR spectra confirm these findings.
The stretching vibrations of C4=O and C2=S appear at 1635 and 1245 cm−1 in the Raman spectrum of 6-metyl-2-thiouracil and 1661 and 1243 cm−1 in that of 6-propyl-2-thiouracil, respectively. In the Raman spectrum of the CuL2, the band for the C=S group was shifted by 13 cm−1 to the lower frequency.
The 1H NMR spectrum of 6-metyl-2-thiouracil (L1) showed four signals: a singlet at 12.29 ppm for H-1 and H-3 (overlap resonances) and the olefin proton at 5.68 ppm (H-5) and 2.06 ppm for H-1′. These assignments were confirmed by 1H-1H COSY, 1H-broadband decoupled 13C-NMR, DEPT-135, and HMBC spectra and are shown in Table 5.
The 1H NMR and 13C NMR spectral data of the Cu(II) and Pd(II) complexes are presented in Table 6 and Table 7, respectively.
The 1H NMR and 13C NMR spectra in the DMSO-d6 solution of CuL1 had the same values of chemical shift as those of L1, but the solid-state NMR differentiated between them (see Table 6, Table 7 and Table 8 and Figure 3). The 13C NMR spectrum of the L1 registered with the cross-polarization (CP) experiment showed five signals. Two of them were observed for the C=S and C=O groups at 174.6 and 163.0 ppm, respectively.
In the 13C NMR solid-state spectrum of CuL1, the two couples at 171.7/174.8 ppm and 162.9/169.5 ppm were observed for the C=S and C=O groups, respectively. This means that the resonance for C=S was upfield shifted by 2.9 ppm, and the signal for C=O was downfield shifted by 6.5 ppm, respectively. This shows that the C=S and C=O groups of the ligand participated in the coordination with the copper. The two couples at 104.7/105.4 ppm and 154.0/156.4 ppm (Table 8), were observed for the carbon atom in positions 5 and 6, respectively.
The 1H NMR solution spectrum of PdL1 showed that the signals for the two amine protons (H-1 and H-3) were upfield shifted by 1.49 and 1.43 ppm. Also, all resonances of the free ligand are present in excess; this could be from the remaining reagent L1 or from the decomposition of PdL1 in the solution. In the 13C NMR solution spectrum of PdL1, only methyl and olefin resonances of the coordinated ligand can be seen; the others are indistinguishable from the noise. This once again shows the limited solubility of the complexes.
The 1H NMR spectrum of 6-propyl-2-thiouracil (L2) showed six signals: two broad singlets at 12.20 ppm (H-1) and 12.31 ppm (H-3) and the olefin proton at 5.67 ppm (H-5) and 2.32 ppm for H-1′, 1.54 ppm for H-2′, and 0.87 ppm for H-3′. These assignments were confirmed by 1H-1H COSY, 1H-broadband decoupled 13C-NMR, and DEPT-135 spectra and are shown in Table 9.
The characterization of the CuL2 complex in solution was obstructed by its low solubility in various solvents including DMSO. In the 1H NMR and 13C NMR solution spectra of CuL2, only the free ligand resonances were present. In the solid-state 13C NMR spectrum, there were resonances for both free and coordinated ligands. In the proton spectrum of CuL2 in DMSO-d6, a singlet at 2.54 ppm was observed for DMSO-h6 that was coordinated to Cu(II) during synthesis. The data about L2 and CuL2 are summarized and shown in Table 10 and Table 11 and Figure 4a–c.
The 13C NMR spectrum of the L2 registered with the cross-polarization experiment showed seven signals. The two signals at 175.5 and 164.8 ppm were observed for the C=S and C=O groups, respectively. In the 13C NMR spectrum with the cross-polarization experiment of CuL2, the signal for C=S was upfield shifted by 7.2 ppm. This showed that the C=S group of the ligand participated in the coordination with the copper. Also, a signal at 40.3 ppm was observed, confirming the coordination of DMSO-h6 to Cu(II).
There are six couples of signals in the 1H NMR spectrum of Pd(II) complex with 6-propyl-2-thiouracil. In each couple, one of the resonances was observed for the free ligand (the L2) and the other for the coordinated L2. The couples at 12.20/10.77 ppm and 12.32/10.87 ppm were observed for NH at the first and third positions. The couple at 5.68/5.31 ppm was observed for olefin proton 5. The three couples at 2.32 ppm (t,7.3)/2.25 (t,7.3) ppm, 1.54 ppm (sx, 7.6)/1.48 ppm (m), and 0.87 ppm (t, 7.3)/0.82 ppm (m) were observed for propyl protons (H-1′), (H-2′), and (H-3′), respectively. A singlet at 2.54 ppm was observed, which corresponds to DMSO-h6. It is interesting to note that all resonances were shifted for coordinated L2 compared to the free L2 but the shifts were higher for NHs. In PdL2, the singlets for NH-1 and NH-3 were upfield shifted by 1.43 and 1.44 ppm, respectively.
