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3PREPARATION AND STRUCTURAL STUDYING OF THE TETRACLORIDOZINCATE (II) COMPLEX WITH METHYLENE BLUE - A POTENTIAL ANTIVIRAL AND ANTIMICROBIAL AGENT 1A.N. Yunuskhodjayev, 2V. Kh. Sabirov, 3M. X. Kadirova
1,2,3Institute of Pharmaceutical Education and Researches, Tashkent, Uzbekistan.
https://doi.org/10.5281/zenodo.8368239
Abstract. Tetrachloridozincate(II) complex [MB]+2[ZnCU]2~ (where [MB]+ -methylthioninium cation; methylene blue cation) was synthesized as a result of the mechanochemical reaction of ZnCh-2H2O hexahydrate with [MB]Cl-5H2O in the molar ratio 1:2. The asymmetric unit of the studied compound consists of a [ZnCU]2' anion and two [MB]+ cations. Coordination polyhedron of the central atom is regular tetrahedron square planar. The planar [MB]+ cations are stacked in an antiparallel mode with sulfur atoms disposed alternatively on opposite sides, and exhibiting ж-ж stacking at the average interplanar distances of3.482 A and 3.478 A.
Keywords: Alzheimer's disease, antifungal, antimalarial therapy, candidiasis, methylene blue, mitochondrial dysfunction, tau proteins.
Аннотация. Комплекс тетрахлороцинката(П) [MB]+2[ZnCl4]2- (где [MB]+ -катион метилтиониния; катион метиленового синего) синтезирован в результате механохимической реакции гексагидрата ZnCh.2H2O с [MB]Cl.5H2O в мольном соотношении 1:2. Асимметричная единица изученного соединения состоит из аниона [ZnCl4]2' и двух катионов [MB]+. Координационный полиэдр центрального атома представляет собой правильный тетраэдр, плоский квадрат. Плоские катионы [MB]+ укладываются антипараллельно, при этом атомы серы расположены попеременно на противоположных сторонах и демонстрируют ж-ж-укладку на средних межплоскостных расстояниях 3,482 A и 3,478 A.
Ключевые слова: болезнь Альцгеймера, противогрибковая, противомалярийная терапия, кандидоз, метиленовый синий, митохондриальная дисфункция, тау-белки.
Annotatsiya. ZnCh.2H2O geksagidratning [MB]Cl.5H2O bilan mexanik kimyoviy reaksiyasi natijasida tetraxloridozinkat(II) kompleksi [MB]+2[ZnCU]2~ (bu yerda [MB]+ -metiltioniniy kationi; metilen ko'k kationi) sintez qilingan. 1:2 molyar nisbatda. O'rganilayotgan birikmaning assimetrik birligi [ZnCl4]2' anion va ikkita [MB]+ kationdan iborat. Markaziy atomning koordinatsion ko'pburchaklari muntazam tetraedr kvadrat tekislikdir. Tekis [MB]+ kationlari antiparallel rejimda yotqizilgan, oltingugurt atomlari muqobil ravishda qarama-qarshi tomonlarga joylashtirilgan va o'rtacha tekisliklararo 3,482 A va 3,478 A masofalarda ж-ж stackingni ko'rsatadi.
Kalit so'zlar: Altsgeymer kasalligi, antifungal, antimalarial terapiya, kandidoz, metilen ko'k, mitoxondriyal disfunktsiya, tau oqsillari.
1. Introduction
Methylene blue (MB), a blue-colored aniline-based dye that was first developed for the
dyeing of cotton, is a phenothiazine derivative that is soluble in water and organic solvents. Its reduced form, leucomethylene blue, is colorless and has a regulatory effect on the redox cycle [1]. This feature allows it to be used in malarial therapy by inducing glutathione reductase (GR), an enzyme of glutathione metabolism. Malaria is a disease characterized by repeated growth
cycles of Plasmodium group parasites in erythrocytes and changes in glutathione metabolism. Methylene blue was recognized as an antimalarial agent when it was observed that it reduced reactive oxygen species (ROS) by inhibiting Plasmodium falciparum glutathione reductase and by selectively inducing oxidative stress. It has also been observed that MB can reduce factors that cause aging and Alzheimer's disease (AD), such as the accumulation of tau proteins in plaques, mitochondrial dysfunction, and ROS increase due to disorders in the electron transport chain (ETC). MB has been used in Alzheimer's treatment, considering its features of tau protein inhibition, anti-ROS antioxidant properties, and ability to regulate ETC. MB, known for its antimalarial and antioxidant effects, has also been used in the treatment of Candida infections as an antifungal agent. In candidiasis infections, MB is aimed to cause mitochondrial dysfunction in yeast and treat the patient. In this review, the history of MB as an antimalarial, antioxidant and antifungal agent; malaria, Alzheimer's, and its role in the treatment of candidiasis [2, 3].
