Bivalent metal complexes of a novel modified nicotinic acid hydrazide drug: Synthesis, characterization, and anti-tubercular studies European Journal of Chemistry 13 (1) (2022) 63-68 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2022 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. https://dx.doi.org/10.5155/eurjchem.13.1.63-68.2183 European Journal of Chemistry View Journal Online View Article Online Bivalent metal complexes of a novel modified nicotinic acid hydrazide drug: Synthesis, characterization, and anti-tubercular studies Cyprian Chunkang Mikwa 1, Gwendoline Mochia Toh-Boyo 1, Romanus Nyako Njong 2, Bridget Ndosiri Ndoye 3, Christophe Adrien Ndamyabera 4, Natsuki Katsuumi 5, Yuta Mitani 5, Emmanuel Ngwang Nfor 1,* and Takashiro Akitsu 5 1 Department of Chemistry, Faculty of Science, University of Buea, Buea, PO Box 63, Cameroon 2 Department of Fundamental Sciences, Higher Technical Teacher Training College, The University of Bamenda, Bambili, PO Box 39, Cameroon 3 Department of Inorganic Chemistry, Faculty of Science, University of Yaoundé 1, Yaoundé, PO Box 812, Cameroon 4 Department of Chemistry, Centre for Supramolecular Chemistry Research, University of Cape Town, Rondebosch 7701, South Africa 5 Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-Ku, Tokyo 162-8601, Japan * Corresponding author at: Department of Chemistry, Faculty of Science, University of Buea, Buea, PO Box 63, Cameroon. e-mail: nfor.emmanuel@ubuea.cm (E.N. Nfor). 10.5155/eurjchem.13.1.63-68.2183 Received: 08 September 2021 Received in revised form: 18 November 2021 Accepted: 20 November 2021 Published online: 31 March 2022 Printed: 31 March 2022 Iron(II) and manganese(II) complexes of N'-(1-(pyridin-2-yl)ethylidene)nicotinohydrazide (LH) have been synthesized and characterized by elemental analysis, IR, and 1H NMR spectroscopy. The crystal structure of the ligand has been determined by single crystal X- ray diffraction and electronic spectroscopic techniques. Crystal data for LH, C13H12N4O: Orthorhombic, space group Pbcn (no. 60), a = 18.0824(3) Å, b = 7.86555(14) Å, c = 16.1614(3) Å, V = 2298.60(7) Å3, Z = 8, T = 103 K, μ(Mo Kα) = 0.093 mm-1, Dcalc = 1.388 g/cm3, 36729 reflections measured (5.042° ≤ 2Θ ≤ 54.966°), 2633 unique (Rint = 0.0224, Rsigma = 0.0124) which were used in all calculations. The final R1 was 0.0383 (F2>2σ(F2)) and wR2 was 0.0988 (all data). The ligand was found to chelate to the metal ions through the azomethine nitrogen and amide oxygen atoms in a bidentate manner. The anti-tubercular activity of the ligand, its iron (II) and manganese (II) complexes were studied against Mycobacterium tuberculosis (ATTC 27294). The results revealed higher activity of the iron (II) complex with MIC value of 8.00±0.83 µM and a moderate activity of the manganese (II) complex having MIC value of 14.20±1.40 µM, compared to the reference drugs having MIC values of 9.41±0.92, 10.74±1.02, 25.34±2.6 µM and parent ligand with MIC value of 17.60±1.80 µM. Schiff base Complexes Hydrazones Crystal structure Anti-tubercular activity Nicotinic acid hydrazide Cite this: Eur. J. Chem. 2022, 13(1), 63-68 Journal website: www.eurjchem.com 1. Introduction Nicotinic acid hydrazide, which was first introduced in tuberculosis therapy in the 1950 [1], is regarded as one of the most commonly used and efficient drugs in the treatment of human tuberculosis [2]. Over one-third of the global population is said to be infected by tuberculosis leading to an