The 13C NMR solution spectrum of PdL2 showed seven groups of signals. The two signals with the highest chemical shift, at 176.02 ppm and 164.19 ppm, were for the C=S and C=O groups in PdL2, respectively. There was also a resonance at 161.09 ppm (free ligand), i.e., there was downfield shift of 2.97 ppm. This shows that the C=O group of the ligand participated in the coordination with Pd(II).
In the CP NMR spectrum of PdL2, the signal for C=S was upfield shifted by 3.2 and 2.6 ppm. In the same spectrum, there were three signals for C=O, shown in Table 8. One was upfield shifted by 4.5 ppm and the other was downfield shifted by 2.2 ppm. This shows that the C=S and C=O groups of the ligand participated in the coordination with the palladium in two different ways.
The ATR spectra of CuL2 and PdL2 showed the presence of H2O and/or OH−.
According to the solid-state NMR, clear shifts in the signals of the carbon atoms were observed in the complex of Cu(II) with L1, indicating the presence of the complex. There were also signals corresponding to the starting ligand L1, which may or may not be included in the second coordination sphere.
In the case of ligand L2, the ligand itself showed doubled signals for the carbon atoms C-5, C-2′, and C-3′, possibly due to a different spatial arrangement of these atoms in the crystalline lattice of the ligand (Figure 4a). In the case of the Cu(II)L2 complex, the ligand signals could still be observed, accompanied by the complex signals. However, in this case, the DMSO in the complex was present as a ligand. Despite the presence of many C-1′ signals around it in the CP spectrum (Figure 4b), the DMSO signal could be easily identified in the CPPI spectrum (Figure 4c).
The 13C spectrum of PdL2 obtained by cross-polarization (Figure 4d) showed unexpected results. There were multiple signals for each type of carbon atom in the ligand, indicating the presence of more than one palladium complex or a palladium complex with two ligands in the coordination sphere simultaneously.
The representation of coordination binding sites for 6-metyl-2-thiouracil and 6-propyl-2-thiouracil with copper and palladium ions is shown in Figure 5.
The coordination binding sites in the CuL2 complex proposed in this study was similar to that reported by Golubyatnikova et al. for Pt(II) and Pd(II) complexes with 6-tert-butyl-2-thiouracil [11]. These results demonstrated the bonding of ligand through sulfur in all complexes [11]. Our suggested coordination binding site for 6-propyl-2-thiouracil in CuL2 was similar to that presented by Paizanos et al. for Cu(I) complexes [14]. Various metal complexes exhibited a monodentate coordination mode with 2-thiouracil derivatives, binding through an S atom (Ru(II), Cu(I), Sn(IV), Pt(II), and Pd(II) complexes) [11,14,23,29] (see Scheme 1, middle). For the Cu(II)L1 complex, we proposed monodentate coordination through an S atom and/or monodentate coordination through an O atom. The coordination binding sites of the abovementioned complex are a combination of structures shown in Scheme 1 (middle). The coordination geometry of Cu(II)L1 and CuL2 complexes is tetrahedral/planar square and octahedral, respectively.
The coordination binding sites of PdL1 and PdL2 complexes proposed here are consistent with the data reported by Khan et al. [43] for Pd(II) complexes with sodium 4-(2-methoxyphenyl)piperazine-1-carbodithioate and diphenyl-p-tolylphosphine or tri-p-tolylphosphine. The S-containing ligands acted as a bidentate ligand, coordinating with the metal ion through the two sulfur atoms [43]. In our study, we proposed that one of the ligands participate in coordination via N1 and S2 atoms, and that the other ligand participates in coordination via N3 and O4 atoms. The coordination binding sites of PdL1 and PdL2 complexes are likely a combination of structures A and C shown in Scheme 1. Complexes with Pt(II), Pd(II), Ru(II), and Zn(II) display coordination mode (A) in which the ligand acted as a bidentate chelate through an N1 atom and a S2 atom as it is described [12,13,28,33].