Zinc is an essential trace element that is crucial for growth, development, and the maintenance of immune function. Its influence reaches all organs and cell types, representing an integral component of approximately 10% of the human proteome, and encompassing hundreds of key enzymes and transcription factors. Zinc deficiency is strikingly common, affecting up to a quarter of the population in developing countries, but also affecting distinct populations in the developed world as a result of lifestyle, age, and disease-mediated factors. Consequently, zinc status is a critical factor that can influence antiviral immunity, particularly as zinc-deficient populations are often most at risk of acquiring viral infections such as HIV or hepatitis C virus. This review summarizes current basic science and clinical evidence examining zinc as a direct antiviral, as well as a stimulant of antiviral immunity. An abundance of evidence has accumulated over the past 50 y to demonstrate the antiviral activity of zinc against a variety of viruses, and via numerous mechanisms. The therapeutic use of zinc for viral infections such as herpes simplex virus and the common cold has stemmed from these findings; however, there remains much to be learned regarding the antiviral mechanisms and clinical benefit of zinc supplementation as a preventative and therapeutic treatment for viral infections.
Zinc is one of the essential trace elements in the human body. This element belongs to the eighth iron-group. In the biological media it occurs in the oxidation form +2. The combination of methylene blue with zinc (II) ion expands the range of the antiviral properties of methylene blue and zinc (2+) ion. However, complexes of J-metals with methylene blue have not yet been synthesized.
Methylene blue (Mb) is a salt of the formula [(C16H18SNs)+Cl-] [IUPAC name: 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride or shortly [MB]+Cl-]]. The [MB]+ cation consists of three condensed six-membered rings and two coplanar NMe2 substituents [6]. The aromaticity is suggested by the total 18 pn electron count, as indicated from the resonant structures in Fig. 1.
Figure 1. Molecular structure of [MB]+ cation with numbering atoms
The [MB]+ has N and S atoms as possible electronic donor centers. The N atoms are harder than S atom in the [MB]+ structure. It is predicted that the eventual coordination of [MB]+ to a hard acid, such as Zn2+ and other two valence J-metals, do not happen neither through the S
and the N atoms, that in accordance to Pearson's acid-base theory [5]. However, this is not observed experimentally.
The crystal structures of Cu+, Ag+, and Au+ complexes with MBCl were studied by Canossa's group [8]. The first two metal complexes showed coordination by the central N atom of [MB]+, forming a distorted trigonal planar structure with [MCh(MB)].
We decided to synthesize a salt-type complex of zinc (II) chloride with MBCl. Replacing of the chlorine ion in this complex allows to modify of the composition and receive new bioactive complexes. In this paper, crystal structure of zinc (II) complex with MB is described.
2. Preparation Syntheses of complex
The complex has been obtained as a result of the mechanochemical reaction of ZnCh x 2H2O with [MB]Cl x 5H2O that eliminate the adverse effect of the solvent on the course of the reaction. Reagents ZnCh x 2H2O (17.2 mg, 0.1 mmol) and [MB]Cl x 5H2O (82 mg, 0.2 mmol) in a 1:2 stoichiometric ratio were ground in an agate mortar until a gold-like thin mass was formed. 5.0 ml of DMF was gradually added dropwise to the reaction mixture and the process was continued until a homogeneous dark blue solution was formed.
Crystals available for X-ray diffraction were obtained by slow evaporation of the reaction solution for one week. Crystal of [ZnCU]x[MB]2 (I) is monoclinic in the space group P21/n, crystal parameters and details of the X-ray study are given in Tables 1.
Table 1
Crystal data and structure refinement for [ZnCU]x[MB]2.
