ABSTRACT
Keeping in mind, the potentials of hydrazones and their metal complexes as drugs, this research work aims at synthesizing a novel hydrazone and its metal complexes, and evaluation of their virtual screening as a potential antiviral drug for severe acute respiratory syndrome coronavirus 2, SARS-CoV-2. The 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA), ligand, and its metal complexes were thus synthesized. Physical measurements, which include, melting point, conductivity and solubility tests and spectroscopic methods; UV-VIS, FTIR, and NMR were adopted to characterize and proffer suitable structures for the ligand and its metal complexes. Thus, crystalline and coloured compounds with yields >80 % and melting points > 150 0C were obtained. Molar conductance values described the complexes as non-electrolytes. In the electronic spectra of the synthesized complexes, shifting of the π→π* transitions to longer or shorter wavelengths indicated the formation of an M-L coordination bond. FTIR spectra showed lowering of the frequency to 1591.6 cm-1, which indicated that the azomethine group actively took part in co-ordinations. The 1HNMR signal appeared for imine proton of the azomethine group in the free ligand at δ 9.1ppm and is shifted upfield to 8.7-8.9 for complexes, which indicates the metal-nitrogen coordination. Also, the 13CNMR indicated a new δ 125.9 which was absent in the δ values for the ligand, which also showed the involvement of the azomethine group in coordination. An octahedral geometry was therefore suggested for the metal complexes. Binding energies > 9.5 kcal./mol., highlights the success rate of docking operation and positive interactions of the compounds with non-structural protein 1, (NSP 1) of SARS-CoV-2 (PDB ID: 7k3N). Hydrophobic interactions were the most abundant interactions followed by hydrogen bonding. The binding site with the highest druggability score of 0.43 was chosen for the structural display of the metal complexes’ interactions with the 7K3N protease. Zero violations were recorded for the drug likeliness test according to Lipinski's Rule of Five (RO5). In SWISSADME analysis, the DNEAA ligand and its metal complexes were predicted human gastrointestinal absorption (HIA), (bioavailability score ≥0.55) but not accessing the brain, blood-brain barrier (BBB) permeation. The moderately active compounds (the metal complexes) had the highest Topological Surface Area, (TPSA) whereas the comparatively less active compound (the ligand) had the lowest TPSA. Zero PAIN alerts were recorded for the ligand and metal complexes meaning that they are free from promiscuous compounds while Synthetic accessibility (SA) scores for the ligand and metal complexes show that the synthetic routes for these compounds are easy and that the reactions are feasible. LD50(mg/Kg) values (1600,1000,1800,1000,1000, 625, and 1920) for the ligand and metal complexes respectively, showed that all belong to toxicity class 4. The PASS prediction analysis discovered other inhibitory actions of these compounds. Reported toxic/adverse effects for the compounds showed Pa values < 0.7, which indicated their low toxicity. CABSFlex protein flexibility post-ligand study shows that all the protein–ligand complexes evaluated were stable in the physiological conditions studied. Following these findings, we hereby recommend biological studies, pre-clinical and clinical trials against SARS-CoV-2 protease.