3.2. Antimicrobial Activity

Table 12 shows the results of the antimicrobial assay of 6-methyl-2-thiouracil and its complexes.
The highest antimicrobial activity was exhibited by the CuL1 complex. It was active against all the test-microorganisms. The Pd(II)L1 complex did not inhibit the growth of S. aureus, E. faecalis, and S. cerevisiae. 6-methyl-2-thiouracil showed the smallest antimicrobial specter; it was not active against S. aureus, E. coli, S. enterica, and S. cerevisiae. The addition of Cu(II) improved the antimicrobial activity of 6-methyl-2-thiouracil against all of the test microorganisms, except B. cereus. However, there were single cell colonies in the inhibition zones (IZ) against E. coli, P. vulgaris, and K. pneumoniae. This is indicative of different levels of resistance in the microbial population. The addition of Pd(II) on the other hand, led to a loss of activity against E. faecalis and lower activity against L. monocytogenes and C. albicans.
The inhibition zone diameters for 6-propyl-2-thiouracil are presented in Table 13.
It showed higher antimicrobial activity against P. vulgaris and both yeasts strains in comparison to the complexes with Cu(II) and Pd(II). The Cu(II) complex inhibited the growth of all test microorganisms to a different degree; the best results were obtained against E. faecalis, S. enterica, and P. aueruginosa. P. vulgaris was resistant to the tested concentration of the Pd(II) complex (unlike against 6-propyl-2-thiouracil), but all other test microorganisms were more sensitive towards its action in comparison to 6-propyl-2-thiouracil. This pattern was also observed in comparison to the Cu(II) complex, except for E. coli, P. vulgaris, and S. cerevisiae. Similar to 6-methyl-2-thiouracil and its complexes, there were single cells in some inhibition zones (e.g., 6-propyl-2-thiouracil against B. cereus, K. pneumonia, and S. cerevisiae). There were two distinct inhibition zones of the Pd(II) complex against S. aureus and B. cereus: a smaller clear zone and an additional larger zone with single cell colonies within. A more concentrated sample would probably completely inhibit the growth of these microorganisms and significantly increase the antimicrobial activity of the complex.
Generally, the presence of Cu(II) and Pd(II) ions in the complexes increased the antimicrobial activity of the tested substances, which is in line with the work of other authors [44].

4. Conclusions

This paper presents the synthesis of four novel complexes of 6-methyl-2-thiouracil and 6-propyl-2-thiouracil. The structures of the new complexes are discussed based on melting point analysis (MP-AES) for Cu and Pd, UV-Vis, IR, ATR, solution and solid-state NMR, and Raman spectroscopy. Based on the spectral data, we proposed the coordination binding site of the ligands. We assume that polymer complexes are formed, as shown by their low solubility in different polarity organic solvents.
The antimicrobial activity of the ligands and their complexes against Gram-positive and Gram-negative bacteria and yeasts was investigated. In general, addition of metal ions improved the antimicrobial activity of both 6-methyl-2-thiouracil and 6-propyl-2-thiouracil. The complex of Cu(II) with 6-methyl-2-thiouracil and Pd(II) with 6-propyl-2-thiouracil demonstrated the highest activity against the test microorganisms.