C32H36N6O4ClZnS
666.142
278 K
triclinic
PI
9.7734(2)
11.5185(2)
16.6554(3)
108.0150(16)
100.2220(16)
92.0898(16)
1746.37(6)
1
1.239 1.235 683.9
0.3 x 0.3 x 0.3 CuKa (X = 1.54184)
20 range for data collection^ 5.7 to 142.82
Index ranges Reflections collected Independent reflections Data/restraints/parameters Goodness-of-fit on F2
-11 < h < 11, -14 < k < 14, -19 < l < 20 16626
6704 [Rint = 0.0366, Rsigma = 0.0482] 6704/0/423 1.028
Final R indexes [I>=2o (I)] Ri = 0.0630, wR2 = 0.1835 Final R indexes [all data] Ri = 0.0812, wR2 = 0.1972 Largest diff. peak/hole / e Á-3 1.30/-0.99
The X-ray diffraction experiment was carried out on an 'XtaLAB Synergy, HyPix3000' diffractometer (CuKa - radiation, X = 1.54184 Á, ro scan mode, mirror monochromator) [15].
The crystal structures were solved with Olex2 [16] using the program Shelxt [17], and refined by full-matrix least-squares method on F2 using the Shelxl refinement package [18].
All non-hydrogen atoms were refined anisotropically. The H atoms of the CH3-groups were included in calculated positions and refined as riding: C-H = 0.95-0.98 Á with £/iso(H) = 1.56req(C-methyl) and 1.2^eq(C) for other H atoms. The positions of all disordered Cl atoms defined from the difference Fourier map of the electron density and refined isotropically.
3. Results and discussions
The crystalline structure of 1 composed of [ZnCU]2- anion and two symmetry-independent Mb+ cations is shown in Fig. 1. The chlorine ions in the [ZnCU]- anion regular tetrahedral configuration. The Zn - Cl distances lie in the range of 2. 2.288(1) - 2.300(1) Á and have an averaged value 2.49 Á. It is shorter than the sum of the ionic radii of Zn(2+) (0.72 Á) and Cl- (1.84 Á) atoms. The bond angles Cl - Zn - Cl lay in the range of 88 - 141.1(1)° (Table 2) and show the degree of the distortion of the [ZnCU]2- tetrahedron.
The [ZnCU]2- anion linked with eight Mb+ cations owing to short contacts of the type C-H...Cl with hydrogen atoms of the aromatic cycles and terminal methyl group. Geometrical parameters these contacts are presented in Table 2. The [ZnCU]2- anions linked with seven [Mb]+ cations through interaction of the types C-H.Cl with terminal methyl groups and aromatic cycles.
The [Mb]+ cations are planar and mutually packed in an antiparallel orientation, forming intermolecular nonclassical hydrogen bonds with each other, the geometrical parameters of which are given in Table 2. The C1- C2 bonds, C4 - C12, C8 - C9 and C6 - C13 in both crystals are shortened compared with other C - C bonds (average length 1.425(6) Á) in the ring.
(a)
(b)
Figure 2: The asymmetric unit of crystal 1 (a) and crystal packing of the subunits (b). Displacement ellipsoids are drawn at the 50% probability level.
Table 2 Bond Lengths for Atom Atom Length/A Zn Cl1 2.288(1) Zn Cl2 2.3000(15) Zn Cl3 2.2474(14) Zn Cl4 2.2569(16) S02 C13B 1.742(4) S02 C11B 1.729(5) S5A C14A 1.724(4) S5A C11A 1.725(4) N10A C13A 1.328(6) N10A C12A 1.330(6) N7B C7B 1.344(6) N7B C71B 1.475(7) N7B C72B 1.463(6) N3A C3A 1.339(6) N3A C32A 1.451(6) N3A C31A 1.468(7) N7A C7A 1.342(6) N7A C71A 1.469(7) N7A C72A 1.448(7) N10B C12B 1.342(6) N10B C14B 1.326(6)
[ZnCl4](Mb)2 Atom Atom Length/A C3A C4A 1.420(6) C3A C2A 1.438(6) C12B C1B 1.418(6) C12B C11B 1.432(6) C14A C13A 1.442(6) C14A C6A 1.378(6) C4A C11A 1.368(6) C13B C14B 1.425(6) C13B C6B 1.369(6) C4B C3B 1.402(6) C4B C11B 1.378(6) C13A C9A 1.409(6) C1B C2B 1.353(7) C1A C2A 1.341(7) C1A C12A 1.429(6) C7A C6A 1.402(6) C7A C8A 1.425(7) C3B C2B 1.432(7) C9B C14B 1.427(6) C9B C8B 1.352(7) C12A C11A 1.438(6)
Table 2 Bond Lengths for [ZnCl4](Mb)2 Atom Atom Length/Â Atom Atom Length/Â N3B C3B 1.346(6) C6B C7B 1.408(6) N3B C32B 1.460(6) C9A C8A 1.356(7) N3B C31B 1.457(7) C8B C7B 1.437(7) The centroid distances between adjacent MB(A)+ and MB(B)+ cations is 4.015 Â, between two adjacent MB(A)+ cations is 4.077 Â, and between two adjacent MB(B)+ cations is 4.476 Â.