approximate death rate of two to three million people annually [3]. There have been reports of increased incidence of multidrug resis- tance and extensively drug resistant strains of mycobacterium tuberculosis which compromises the recurrent effective treatment, prompting the need for the search of novel anti- tuberculosis agents [4-6]. The modification of existing drugs and the development of novel active compounds by synthetic medicinal chemists have been contributing to the strategies adopted to improve tuberculosis therapy [7-9]. In this regards, nicotinic acid hydrazide is one of the most researched anti- tubercular agents as evident in several reports of a range of its analogues, with anti-tubercular potentials and a number of promising candidates [10,11-15]. Inspired by these considera- tions, and in continuation with our studies on hydrazone Schiff bases derived from similar acid hydrazides [15,16-18], we herein report on the synthesis and characterization of iron (II) and manganese (II) complexes of a Schiff base for anti- tubercular activities. 2. Experimental 2.1. Materials and physical measurements Elemental analysis was performed on a Thermo Flash EA- 1112 Series CHNS-O Elemental Analyzer. The IR spectra were obtained from KBr pellets in the range 4000-400 cm−1, using a Perkin-Elmer Spectrum 100 FT-IR spectrometer. UV-Vis spectra were recorded at room temperature on a Cintra 5GBC spectrophotometer in ethanol. 1H NMR spectra were recorded on a Varian Unity plus 400 MHz instrument. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.13.1.63-68.2183 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.13.1.63-68.2183 mailto:nfor.emmanuel@ubuea.cm http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.13.1.63-68.2183&domain=pdf&date_stamp=2022-03-31 64 Mikwa et al. / European Journal of Chemistry 13 (1) (2022) 63-68 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.63-68.2183 N O N H N NO N N O N H NH2 Scheme 1. Synthesis of N'-(1-(pyridin-2-yl)ethylidene)nicotinohydrazide. 2.2. Single crystal X-ray diffraction analysis and structure determination A colorless block crystal of C13H12N4O having approximated dimensions of 0.120×0.110×0.100 mm was mounted on a glass fiber. All measurements were made at 203 K on a Rigaku R-AXIS RAPID diffractometer using multi-layer mirror monochro- mated MoKα radiation (λ = 0.071069 nm). The structure was solved by direct methods [19] and expanded using Fourier techniques. The non-hydrogen atoms were refined anisotro- pically. Hydrogen atoms were refined using the riding model. The final cycle of full-matrix least-squares refinement [20] on F2 was based on 2633 observed reflections and converged (The largest parameter shift was 0.00 times its e.s.d.) with an un weighted and weighted agreement factor. All calculations were performed using the crystal structure crystallographic software package [21] except for refinement, which was performed using SHELXL Version 2018/3 [19]. 2.3. Anti-tuberculosis evaluation The antimicrobial activities of the new hydrazone ligand (LH), its iron (II), and manganese (II) complexes against M. tuberculosis (ATTC 27294) were evaluated by the method reported by Maria and Lourenco [22]. The reference drugs used to evaluate the potency of the synthesized compounds were ciprofloxain (MIC = 9.41±0.92 µM), pyrazinamide (MIC = 25.34±2.6 µM) and streptomycin (MIC = 10.74±1.02 µM). 