TABLE OF CONTENTS
PRELIMINARY PAGES ……………………………………………………… i
Title Page ………………………………………………………………………... i
Declaration ……………………………………………………………………… ii
Certification …………………………………………………………………….. iii
Dedication ……………………………………………………………………… Iv
Acknowledgement ……………………………………………………………… v
Table of Contents ………………………………………………………………. vi
List of Tables …………………………………………………………………… xi
List of Figures ………………………………………………………………….. xiii
List of Equations and Structures ……………………………………………….. xvii
List of Appendices ………………………………………………………………. xviii
Abstract ………………………………………………………………………… xix
CHAPTER 1 INTRODUCTION ………………………………………….. 1
1.1 Background of the Study …………………………………….. 1
1.2 Scope of the Study …………………………………………… 6
1.3 Aim and Objectives of the Study …………………………….. 7
1.4 Statement of the Problem …………………………………….. 8
1.5 Justification of the Study ……………………………………... 9
CHAPTER 2 LITERATURE REVIEW ………………………………...... 10
2.1 REVIEW OF UNDERLYING CONCEPT……………..... 10
2.1.1 Reactions of Carbonyl Compounds with Hydrazines………… 10
2.1.2 Definitions of Some Important Terms in Coordination Chemistry…………………………………………………….. 13
2.1.2.1 Coordination entit…………………………………………….. 13
2.1.2.2 Central atom/ion……………………………………………… 13
2.1.2.3 Ligands………………………………………………………... 13
2.1.2.4 Coordination number…………………………………………. 14
2.1.2.5 Coordination sphere…………………………………………... 14
2.1.2.6 Coordination polyhedron……………………………………... 15
2.1.2.7 Oxidation number of central atom……………………………. 15
2.1.2.8 Homoleptic and heteroleptic complexes……………………… 16
2.1.2.9 Isomerism in Coordination Compounds……………………… 16
2.1.2.10 Stereoisomerism……………………………………………… 16
2.1.2.11 Structural isomerism…………………………………………. 16
2.1.2.12 Geometric Isomerism…………………………………………. 16
2.1.2.13 Optical Isomerism……………………………………………. 18
2.1.3 Bonding in Coordination Compounds……………………….. 19
2.1.3.1 d-Orbitals in Bonding………………………………………… 20
2.1.3.2 Valence Bond Theory………………………………………… 22
2.1.3.3 Magnetic Properties of Coordination Compounds…………… 23
2.1.3.4 Crystal Field Theory………………………………………….. 24
2.1.3.4.1 Crystal field splitting in octahedral coordination entities…… 24
2.1.3.5 Colour in Coordination Compounds………………………….. 27
2.1.3.6 Ligand Field Theory…………………………………………. 28
2.1.3.7 Ligand Field Theory for Octahedral Complexes…………….. 28
2.1.3.8 d-d Transitions and Light Absorption………………………… 33
2.1.3.9 π-Bonding in Metal Complexes………………………………. 34
2.1.3.10 Factors that influence the value of Δ0………………………… 35
2.1.3.10.1 Nature of the ligand…………………………………………... 35
2.1.3.10.2 Ionic charge of the central metal ion…………………………. 36
2.1.3.11 Effect of the Nature of the Metal and Ligand on the Stabilities of Complexes…………………………………………………
37
2.1.3.12 Chelation and Stability……………………………………….. 38
2.1.3.13 Factors affecting chelate formation…………………………... 40
2.1.4 Importance and Applications of Coordination Compounds….. 41
2.1.5 The Chemistry of Coordination Compounds………………… 42
2.1.5.1 The Coordination Chemistry of Nickel(II)…………………… 43
2.1.5.2 The Coordination Chemistry of Copper (II)………………….. 45
2.1.6 Overview of the concepts of bio-inorganic chemistry………... 46
2.1.7 Metal Ions in the Biological System………………………….. 47
2.1.8 Use of Chelating Agents in Medicine; or chelation therapy…. 54
2.1.9 Criteria for a potential chelating drug……………………….. 54
2.1.9.1 Hydrazones as Chelating Agents…………………………….. 57
2.2 RELATED OF LITERATURE…………………………….. 58
2.2.1 Applications of Hydrazones and their Metal Complexes…… 58
2.2.1.1 In Analytical Chemistry………………………………………. 58
2.2.1.2 Derivative Spectrophotometric Assessment of Metal Ions….. 59
2.2.1.3 Biological Scope……………………………………………… 60
2.2.1.4 Antimicrobial activity………………………………………… 62
2.2.1.5 Antiplatelet activity…………………………………………… 63
2.2.2 Synthesis of Nickel Coordination Complexes………………... 67
2.2.2.1 The preparation of [Ni(en)3]Cl2 . 2H2O………………………. 67
2.2.2.2 The preparation of [Ni(NH3)6]Cl2…………………………….. 67
2.2.2.3 The preparation of [Ni(en)2]Cl2 . 2H2O………………………. 68