The dihedral angle between average planes (except of H atoms) of the [MB(A)]+ and [MB(B)]+ cations in the n-n stack is 2.1°.
D-H
d(D-H)
d(H..A)
<DHA
d(D..A),
Symmetry
C4A-H.. . Cl1 0.93 2.755 156.89 3.157 [x, y+1, z]
O1W-H.. .Cl2 1.053 2.162 156.66 3.157 [ x, y+1, z ]
O1w-H2. ..Cl1 1.080 2.404 138.75 3.294 [ x, y+1, z ]
C1B-H... Cl3 0.930 2.913 139.39 3.669 [ x-1, У, z ]
C1A-H.. Cl2 0.930 2.863 138.93 3.616 [ -x+2, -y, -z+1 ]
C9B-H. Cl3 0.930 2.967 131.94 3.655 [ -x+1, -y, -z ]
C6B-H. O1W 0.930 2.499 149.20 3.332
C8B-H... Cl1 0.930 2.873 175.10 3.801 1 [ -x+1, -y, -z ]
C8A-H. Cl4 0.930 2.719 149.48 3.552 [ x-1, У, z ]
C32A-H. ..O1W 0.960 2.488 149.66 3.352 [ -x+2, -y+1, -z+1 ]
C72B-H. Cl1 0.960 2.904 136.92 3.664 [ -x+1, -y, -z ]
C71A-H. Cl3 0.960 2.863 113.15 3.359 [ -x+1, -y, -z ]
C72A-H. Cl3 0.960 2.841 132.07 3.557 [ x-1, У, z ]
C72A-H. ..S5A 0.960 2.893 148.94 3.749 [ x-1, У, z ]
O1W-H1 .Cl2 1.053 2.162 156.66 3.157 [ x, y+1, z ]
Conclusion
During the solution-assistance mechanochemical synthesis of cobalt chloride with methylene blue has been obtained a salt-type complex [MB]+2[ZnCU]2-. Chemical composition and structure of the complex were determined by the single crystal X-ray diffraction crystallography. The [MB]+ cations are planar and stacked in an antiparallel fashion with the
sulfur atom disposed alternatively on opposite sides, and exhibiting n-n stacking at an with average intercationic separations 3.482 and 3.47 A.
REFERENCES
1. Yaren Kayaba§i, Oytun Erba§. Methylene blue and its importance in medicine. D. J. Med. Sci. 2020, 6(3):136-145.
2. Mot A. I., Crouch P. J. Biometals and Alzheimer's Disease. In Biometals in Neurodegenerative Diseases Mechanisms and Therapeutics. 2017, Pages 1-17.
3. Oz M., Lorke D.E., Petroianu G.A. Methylene blue and Alzheimer's disease. Biochem Pharmacol, (2009). 78, 927-932. doi:10.1016/j.bcp.2009.04.034 PMID:19433072
4. Darago A, Sapota A. Cobalt and its inorganic compounds - calculated as Co. Basics and Methods of Work Environment Assessment. 2011;3:47-94.
5. Czarnek K., Terpilowska S., and Siwicki A. K. Selected aspects of the action of cobalt ions in the human body. Cent Eur J Immunol. 2015; 40(2): 236-242.
6. EDQM (2008). Methylthionimium chloride. In: European Pharmacopoeia. Strasbourg, France: European Directorate for the Quality of Medicines & HealthCare.
7. M.M. Raj, A. Dharmaraja, S.J. Kavitha, K. Panchanatheswaran, D.E. Lynch, Inorg. Chim. Acta 360 (2007) 1799.
8. Cannosa S., A. Bacchi, C. Graiff, P. Pelagatti, G. Predieri, A. Ienco, G. Manca, C. Mealli, Inorg. Chem. 56 (2017) 3512.
9. R.G. Pearson, Hard and Soft Acids and Bases. J. Am. Chem. Soc. 1963, 85, 22, 3533-3539.