Author Contributions

Conceptualization, P.M. and P.P.; methodology, P.M. and M.H.; formal analysis, P.P., N.B., S.T. and E.V.; investigation, S.T., N.B., D.B., A.S. and E.V.; resources, N.B.; data curation, P.M.; writing—original draft preparation, P.M., N.B., D.B., A.S. and P.P.; writing—review and editing, P.M., P.P. and N.B.; supervision, P.M.; project administration, S.T.; funding acquisition, P.P. All authors have read and agreed to the published version of the manuscript.

Funding

We acknowledge the financial support from the Fund for Scientific Research of the Plovdiv University, project CП 23-XФ-006.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

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Applsci 13 13150 sch001
Scheme 1. Structure of 6-methyl-2-thiouracil and 6-propyl-2-thiouracil, including the atoms numbering and representation of coordination binding sites.
Scheme 1. Structure of 6-methyl-2-thiouracil and 6-propyl-2-thiouracil, including the atoms numbering and representation of coordination binding sites.
Applsci 13 13150 sch001
Applsci 13 13150 g001
Figure 1. Synthesis of metal complexes of 6-methyl-2-thiouracil (L1) and 6-propyl-2-thiouracil (L2) with Cu(II).
Figure 1. Synthesis of metal complexes of 6-methyl-2-thiouracil (L1) and 6-propyl-2-thiouracil (L2) with Cu(II).
Applsci 13 13150 g001
Applsci 13 13150 g002
Figure 2. Synthesis of metal complexes of 6-methyl-2-thiouracil (L1) and 6-propyl-2-thiouracil (L2) with Pd(II).
Figure 2. Synthesis of metal complexes of 6-methyl-2-thiouracil (L1) and 6-propyl-2-thiouracil (L2) with Pd(II).
Applsci 13 13150 g002
Applsci 13 13150 g003
Figure 3. Solid-state CP MAS 13C NMR of the ligand L1 (a) and its complex with copper (b).
Figure 3. Solid-state CP MAS 13C NMR of the ligand L1 (a) and its complex with copper (b).
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Figure 4. Solid-state 13C NMR of the ligand L2 and its complexes: (a) 13C CP spectrum of L2, (b) 13C CP spectrum of Cu(II)L2, (c) 13C CPPI spectrum of Cu(II)L2, and (d) 13C CP spectrum of Pd(II)L2.
Figure 4. Solid-state 13C NMR of the ligand L2 and its complexes: (a) 13C CP spectrum of L2, (b) 13C CP spectrum of Cu(II)L2, (c) 13C CPPI spectrum of Cu(II)L2, and (d) 13C CP spectrum of Pd(II)L2.
Applsci 13 13150 g004
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Figure 5. The representation of suggested coordination binding sites for 6-metyl-2-thiouracil and 6-propyl-2-thiouracil.
Figure 5. The representation of suggested coordination binding sites for 6-metyl-2-thiouracil and 6-propyl-2-thiouracil.
Applsci 13 13150 g005
Table 1. Elemental analysis data for the metal ions of the complexes.
Table 1. Elemental analysis data for the metal ions of the complexes.
Metal ComplexComposition *FormulaMolecular WeightW(M)% Calc./Exp.
CuL1[3LCu.(DMSO)]C17H24N6O4S4CuM = 568.22 g/mol11.2/11.6 ± 0.6
PdL1[5LPd.(DMSO)].H2OC27H38N10O7S6PdM = 913.46 g/mol11.6/11.1 ± 0.6
CuL2[LCu.H2O.(OH−)2.(DMSO)2]C11H26N2O6S3CuM = 442.07 g/mol14.4/14.3 ± 0.7
PdL2[4LPd.(DMSO)2].H2OC32H54N8O7S6PdM = 961.63 g/mol11.1/11.5 ± 0.5
* Putative average composition of different complexes.
Table 2. Analytical and physical characteristics of metal complexes with 6-methyl-2-thiouracil.
Table 2. Analytical and physical characteristics of metal complexes with 6-methyl-2-thiouracil.
ComplexesColorYield (%)Melting Point (°C)Solubility, * Limited
L1colorless 330soluble in DMSO
CuL1yellow-green61>350 °Csoluble in DMSO *, DMF *, C2H5OH *, H2O * and insoluble in THF, EtOAc, and C6H12.