2.2.3 In Silico Studies: Computational Analysis of Protein-Ligand Interaction……………………………………………………..
69
2.2.3.1 Molecular docking……………………………………………. 69
2.2.3.2 Molecular recognition………………………………………… 70
2.2.3.3 Molecular Docking Models………………………………….. 71
2.2.3.4 Computational Docking………………………………………. 72
2.2.3.5 Docking Classification……………………………………….. 73
2.2.3.6 Definition of the "Pose"……………………………………… 73
2.2.3.7 Molecular Complementarity in Computational Docking……. 73
2.2.3.8 Energy Dictates Molecular Associations……………………. 73
2.2.3.8.1 Interaction Energies………………………………………….. 74
2.2.3.8.2 Desolvation Energies…………………………………………. 74
2.2.3.8.3 Entropic Effects………………………………………………. 74
2.2.3.8.4 Calculation of the Binding Energies…………………………. 74
2.2.3.9 Protein Side-Chains Flexibility………………………………. 75
2.2.3.10 Computational Docking in Drug Discovery…………………. 75
2.2.3.11 Virtual Screening…………………………………………….. 75
2.2.3.12 Lead Hopping………………………………………………… 76
2.2.3.13 Increasing HTS Hit Rates…………………………………….. 76
2.2.3.14 Limitations in Computational Docking………………………. 76
2.2.3.15 The Protein Data Bank (PDB)………………………………... 76
2.2.3.16 Protein-ligand Interactions……………………………………. 77
2.2.3.17 Ligand-Binding Sites on SARS-CoV-2 Non-Structural Protein…………………………………………………………
78
2.2.3.18 Structure of SARS-CoV-2 to Atomic Resolution…………… 81
2.2.3.19 Detailed Description of SARS-CoV-2 Nsp110-126-Fragment………………………………………………………
84
2.2.3.20 Protein-Ligand Interaction Profiler (PLIP) algorithm for DNA/RNA detection…………………………………………..
87
2.2.3.21 Solvation and Desolvation…………………………………… 90
2.2.3.22 Molecular Dynamics (MD) Flexibility……………………….. 90
2.2.3.23 Binding Site Detection……………………………………….. 92
2.2.3.24 Molecule Assemble Ensemble………………………………... 92
2.2.3.25 Drug Development Assessment of Absorption, distribution, metabolism, and Excretion (ADME)………………………….
93
2.2.3.25.1 Bioavailability Radar…………………………………………. 94
2.2.3.25.2 Physicochemical Properties………………………………….. 94
2.2.3.25.3 Lipophilicity…………………………………………………. 95
2.2.3.25.4 Water Solubility………………………………………………. 95
2.2.3.25.5 Pharmacokinetics……………………………………………... 95
2.2.3.25.6 Drug-likeness…………………………………………………. 97
2.2.3.25.7 Medicinal Chemistry………………………………………….. 98
2.2.3.25.8 The BOILED-Egg…………………………………………….. 99
2.2.3.26 Prediction of activity spectra for substances…………………. 100
2.2.3.27 Prediction of toxicity of chemicals…………………………… 102
2.2.3.28 Lipinski Rule of Five…………………………………………. 106
2.2.4 Calculation of Thermodynamic Parameters………………….. 109
2.2.4.1 Free energy of formation……………………………………. 109
2.2.4.2 Enthalpy and Entropy of Formation………………………….. 109
CHAPTER 3
MATERIALS AND METHODS …………………………….
111
3.1 MATERIALS …………………………………………………. 111
3.1.1 Chemicals and Reagents ………………………………………. 111
3.1.2 Instruments…………………………………………………….. 111
3.2 METHODS ……………………………………………………. 112
3.2.1 Synthesis of hydrazones ……………………………………..... 112
3.2.2 Synthesis of hydrazone metal Complexes……………………... 114
3.2.3 Physical measurements………………………………………... 115
3.2.3.1 Melting Point and Solubility Determinations ………………..... 115
3.2.3.2 Molar Conductivity ………………………………………….... 115
3.2.4 Characterization studies……………………………………….. 115
3.2.4.1 Electronic spectra and magnetic moments …………………..... 115
3.2.4.2 Infrared Spectroscopy of the DNEAA ligand and its Metal Complexes ………………………………………………….....
115
3.2.4.3 Nuclear magnetic resonance (NMR) of the DNEAA Ligand and its Metal Complexes ……………………………………....
116
3.2.5 In Silico Studies of the DNEAA Ligand and its Metal Complexes ……………………………………………………..
117
3.2.5.1 Docking of DNEAA Ligand and its Metal Complexes……………………………………………...
117
3.2.5.2 Drug-likeness Prediction of the DNEAA Ligand and its Metal Complexes ………………………………………………..........
117
3.2.5.3 Toxicity Prediction Study of the DNEAA Ligand and its Metal Complexes………………………………………………….......
118
3.2.5.4 Prediction of Substance Activity Spectra (PASS) Study of the DNEAA Ligand and its Metal Complexes………………..........