2.4. Synthesis of N'-(1-(pyridin-2-yl)ethylidene)nicotine hydrazide 2-Acetylpyridine (1.620 g, 0.01 mmol) was added to nicotinic acid hydrazide (1.837 g, 0.01 mmol) in 25 mL of ethanolic solution with three drops of glacial acetic acid added as catalyst. The resulting mixture was refluxed for five hours at a temperature of 80 °C with continuous stirring. The product was left to cool overnight, removed by vacuum filtration; the precipitate was washed several times with water, ethanol, and diethyl ether and dried in a desiccator. Yellow crystals suitable for single crystal X-ray diffraction studies were obtained from the ethanolic filtrate after 30 days (Scheme 1). N'-(1-(pyridin-2-yl)ethylidene)nicotinohydrazide: Color: Yellow. Yield: 80%. M.p.: 205-207 °C. FT-IR (KBr, ν, cm-1): 3600 (OH), 3200 (N-H), 1700 (C=O), 1583 (C=N), 900-781 (C-H, Ar). 1H-NMR (400 MHz, DMSO-d6, δ, ppm): 1.62 (s, 3H, CH3), 7.28 (m, 1H, Ar-H), 7.43 (m, 1H, Ar-H),7.66 (sbr, 1H, Ar-H), 7.83 (sbr, 1H, Ar-H), 8.23 (d, J = 10.4 Hz, 1H, Ar-H), 8.57 (d, J = 6.0 Hz, 1H, Ar- H), 8.76 (sbr, 1H, Ar-H), 8.99 (sbr, 1H, Ar-H), 9.19 (sbr, 1H, N- H). MS (EI, m/z (%)): 240.10 (M+, 100). HRMS (EI, m/z) calcd. for C13H12N4O, 240.10; Found: 241.10. UV/Vis (CHCl3, λmax, nm, (ε)): 230 (3.42), 280 (3.62), 330 (4.62), 308 (4.48), 391 (5.32). Anal. calcd. for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found: C, 64.97; H, 4.96; N, 23.37%. 2.5. Synthesis of manganese (II) complex Manganese (II) chloride tetrahydrate (0.199 g, 1.0 mmol) was added to N'-(1-(pyridin-2-yl)ethylidene)nicotinohydrazide (0.480 g, 2.0 mmol) in a 25 mL ethanolic solution. The resulting mixture was refluxed for 5 hours at a temperature of 90 °C with continuous stirring using a magnetic stirrer. The pale-yellow solution obtained was allowed to cool overnight, the precipitate removed by filtration; washed with ethanol and stored in a desiccator. Manganese (II) complex: Color: Yellowish. Yield: 85%. FT-IR (KBr, ν, cm-1): 3600 (OH), 2990 (N-H), 1620 (C=O), 1470 (C=N), 600-750 (C-H), 580 (Mn-O), 470 (Mn-N). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.08 (s, 6H, CH3), 6.86 (m, 3H, Ar- H), 6.99 (s, J = 8 Hz, 2H, Ar-H), 7.12 (d, J = 8 Hz, 2H, Ar-H), 7.53 (t, J = 8 Hz, 2H, Ar-H), 7.61 (sbr, 3H, Ar-H), 7.90 (d, J = 8 Hz, 1H, Ar-H), 8.25 (s, 1H, Ar-H), 10.81 (d, 2H, Ar-H), 11.97 (s, 2H, N-H). Anal. calcd. for C26H24Cl2MnN8O2: C, 51.50; H, 3.99; N, 18.48. Found: C, 51.97; H, 3.90; N, 18.37%. 2.6. Synthesis of iron (II) complex Iron (II) chloride tetrahydrate (0.198 g, 1.0 mmol) was added to N'-(1-(pyridin-2-yl)ethylidene)nicotinohydrazide (0.480 g, 2.0 mmol) in a 25 mL ethanolic solution. The resulting mixture was refluxed for 5 hours at a temperature of 80 °C with continuous stirring using a magnetic stirrer. The reddish- brown solution obtained was allowed to cool overnight; the precipitate was removed by filtration, washed with ethanol and stored in a desiccator. Iron (II) complex: Color: Brownish. Yield: 85%. FT-IR (KBr, ν, cm-1): 3600 (OH), 2980 (N-H), 1650 (C=O), 1525 (C=N), 750-800 (C-H), 530 (Fe-O), 460 (Fe-N). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.08 (s, 6H, CH3), 6.97 (m, 3H, Ar- H), 6.99 (s, J = 8 Hz, 2H, Ar-H), 7.13 (d, J = 8 Hz, 2H, Ar-H), 7.40 (t, J = 8 Hz, 2H, Ar-H), 7.44 (sbr, 3H, Ar-H), 7.60 (d, J = 8 Hz, 1H, Ar-H), 8.29 (s, 1H, Ar-H), 8.31 (d, 2H, Ar-H), 11.38 (s, 2H, N-H). Anal. calcd. for C26H24Cl2FeN8O2: C, 51.42; H, 3.98; N, 18.45. Found: C, 51.60; H, 3.98; N, 18.30%. 