PdL1brown72>350 °Csoluble in DMSO *, DMF * and insoluble in H2O, THF, C2H5OH, EtOAc, and C6H12.
L2colorless 218–220soluble in DMSO
CuL2yellow-green43260–263 °Csoluble in DMSO * and insoluble in H2O, THF, C2H5OH, EtOAc, and C6H12.
PdL2brown70255–257 °CSoluble in DMSO *, DMF * and insoluble in H2O, THF, C2H5OH, EtOAc, and C6H12.
Table 3. Selected experimental IR data (in KBr, wavenumber in cm−1) for 6-methyl-2-thiouracil and its complexes.
Table 3. Selected experimental IR data (in KBr, wavenumber in cm−1) for 6-methyl-2-thiouracil and its complexes.
AssignmentL1CuL1PdL1
ν(OH)--3442
ν(NH)3115 sh31153111
ν(NH)308030803071
ν(=CH)301430033052
ν(C=O)1676 m16371678
1560 w15591559
ν(C=S)124212421244
1167 s11671168
Table 4. Selected experimental IR data (in KBr, wavenumber in cm−1) for 6-propyl-2-thiouracil and its complexes.
Table 4. Selected experimental IR data (in KBr, wavenumber in cm−1) for 6-propyl-2-thiouracil and its complexes.
AssignmentL2CuL2PdL2
ν(OH)-34513437
ν(NH)3112-3117
ν(NH)309330933080
ν(=CH)30423042
ν(C=O)165616511657
155715531545
ν(C=S)124312321261
116511661175
Table 5. 1H and 13C NMR spectral data and 1H-1H COSY and HMBC correlations for 6-methyl-2-thiouracil [600.13 MHz (1H) and 150.903 MHz (13C)] a.
Table 5. 1H and 13C NMR spectral data and 1H-1H COSY and HMBC correlations for 6-methyl-2-thiouracil [600.13 MHz (1H) and 150.903 MHz (13C)] a.
Atomδ (13C) ppmDEPT-135δ (1H) ppmMultiplicity (J, Hz)1H-1H COSYHMBC
1 (NH) 12.29s
2 (C=S)175.87C
3 (NH) 12.29s
4 (C=O)161.06C
5103.72CH5.68d (0.9)74 b, 6, 7
6153.20C
1′18.11CH32.06d (0.7)55, 6
a In DMSO-d6 solution. All these assignments were in agreement with COSY, HMQC, and HMBC spectra. b These correlations are weak.
Table 6. 1H NMR spectral data (in ppm) for complexes of 6-methyl-2-thiouracil with Cu(II) and Pd(II).
Table 6. 1H NMR spectral data (in ppm) for complexes of 6-methyl-2-thiouracil with Cu(II) and Pd(II).
AtomL1
(6-Methyl-2-Thiouracil)		CuL1
Multiplicity (J, Hz)		PdL1
Multiplicity (J, Hz)
1 (NH)12.29 s12.24 s12.24 s and 10.80
2 (C=S)---
3 (NH)12.29 s12.29 s12.30 s and 10.86
4 (C=O)---
55.685.68 s5.68 s and 5.31
6---
1′2.062.072.07 and 2.01
DMSO-H6 2.54 s2.54 s
Table 7. 13C NMR spectral data (in ppm) for complexes of 6-methyl-2-thiouracil with Cu(II) and Pd(II).
Table 7. 13C NMR spectral data (in ppm) for complexes of 6-methyl-2-thiouracil with Cu(II) and Pd(II).
Atomδ (13C) ppm, L1CuL1PdL1
1 (NH)---
2 (C=S)175.87175.86175.86/?
3 (NH)---
4 (C=O)161.06161.01161.01/?
5103.72103.69103.69 and 98.71
6153.20153.12153.12/?
1′18.1118.0618.06 and 18.20
Table 8. 13C NMR spectral data (in ppm) for L1, L2, and some of the complexes acquired with cross-polarization experiments, calibrated with the external reference α-glycine carbonyl C (176.03 ppm).
Table 8. 13C NMR spectral data (in ppm) for L1, L2, and some of the complexes acquired with cross-polarization experiments, calibrated with the external reference α-glycine carbonyl C (176.03 ppm).
AtomL1L2CuL1CuL2PdL2
1 (NH)
2 (C=S)174.6175.5171.7/174.8168.3/175.4172.3/172.9/174.0
3 (NH)
4 (C=O)163.0164.8162.9/169.5164.9/166.1160.3/166.4/167.0
5 (CH)104.7103.8/104.6104.7/105.4103.8/104.6/105.4/107.295.8/103.1/105.0
6 (C)156.2159.9154.0/156.4159.9/161.3153.0/156.0/159.7
1′20.232.720.132.7/39.3/39.6/40.933.4/34.2/38.6
2′ 19.6/20.2 18.2/19.7/20.2/24.418.2/19.3/19.7
3′ 13.1/14.7 13.1/13.6/14.7/15.712.9/15.4
DMSO 40.3
Table 9. 1H and 13C NMR spectral data and 1H-1H COSY and HMBC correlations for 6-propyl-2-thiouracil [500.13 MHz (1H) and 150.903 MHz (13C)] a.