118
3.2.5.5 Protein Flexibility and Molecular Dynamic (MD) Simulation of the DNEAA Ligand and its Metal Complexes……………...
118
CHAPTER 4 RESULTS AND DISCUSSIONS 119
4.1 Physical Measurements of the DNEAA Ligand and its Metal Complexes …………………………………………………..
119
4.4 Characterization Studies of the DNEAA Ligand and its Metal Complexes……………………………………………………
122
4.4.1 Electronic Spectra of the synthesized Compounds ………….. 122
4.4.2 Infrared spectroscopy of the DNEAA Ligand and its Metal Complexes…………………………………………………….
129
4.4.3 Nuclear Magnetic Resonance (NMR) of the DNEAA Ligand and its Metal Complexes ……………………………………..
135
4.5 Thermodynamics parameters of the DNEAA Complexes (Enthalpy, Entropy, and Free energy Change for the reactions)…………………………………………152
4.6 Structures of the DNEAA Ligand and its Metal Complexes ………………………………………………………………..
154
4.7 In Silico Studies of the DNEAA Ligand and its Metal Complexes…………………………………………………….
154
4.7.1 Binding energies of the docking operations …………………. 154
4.7.2 DNEAA and [M(NEAA)]’s Interactions with SARS-CoV-2... 157
4.7.3 Structure assemble ensemble of the DNEAA Ligand and its Metal Complexes’ Interactions with SARS-CoV-2…………..
172
4.7.4 Binding site detection and druggability scores of the DNEAA Ligand and its Metal Complexes’ interactions with SARS-CoV-2………………………………………………………. 172
4.7.5 Drug-likeness prediction of the DNEAA Ligand and its Metal Complexes……………………………………………………. 176
4.7.6 Drug Assessment of Absorption, Distribution, Metabolism, and Excretion (ADME) of the DNEAA Ligand and its Metal Complexes……………………………………………………
177
4.7.7 Bioavailability Radars of the DNEAA Ligand and its Metal Complexes……………………………………………………
180
4.7.8 BoiledEgg diagrams of the DNEAA Ligand and its Metal Complexes………………………………………………….. 185
4.7.9 Pharmacokinetics of the DNEAA Ligand and its Metal Complexes…………………………………………………… 190
4.7.10 Toxicity of the DNEAA ligand and its metal complexes 191
4.7.11 Prediction of Biological Activity Spectra for Substances (PASS) for the DNEAA Ligand and its Metal Complexes…... 197
4.7.12 Molecular Dynamics simulation of the DNEAA Ligand and its Metal Complexes……………………………………….….
200
CHAPTER 5 CONCLUSION AND RECOMMENDATIONS 206
5.1 CONCLUSION………………………………………………….. 206
5.2 RECOMMENDATION…………………………………………. 207
REFERENCES……………………………………………………
APPENDICES…………………………………………………..
LIST OF TABLES
Table Title Page No.
2.1 Relationship between the Wavelength of Light absorbed and the Colour observed in some Coordination Entities……………………………………….
27
2.2 Unpaired electrons in uncomplexed metal ions…………………………………... 32
2.3 Ligand-Protein interaction models……………………………………………… 71
2.4 List of SARS-CoV-2 nsp110-126 amino acids defining binding sites I and II…….. 83
4.1 Reaction conditions and Physical Properties of the newly Synthesized 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA) and its Metal Complexes …………………………………………………………
120
4.2 Physical Properties of the Synthesized DNEAA Metal Complexes ……………. 120
4.3 Molar conductivity of the complexes and Solubility of the DNEAA Ligand and its Metal Complexes …………………………………………………………….
121
4.5 Absorption Bands (in cm-1) of the complexes of the synthesized ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA) and its metal complexes ………………………………………………………….
123
4.6 FTIR Spectral data of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA) and its Metal Complexes …………………………………………………………………………………..
130
4.7 Nuclear Magnetic Resonance (1HNMR) Spectral data of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA) and its Metal Complexes ……………………………………………………………..
136
4.8 Carbon-13 Nuclear Magnetic Resonance (13C-NMR) Spectral data of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA) and its Metal Complexes ………………………………………………
142
4.9 Thermodynamic Parameters of the DNEAA Metal Complexes…………………. 148
4.10 Binding energies, Mode, and RMSD Scores of 1YHQ, the ligand and its metal complexes with sars-cov-2 (PDB id: 7k3N) ……………………………………..