3. Results and discussion 3.1. Synthesis The elemental analysis for C, H, and N revealed that the calculated and experimental data for the Schiff base ligand LH are in agreement, thus confirming the proposed molecular formula C13H12N4O for the ligand. The agreement between the calculated and experimental elemental analyses values for the metal complexes revealed a 1:2 (metal-ligand) stoichiometry, thus confirming their suggested formulae. These results further confirm the high purity of the prepared compounds. The infrared spectra of the ligand LH and its metal (II) complexes were recorded within the 4000-400 cm-1 region. The IR-spectrum of the hydrazone ligand exhibited a medium band at 3600 cm-1 and a broad band at 3200 cm-1 attributed to ν(OH) of the coordinated water molecule and ν(NH) stretching vibrations, respectively. The strong bands at 1700 and 1583 cm- 1 in the spectrum of the ligand, corresponds to the presence of ν(C=O) [23] and ν(C=N) vibration modes [16]. Bands appearing at 995, 939, 800, and 781 cm-1 in the spectrum of LH are the usual modes of C-H of the aromatic ring vibrations and these revealed small shifts in the metal (II) complexes compared to the free ligand, which is the expected electronic structure changes that occur with coordination of the ligand to metal (II) ions. Mikwa et al. / European Journal of Chemistry 13 (1) (2022) 63-68 65 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.63-68.2183 Table 1. Crystal data and structure refinement of N'-(1-(pyridin-2-yl)ethylidene)nicotinohydrazide. Empirical formula C13H12N4O Formula weight 240.26 Temperature (K) 103 Crystal system Orthorhombic Space group Pbcn a, (Å) 18.0824(3) b, (Å) 7.86555(14) c, (Å) 16.1614(3) Volume (Å3) 2298.60(7) Z 8 ρcalc(g/cm3) 1.388 μ (mm-1) 0.093 F(000) 1008 Crystal size (mm3) 0.12 × 0.11 × 0.1 Radiation Mo Kα (λ = 0.71075) 2Θ range for data collection (°) 5.042 to 54.966 Index ranges -23 ≤ h ≤ 23, -10 ≤ k ≤ 10, -20 ≤ l ≤ 20 Reflections collected 36729 Independent reflections 2633 [Rint = 0.0224, Rsigma = 0.0124] Data/restraints/parameters 2633/0/164 Goodness-of-fit on F2 1.049 Final R indexes [I≥2σ (I)] R1 = 0.0383, wR2 = 0.0974 Final R indexes [all data] R1 = 0.0402, wR2 = 0.0988 Largest diff. peak/hole (e.Å-3) 0.44/-0.27 Figure 1. Molecular structure of LH with atom numbering scheme. In the spectrum of the manganese (II) complex, the ν(C=O) and ν(C=N) vibration bands experience negative shifts to 1620 cm-1 and 1470 cm-1, respectively, compared to the ligand. This indicates the coordination the carbonyl oxygen and the azomethine nitrogen atoms to the manganese (II) ion. In the low frequency region, the bands in the region 580 and 470 cm-1 are probably due to ν(Mn-O) and ν(Mn-N) vibrations, respectively. In the spectrum of the iron (II) complex, the ν(C=O) and ν(C=N) vibration bands have also experienced a negative shift to the frequencies of 1650 and 1525 cm-1, respectively, indicating coordination of the carbonyl oxygen and the azomethine nitrogen atoms to the iron (II) ion. In the low frequency region, the bands in the regions 460 and 530 cm-1 are probably due to the ν(Fe-O) and ν(Fe-N) vibrations, respectively [24-26]. In both complexes, the broad bands at 3600 and 2980 cm-1 are attributed to ν(OH) of the coordinated water molecule and ν(NH) of the amide. The structural features of the ligand and its metal (II) complexes in this investigation are supported by the 1H NMR spectra obtained in DMSO-d6 solution. In the 1H NMR spectrum of the ligand, the multiplets at δ 7.28-8.99 ppm are attributed to the pyridyl rings