Table 9. 1H and 13C NMR spectral data and 1H-1H COSY and HMBC correlations for 6-propyl-2-thiouracil [500.13 MHz (1H) and 150.903 MHz (13C)] a.
Atomδ (13C) ppmDEPT -135δ (1H) ppmMultiplicity (J, Hz)1H-1H COSY
1 (NH)--12.20s
2 (C=S)176.08C-
3 (NH)--12.31s
4 (C=O)161.22C-
5103.06CH5.67s
6156.74C
1′33.21CH22.32t(7.5)2′
2′20.58CH21.54sx(7.4)1′, 3′
3′13.26CH30.87t(7.4)2′
a In DMSO-d6 solution. All these assignments were in agreement with COSY spectra.
Table 10. 1H NMR spectral data (in ppm) for complexes of 6-propyl-2-thiouracil with Cu(II) and Pd(II).
Table 10. 1H NMR spectral data (in ppm) for complexes of 6-propyl-2-thiouracil with Cu(II) and Pd(II).
AtomL2
(6-Propyl-2-Thiouracil)		CuL2
Multiplicity (J, Hz)		PdL2
Multiplicity (J, Hz)
1 (NH)12.20 s12.20 s12.20 and 10.77 s
2 (C=S)---
3 (NH)12.31 s12.31 s12.32 and 10.87 s
4 (C=O)---
55.67 s5.67 s5.68 and 5.31 s and t(1.8)
6---
1′2.32 t(7.5)2.32 t(7.4)2.32 and 2.25 t(7.3) and t(7.3)
2′1.54 sx(7.4)1.54 sx(7.5)1.54 and 1.48 sx(7.6) and m
3′0.87 t(7.4)0.88 t(7.3)0.87 and 0.82 t(7.3) and m
DMSO-2.54 s2.54 s
In DMSO-d6 solution.
Table 11. 13C NMR spectral data (in ppm) for complexes of 6-propyl-2-thiouracil with Cu(II) and Pd(II).
Table 11. 13C NMR spectral data (in ppm) for complexes of 6-propyl-2-thiouracil with Cu(II) and Pd(II).
Atomδ (13C) ppm, L2CuL2PdL2
1 (NH)---
2 (C=S)176.08 176.02
3 (NH)---
4 (C=O)161.22 164.19 and 161.09
5103.06 98.03
6156.74 156.61 and 156.33 and 151.71
1′33.2133.2433.56 and 33.14
2′20.5820.5520.50 and 20.24
3′13.2613.2513.20
In DMSO-d6 solution.
Table 12. Antimicrobial activity of 6-methyl-2-thiouracil and its complexes.
Table 12. Antimicrobial activity of 6-methyl-2-thiouracil and its complexes.
Test MicroorganismsComplexes
6-Methyl-2-
Thiouracil		CuL1PdL1
Inhibition Zone, mm
Staphylococcus aureus ATCC 25923-8-
Escherichia coli ATCC 8739-11 *10 *
Eterococcus faecalis ATCC 194331113-
Salmonella enterica ssp. enterica ser. Enetritidis ATCC 13076-138
Pseudomonas aeruginosa ATCC 90279129
Proteus vulgaris G9 *11 *9 *
Bacillus subtilis ATCC 66339 *910 *
Bacillus cereus ATCC 117789 *89 *
Listeria monocytogenes ATCC 87879 *118
Klebsiella pneumoniae ATCC 138839 *13 *11 *
Candida albicans ATCC 1023111119/10 *
Saccharomyces cerevisiae-9-
Well diameter—7 mm, * Inhibition zone with single cell colonies.
Table 13. Antimicrobial activity of 6-propyl-2-thiouracil and its complexes.
Table 13. Antimicrobial activity of 6-propyl-2-thiouracil and its complexes.
Test MicroorganismsComplexes
6-Propyl-2-ThiouracilCuL2PdL2
Inhibition Zone, mm
Staphylococcus aureus ATCC 25923-811/16 *
Escherichia coli ATCC 8739-10 *-
Eterococcus faecalis ATCC 19433-1215
Salmonella enterica ssp. enterica ser. Enetritidis ATCC 1307681215
Pseudomonas aeruginosa ATCC 902781214
Proteus vulgaris G109 *-
Bacillus subtilis ATCC 6633812 *12
Bacillus cereus ATCC 1177810 *811/15 *
Listeria monocytogenes ATCC 87878914
Klebsiella pneumoniae ATCC 1388311 *12 *12 *
Candida albicans ATCC 10231121111
Saccharomyces cerevisiae11 *98
Well diameter—7 mm, * Inhibition zone with single cell colonies.
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Marinova, P.; Hristov, M.; Tsoneva, S.; Burdzhiev, N.; Blazheva, D.; Slavchev, A.; Varbanova, E.; Penchev, P. Synthesis, Characterization, and Antibacterial Studies of New Cu(II) and Pd(II) Complexes with 6-Methyl-2-Thiouracil and 6-Propyl-2-Thiouracil. Appl. Sci. 2023, 13, 13150. https://doi.org/10.3390/app132413150