156
4.11a Hydrogen Bond Interactions for [1YHQ-7K3N]………………………………… 158
4.11b Metal Complexe Interactions for [1YHQ-7K3N]………………………………… 158
4.12a Hydrophobic Interactions for DNEAA-7K3N……………………………………. 159
4.12b Hydrogen bonding Interactions for DNEAA-7K3N …………………………….. 159
4.13a Hydrophobic Interactions for [Mn-DNEAA]-7K3N…………………………….. 159
4.13b Hydrogen Bonds Interactions for [Mn-DNEAA-7K3N] ………………………… 159
4.13c Metal Complexes’ Interactions for [Mn-DNEAA-7K3N] ……………………….. 160
4.14a Hydrophobic Interactions for [Cu-DNEAA-7K3N] ……………………………… 160
4.14b Hydrogen Bonds Interactions for [Cu-DNEAA-7K3N] …………………………. 160
4.14c Salt bridges Interactions for [Cu-DNEAA-7K3N] ………………………………. 160
4.14d Metal Complexes Interactions for [Cu-DNEAA-7K3N] ………………………… 160
4.15a Hydrophobic Interactions for [V-DNEAA-7K3N] ………………………………. 160
4.15b Hydrogen Bonds Interactions for [V-DNEAA-7K3N] …………………………... 161
4.16a Hydrophobic Interactions for [Ni-DNEAA-7K3N] ……………………………… 161
4.16b Hydrogen Bonds Interactions for [Ni-DNEAA-7K3N] …………………………. 161
4.16c Salt bridges Interactions for [Ni-DNEAA-7K3N] ……………………………….. 161
4.16d Metal complexes Interactions for [Ni-DNEAA-7K3N] …………………………. 161
4.17a Hydrophobic Interactions for [Zn-DNEAA-7K3N] ……………………………… 161
4.17b Hydrogen Bonds Interactions for [Zn-DNEAA-7K3N] …………………………. 162
4.17c Metal complexes Interactions for [Zn-DNEAA-7K3N] ………………………….. 162
4.18a Hydrophobic Interactions for [Fe-DNEAA-7K3N] ……………………………… 162
4.18b Hydrogen Bonds Interactions for [Fe-DNEAA-7K3N] …………………………. 162
4.19 Drug-likeness prediction of the ligand and metal complexes …………………… 177
4.20 Drug assessment of absorption, distribution, metabolism and excretion (ADME) Parameters for DNEAA ligand and its metal complexes ………………………..
179
4.21 Pharmacokinetics for DNEAA ligand and its metal complexes …………………. 191
4.22 LD50, Toxicity class, Average similarity and Prediction accuracy of the ligand, DNEAA and its metal complexes ………………………………………………..
193
4.23 Toxicity Model Report for the DNEAA ligand …………………………………. 193
4.24 Toxicity Model Report for the [Mn-DNEAA] complex…….……………………. 193
4.25 Toxicity Model Report for the [Cu-DNEAA] complex…….……………………. 194
4.26 Toxicity Model Report for the [V-DNEAA] complex…….……………………. 194
4.27 Toxicity Model Report for the [Ni-DNEAA] complex…….……………………. 195
4.28 Toxicity Model Report for the [Zn-DNEAA] complex…….……………………. 195
4.29 Toxicity Model Report for the [Fe-DNEAA] complex…….……………………. 196
4.30 Prediction of biological Activity Spectra for Substances (PASS) in the DNEAA ligand and metal complexes………………………………………………………
200
4.31 Reported Toxic/Adverse effects of the DNEAA Ligand and its Metal Complexes under study ……………………………………………………………………….. 200
LIST OF FIGURES
Figure Title Page Number
1.1 Synthetic Structures of typical hydrazones I and II: …………………………. 2
1.2 Bezophenone hydrazone ……………………………………………………… 2
1.3 Acetone hydrazone …………………………………………………………… 2
1.4 Benzophenone (2,4-dinitrophenyl)hydrazone …………………….................... 3
1.5 Tautomerism of hydrazones ………………………………………………….. 3
1.6 Structural and functional diversity of the hrdrazone group ……....................... 4
2.1 Shapes of different coordination polyhedra. …………………………………. 15
2.2 Geometrical isomers (cis and trans) of Pt [NH3)2Cl2] ……………................... 17
2.3 Geometrical isomers (cis and trans) of [Co(NH3)4Cl2]+ ……………………… 17
2.4 Geometrical isomers (cis and trans) of [CoCl2(en)2] . ……………………….. 17
2.5 The facial (fac) and meridional (mer) isomers of [Co(NH3)3(NO2)3] ………… 18
2.6 Optical isomers (d and l) of [Co(en)3] 3+ ……………………………………… 18
2.7 Optical isomers (d and l) of cis-[PtCl2(en)2]+ ………………………………... 18
2.8 Structure of the ReH92- ion. ……………………………………….. 21