protons. The amide proton is attributed to the signals at δ 9.19 ppm in the ligand. The methyl protons in this ligand are visible at δ 1.62 ppm. In the manganese complex, the pyridyl ring protons are attributed to the signals at δ 6.86-10.81 ppm, with the amide proton attributed to the signal at δ 11.97 ppm. The methyl proton in this complex is attributed to the signal at δ 2.08 ppm. The iron complex also exhibited signals at between δ 6.97-8.31 ppm attributed to the pyridyl ring protons, while the amide proton further exhibited signal at δ 11.38 ppm. The methyl proton signal in this complex is visible at δ 2.08 ppm. All the changes in the signals of the pyridyl ring, amide and methyl protons in the metal (II) complexes, suggests the involvement of the azomethine nitrogen and carbonyl oxygen atoms in coordination [16,27]. In the UV spectrum of LH, two relatively intense peaks were observed at 230 and 280 nm, attributed to the n-π* of the aromatic rings and the others peaks attributed to the azomethine group transitions are observed at 308-315 nm [28]. 3.2. Crystal structure analysis The molecular structure of N'-(1-(pyridin-2-yl)ethylidene) nicotinohydrazide is shown in Figure 1 along with the atomic numbering scheme. The crystal structure refinement data for LH is shown in Table 1. The bond lengths, bond angles, and torsion angles of LH are listed in Table 2. The Schiff base LH crystallizes in the orthorhombic system in the space group Pcbn. In LH, the bond distance C(6)-N(2) is equal to 1.2781(2) Å indicating its double bond nature. The bond lengths N(1)- C(1), N(1)-C(5), N(4)-C(10), and N(4)-C(11) are equal to 1.3427(14), 1.3472(13), 1.3408(13), and 1.3388(14), respect- tively. These data are indicated that this molecule has the endocyclic double bonds. The bond distance C(11)-O(18) is equal to 1.2282(2) Å, corresponding to the double bond length reported in similar Schiff bases [29,30]. Hydrogen bond interactions are listed in Table 3. The packing of the molecules when viewed along the a-axis is shown in Figure 2. 3.3. Anti-tuberculosis activity The evaluation of the antitubercular activities of the ligand, its iron (II) and manganese (II) complexes against Mycobac- terium tuberculosis was carried out using streptomycin, Ciprof- 66 Mikwa et al. / European Journal of Chemistry 13 (1) (2022) 63-68 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.63-68.2183 Table 2. The bond lengths, bond angles, and torsion angles of N'-(1-(pyridin-2-yl)ethylidene)nicotinohydrazide. Atom Atom Length (Å) Atom Atom Length (Å) O1 C8 1.2282(13) C3 C4 1.3846(15) N1 C1 1.3427(14) C4 C5 1.3946(14) N1 C5 1.3472(13) C5 C6 1.4908(14) N2 N3 1.3783(12) C6 C7 1.5002(14) N2 C6 1.2871(13) C8 C9 1.4966(14) N3 C8 1.3608(13) C9 C10 1.3922(14) N4 C10 1.3408(13) C9 C13 1.3919(14) N4 C11 1.3388(14) C11 C12 1.3910(15) C1 C2 1.3878(16) C12 C13 1.3879(15) C2 C3 1.3915(15) Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) C1 N1 C5 117.47(9) N2 C6 C7 127.93(10) C6 N2 N3 118.60(9) C5 C6 C7 118.09(9) C8 N3 N2 116.90(8) O1 C8 N3 124.04(9) C11 N4 C10 116.78(9) O1 C8 C9 121.81(9) N1 C1 C2 123.43(10) N3 C8 C9 114.14(9) C1 C2 C3 118.60(10) C10 C9 C8 122.07(9) C4 C3 C2 118.74(10) C13 C9 C8 119.17(9) C3 C4 C5 118.98(9) C13 C9 C10 118.75(9) N1 C5 C4 122.76(9) N4 C10 C9 123.53(9) N1 C5 C6 115.75(9) N4 C11 C12 123.93(10) C4 C5 C6 121.49(9) C13 C12 C11 118.57(10) N2 C6 C5 113.93(9) C12 C13 C9 118.30(10) A B C D Angle (°) A B C D Angle (°) O1 C8 C9 C10 126.73(11) C2 C3 C4 C5 0.34(15) O1 