AMA Style

Marinova P, Hristov M, Tsoneva S, Burdzhiev N, Blazheva D, Slavchev A, Varbanova E, Penchev P. Synthesis, Characterization, and Antibacterial Studies of New Cu(II) and Pd(II) Complexes with 6-Methyl-2-Thiouracil and 6-Propyl-2-Thiouracil. Applied Sciences. 2023; 13(24):13150. https://doi.org/10.3390/app132413150

Chicago/Turabian Style

Marinova, Petya, Mariyan Hristov, Slava Tsoneva, Nikola Burdzhiev, Denica Blazheva, Aleksandar Slavchev, Evelina Varbanova, and Plamen Penchev. 2023. "Synthesis, Characterization, and Antibacterial Studies of New Cu(II) and Pd(II) Complexes with 6-Methyl-2-Thiouracil and 6-Propyl-2-Thiouracil" Applied Sciences 13, no. 24: 13150. https://doi.org/10.3390/app132413150

APA Style

Marinova, P., Hristov, M., Tsoneva, S., Burdzhiev, N., Blazheva, D., Slavchev, A., Varbanova, E., & Penchev, P. (2023). Synthesis, Characterization, and Antibacterial Studies of New Cu(II) and Pd(II) Complexes with 6-Methyl-2-Thiouracil and 6-Propyl-2-Thiouracil. Applied Sciences, 13(24), 13150. https://doi.org/10.3390/app132413150

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