2.9 Spatial orientation of the dz2 and dx2 - y2 orbitals in an octahedral complex … 21
2.10 Localized electron-pair bonding representation of Co(NH3)63+ ……………… 22
2.11 d-orbital splitting in an octahedral crystal field ………………………………. 26
2.12 Overlap of the 3d orbitals with the σ orbitals of the ammonia molecules ……. 28
2.13 Ligand-field splitting in an octahedral complex. . ……………………………. 29
2.14 Overlap of a metal d(π) orbital with four ligand p(π) orbitals.……………….. 34
2.15 Structure of Ethylenediamine …………………………………………… 38
2.16 Hexadentate chelating agent ethylenediamine- tetraacetate (EDTA)…………. 39
2.17 Elements in Biological Systems …………………………………………… 47
2.18 Porphyrin and corrin ring systems 56
2.19 Sulfonylhydrazone ……………………………………………………………. 62
2.20 5‑en‑3‑oxazoloquinoxaline ………………………………………………….. 63
2.21 5‑en‑3‑oxazolo thiazoloquinoxaline…………………………………………. 63
2.22 Indole hydrazone……………………………………………………………… 63
2.23, 2.24 Arylsulfonate – Acylhydrazone derivatives………………………………….. 64
2.25 NI(II) complex of GHL1 Ligand……………………………………………… 65
2.26 Zn(II) complex of GHL1……………………………………………………… 65
2.27 Structure of SARS-CoV-2 nsp110-126 at high resolution……………………. 82
2.28 Binding sites I and II in SARS-CoV-2 nsp110-126…………………………... 83
2.29 Molecular interactions of fragment hits binding to SARS-CoV-2 nsp110-126. 87
2.30 Major types of non-bonded interactions in protein-ligand complexes……….. 88
2.31 Water molecules at protein-ligand interface………………………………….. 90
4.1 Electronic spectrum of hydrazone (DNEAA) Ligand………………………… 124
4.2 Electronic spectrum of [Mn(DNEAA)] complex…………………………….. 124
4.3 Electronic spectrum of [Cu(DNEAA)] complex……………………………… 125
4.4 Electronic spectrum of [V(DNEAA)] complex ………………………………. 125
4.5 Electronic spectrum of [Ni(DNEAA)] complex ……………………………… 126
4.6 Electronic spectrum of [Zn(DNEAA)] complex ……………………………… 126
4.7 Electronic spectrum of [Fe(DNEAA)] complex ……………………………… 127
4.8 FTIR Spectrum for the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)………………………………………… 131
4.9 FTIR Spectrum for the Manganese (II) complex of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Mn-DNEAA)…… 131
4.10 FTIR Spectrum for the Manganese (II) complex of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Cu-DNEAA)…… 132
4.11 FTIR Spectrum for the Manganese (II) complex of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (V-DNEAA)…….. 132
4.12 FTIR Spectrum for the Manganese (II) complex of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Ni-DNEAA)…… 133
4.13 FTIR Spectrum for the Manganese (II) complex of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Zn-DNEAA)…… 133
4.14 FTIR Spectrum for the Manganese (II) complex of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Fe-DNEAA)……. 134
4.16 1HNMR Chemical Shifts ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)………………………. 137
4.17 1HNMR Chemical Shifts for the Manganese metal complex of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Mn-DNEAA)………………………………………………………………………. 137
4.18 1HNMR Chemical Shifts for the Copper metal complex of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Cu-DNEAA)………………………………………………………………………. 138
4.19 1HNMR Chemical Shifts for the Vanadium metal complex of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (V-DNEAA)……………………………………………………………………… 138
4.20 1HNMR Chemical Shifts for the Nickel metal complex of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Ni-DNEAA)…………………………………………………………………….. 139
4.21 1HNMR Chemical Shifts for the Zinc metal complex of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Zn-DNEAA)……………………………………………………………………… 139
4.22 1HNMR Chemical Shifts for the Iron metal complex of the ligand: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (Fe-DNEAA)………………………………………………………………………. 140