C8 C9 C13 -54.36(14) C3 C4 C5 N1 1.10(15) N1 C1 C2 C3 -0.04(17) C3 C4 C5 C6 -178.88(9) N1 C5 C6 N2 -147.36(9) C4 C5 C6 N2 32.62(13) N1 C5 C6 C7 30.35(13) C4 C5 C6 C7 -149.68(10) N2 N3 C8 O1 3.17(15) C5 N1 C1 C2 1.41(16) N2 N3 C8 C9 -175.91(8) C6 N2 N3 C8 178.93(9) N3 N2 C6 C5 177.57(8) C8 C9 C10 N4 177.63(9) N3 N2 C6 C7 0.13(16) C8 C9 C13 C12 -175.56(9) N3 C8 C9 C10 -54.17(13) C10 N4 C11 C12 3.12(16) N3 C8 C9 C13 124.75(10) C10 C9 C13 C12 3.39(15) N4 C11 C12 C13 -1.02(17) C11 N4 C10 C9 -1.93(15) C1 N1 C5 C4 -1.94(15) C11 C12 C13 C9 -2.32(16) C1 N1 C5 C6 178.04(9) C13 C9 C10 N4 -1.29(16) C1 C2 C3 C4 -0.84(16) Table 3. Geometry of hydrogen bond interactions for N'-(1-(pyridin-2-yl)ethylidene)nicotinohydrazide. Donor-H···Acceptor D-H (Å) H···A (Å) D···A (Å) ∠ D-H···A (°) Symmetry N(3)-H(3)···O(1) 0.88 2.22 3.0887(12) 169 1/2-x, 1/2+y, z N(3)-H(3)···N(2) 0.88 2.58 3.1080(12) 119' 1/2-x, 1/2+y, z C(7)-H(7A)···N(3) 0.98 2.51 2.8691(14) 101 - C(7)-H(7A)···O(1) 0.98 2.32 3.1900(14) 148' 1/2-x, 1/2+y, z Figure 2. Packing of molecules viewed along the a-axis. loxacin, and pyrazinamide as reference drugs. The iron (II) complex with MIC 8.00±0.83 µM exhibited the highest anti- tuberculosis activity compared to the manganese (II) complex with MIC value of 14.2±1.40 µM and all standards as shown in Table 4. The ligand with MIC value 17.6±1.80 µM exhibited the least activity compared to its metal complexes. This may be attributed to the reduced polarity of the central metals (II) ions which partially share their positive charges with the donor groups as well as the possible π-electron delocalization within the entire chelating ring system formed during coordination. This enhances the lipophilic character of the central metal atoms/ions, thereby increasing their hydrophobic character and favoring their ability to permeate the lipid layers of the cell membrane as explained by the Tweedy’s chelation theory [31]. Mikwa et al. / European Journal of Chemistry 13 (1) (2022) 63-68 67 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.63-68.2183 Table 4. Anti-tubercular activity of ligand and its metal (II) complexes *. Test sample Sample concentration in µM (MIC)±SD Ligand (LH) 17.60±1.80 Fe(LH)2Cl2 8.00±0.83 Mn(LH)2Cl2 14.20±1.40 Ciprofloxacin 9.41±0.92 Streptomycin 10.74±1.02 Pyrazinamide 25.34±2.60 * Values expressed are mean±SD of three parallel measurements. Overall, the results showed higher activity of the metal (II) complexes against M. tuberculosis as compared to the standard drug pyrazinamide, and a moderate activity as compared to streptomycin and ciprofloxacin drugs. 4. Conclusion We have synthesized iron (II) and manganese (II) comp- lexes of nicotinic acid hydrazide derived Schiff base compound. The prepared compounds were characterized using FT-IR, 1H NMR spectroscopy, XRD, and UV-vis spectroscopic techniques and investigated for anti-tuberculosis activities. The prepared ligand chelates to the metal center in a bidentate manner through the azomethine nitrogen and the amide oxygen atoms to form an octahedral geometry of the metal (II) complexes. The iron (II) complex exhibited a higher activity while the manganese (II) complex showed a moderate activity against Mycobacterium tuberculosis compared to the reference drugs and parent ligand. Acknowledgements This work was supported (in part) by Nanotechnology Platform of Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, Number JPMXP09S20NR0016 and by a Grant-in-Aid for Scientific Research (KAKENHI) number 20H00336. The authors thank Shohei Katao, Nara Institute of Science and Technology (NAIST), Japan, for X-ray crystallography. The authors are grateful to Professor Susan A. Bourne of Cape Town University in South Africa for the spectral analysis. Supporting information CCDC-2090758 contains the supplementary crystallographic data for N'-(1- (pyridin-2-yl)ethylidene)nicotinohydrazide. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or by e- mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. CRediT authorship contribution statement Conceptualization: Emmanuel Ngwang Nfor, Takashiro Akitsu; Methodology: Cyprian Chunkang Mikwa, Gwendoline Mochia Toh-Boyo; Software: Yuta Mitani, Natsuki Katsuumi; Formal Analysis: Christophe Adrien Ndamyabera; Writing - Original Draft: Bridget Ndosiri Ndoye, Romanus Nyako Njong; Writing - Review and Editing: Emmanuel Ngwang Nfor, Takashiro Akitsu; Funding acquisition: Takashiro Akitsu. ORCID and Email Cyprian Chunkang Mikwa mchunkang@yahoo.com https://orcid.org/0000-0003-4101-0195 Gwendoline Mochia Toh-Boyo gwendoline.mochia@ubuea.cm https://orcid.org/0000-0002-9785-6678 Romanus Nyako Njong njong74@gmail.com https://orcid.org/0000-0001-7429-6332 Bridget Ndosiri Ndoye ndosirin@yahoo.com https://orcid.org/0000-0001-7969-8963 Christophe Adrien Ndamyabera ndmchr002@myuct.ac.za https://orcid.org/0000-0002-2605-319X Natsuki Katsuumi 1320529@ed.tus.ac.jp https://orcid.org/0000-0002-0423-4360 Yuta Mitani 1320605@ed.tus.ac.jp https://orcid.org/0000-0001-8082-4293 Emmanuel Ngwang Nfor nfor.emmanuel@ubuea.cm https://orcid.org/0000-0002-0868-8917 Takashiro Akitsu akitsu2@rs.tus.ac.jp https://orcid.org/0000-0003-4410-4912 References [1]. Judge, V.; Narasimhan, B.; Ahuja, M. Isoniazid: The Magic Molecule. Med. Chem. Res. 2012, 21 (12), 3940–3957. [2]. van den Boogaard, J.; Kibiki, G. S.; Kisanga, E. R.; Boeree, M. J.; Aarnoutse, R. E. 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Res. 2013, 7 (4), 313–317. http://www.ccdc.cam.ac.uk/conts/retrieving.html mailto:data_request@ccdc.cam.ac.uk mailto:mchunkang@yahoo.com https://orcid.org/0000-0003-4101-0195 mailto:gwendoline.mochia@ubuea.cm https://orcid.org/0000-0002-9785-6678 mailto:njong74@gmail.com https://orcid.org/0000-0001-7429-6332 mailto:ndosirin@yahoo.com https://orcid.org/0000-0001-7969-8963 mailto:ndmchr002@myuct.ac.za https://orcid.org/0000-0002-2605-319X mailto:1320529@ed.tus.ac.jp https://orcid.org/0000-0002-0423-4360 mailto:1320605@ed.tus.ac.jp https://orcid.org/0000-0001-8082-4293 mailto:nfor.emmanuel@ubuea.cm https://orcid.org/0000-0002-0868-8917 mailto:akitsu2@rs.tus.ac.jp https://orcid.org/0000-0003-4410-4912 https://www.who.int/tb/publications/global_report/gtbr2017 68 Mikwa et al. / European Journal of Chemistry 13 (1) (2022) 63-68 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.1.63-68.2183 [12]. 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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). https://doi.org/10.21060/cis.v3i3.2260 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. Materials and physical measurements 2.2. Single crystal X-ray diffraction analysis and structure determination 2.3. Anti-tuberculosis evaluation 2.4. Synthesis of N'-(1-(pyridin-2-yl)ethylidene)nicotine hydrazide 2.5. Synthesis of manganese (II) complex 2.6. Synthesis of iron (II) complex 3. Results and discussion 3.1. Synthesis 3.2. Crystal structure analysis 3.3. 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