4.23 13C-NMR Spectrum for the ligand, DNEAA Ligand ………………………… 143
4.24 13C-NMR Spectrum for the complex, [Mn-DNEAA] complex ……………… 143
4.25 13C-NMR Spectrum for the complex, [Cu-DNEAA] complex ………………. 144
4.26 13C-NMR Spectrum for the complex, [V-DNEAA] complex ………………... 144
4.27 13C-NMR Spectrum for the complex, [Ni-DNEAA] complex ……………….. 145
4.28 13C-NMR Spectrum for the complex, [Zn-DNEAA] complex ………………. 145
4.29 13C-NMR Spectrum for the complex, [Fe-DNEAA] complex ………………. 146
4.30 Van’t Hoff’s plots of lnK against 1/T for the Mn(II) complex of DNEAA ligand………………………………………………………………………….
149
4.31 Van’t Hoff’s plots of lnK against 1/T for the Cu(II) complex of DNEAA ligand………………………………………………………………………….. 149
4.32 Van’t Hoff’s plots of lnK against 1/T for the V(II) complex of DNEAA ligand………………………………………………………………………….. 150
4.33 Van’t Hoff’s plots of lnK against 1/T for the Ni(II) complex of DNEAA ligand………………………………………………………………………….. 150
4.34 Van’t Hoff’s plots of lnK against 1/T for the Zn(II) complex of DNEAA ligand…………………………………………………………………………. 151
4.35 Van’t Hoff’s plots of lnK against 1/T for the Fe(II) complex of DNEAA ligand…………………………………………………………………………. 151
4.36 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)……………………………………………………………………… 153
4.47 Structure of the manganese (II) metal complex, Mn(II)-(DNEAA) of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)………………………………………….. 153
4.38 Structure of the manganese (II) metal complex, Cu(II)-(DNEAA) of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)…………………………………………. 154
4.39 Structure of the manganese (II) metal complex, V(II)-(DNEAA) of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)………………………………………….. 154
4.40 Structure of the manganese (II) metal complex, Ni(II)-(DNEAA) of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)………………………………………….. 155
4.41 Structure of the manganese (II) metal complex, Zn(II)-(DNEAA) of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)………………………………………….. 155
4.42 Structure of the manganese (II) metal complex, Fe(II)-(DNEAA) of the ligand; 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)…………………………………………… 155
4.43 3D Visualization of Binding interaction between 1YHQ and 7k3……………. 163
4.44 3D Visualization of Binding interaction and Structure Assemble Ensemble between DNEAA and 7k3N………... 164
4.45 3D Visualization of Binding interaction and Structure Assemble Ensemble between [Mn-DNEAA] and 7k3N…. 165
4.46 3D Visualization of Binding interaction and Structure Assemble Ensemble between [Cu-DNEAA] and 7k3N….. 166
4.47 3D Visualization of Binding interaction and Structure Assemble Ensemble between [V-DNEAA] and 7k3N…… 167
4.48 3D Visualization of Binding interaction and Structure Assemble Ensemble between [Ni-DNEAA] and 7k3N…... 168
4.49 3D Visualization of Binding interaction and Structure Assemble Ensemble n between [Zn-DNEAA] and 7k3N….. 169
4.50 3D Visualization of Binding interaction and Structure Assemble Ensemble between [Fe-DNEAA] and 7k3N….. 170
4.51a Binding site detection diagram for DNEAA binding with SARS-CoV-2 Protein (Drugability Score, 0.43)………………………………………………
174
4.51b Binding site detection diagram for DNEAA binding with SARS-CoV-2 protein (Drugability Score, 0.35)…………………………………………….. 174
4.51c Binding site detection diagram for DNEAA binding with ARS-CoV-2 protein (Drugability Score, 0.38)……………………………………………………… 175
4.51d Binding site detection diagram for DNEAA binding with SARS-CoV-2 Protein (Druggability Score, 0.24)…………………………………………… 175
4.51e Binding site detection diagram for DNEAA binding with SARS-CoV-2 protein showing all binding sites with Druggability Scores: 0.43……………. 176
4.52 Bioavailability Radar diagram for DNEAA ligand…………………………… 182
4.53 Bioavailability Radar diagram for [Mn-DNEAA] complex…………………... 182
4.54 Bioavailability Radar diagram for [Cu-DNEAA] complex…………………… 183
4.55 Bioavailability Radar diagram for [V-DNEAA] complex……………………. 183
4.56 Bioavailability Radar diagram for [Ni-DNEAA] complex……………………. 184
4.57 Bioavailability Radar diagram for [Zn-DNEAA] complex…………………… 184
4.58 Bioavailability Radar diagram for [Fe-DNEAA] complex…………………… 185
4.59 BOILED-Egg diagram for DNEAA ligand…………………………………… 187
4.60 BOILED-Egg diagram for [Mn-DNEAA] Complex…………………………. 187
4.61 BOILED-Egg diagram for [Cu-DNEAA] Complex………………………….. 188
4.62 BOILED-Egg diagram for [V-DNEAA] Complex…………………………… 188
4.63 BOILED-Egg diagram for [Ni-DNEAA] Complex…………………………… 189
4.64 BOILED-Egg diagram for [Zn-DNEAA] Complex…………………………... 189
4.65 BOILED-Egg diagram for [Fe-DNEAA] Complex…………………………… 190
4.66 CABS-Flex fluctuation plot for 1YHQ-7K3N interaction…………………….. 202
4.67 CABS-Flex fluctuation plot for 7K3N Protein……………………………….. 203
4.68 CABS-Flex fluctuation plot for DNEAA-7K3N interaction…………………. 203
4.69 CABS-Flex fluctuation plot for [Mn-DNEAA]-7K3N interaction…………… 204
4.70 CABS-Flex fluctuation plot for [Cu-DNEAA]-7K3N interaction……………. 204
4.71 CABS-Flex fluctuation plot for [V-DNEAA]-7K3N interaction…………….. 205
4.72 CABS-Flex fluctuation plot for [Ni-DNEAA]-7K3N interaction……………. 205
4.73 CABS-Flex fluctuation plot for [Zn-DNEAA]-7K3N interaction……………. 206
4.74 CABS-Flex fluctuation plot for [Fe-DNEAA]-7K3N interaction…………….. 206
LIST OF EQUATIONS AND SCHEMES
Equation Title Page No.
2.1 Reaction of carbonyls with hydrazines to form hydrazones …………………………………………………………………………………..
10
2.2 Reaction of carbonyls with Phenylhydrazines to form phenylhydrazones……... 10
2.3 Schematic illustration of Japp-Klingmann Synthesis …………………………. 11
2.4 Indole via the Fischer indole synthesis………………………………………… 12
2.5 General routes for the synthesized hydrazones………………………………... 66
2.6 Calculation of free energy formation of a complex …………………………… 109
2.8 Van’t Hoff’s equation for calculation of enthalpy and entropy……………… 109
2.9 Gibb’s free energy change (ΔG) calculation………………………………….. 108
3.1 Synthesis of the metal Complexes of the hydrazone ligand through the direct reaction method………………………………………………………………… 114
Schemes
2.1 Synthesis of [Zn(pbh)2] and Zn(acpbh)2] complexes …………………………. 68
3.1 Synthetic route for 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA)…………………………………………..
113
LIST OF AAPENDICES
Appendix Title
1 Elemental Analysis result for 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline, DNEAA ligand
2 Elemental Analysis result for 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline, [Mn-DNEAA] Complex
3 Elemental Analysis result for 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline, [Cu-DNEAA] Complex
4 Elemental Analysis result for 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline, [V-DNEAA] Complex
5 Elemental Analysis result for 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline, [Ni-DNEAA] Complex
6 Elemental Analysis result for 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline, [Zn-DNEAA] Complex
7 Elemental Analysis result for 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline, [Fe-DNEAA] Complex
CHAPTER 1
INTRODUCTION
1.1 BACKGROUND OF THE STUDY
Among
the numerous organic compounds with versatile applications, hydrazones have
provided a formidable Centre of fecund research. They are a class of organic
compounds having the basic structure R1R2C=NNH2
and are related to aldehydes and ketones, by the replacement of the oxygen with
the −NNH2 group, that is, they are formed by the action of hydrazine
on carbonyl compounds (ketones or aldehydes). Hydrazones are usually
named after the carbonyl compounds from which they are obtained. Hydrazone
moieties play important roles in heterocyclic chemistry. Figures 1.1 to 1.4
show the structure of some hydrazones. The azomethine -NHN=CH- proton
constitutes an important class of compounds for new drug development (Yasmin et al, 2021). They act as reactants in
various important reactions such as Barton hydrazone iodination, Shapiro
reaction, and Bamford-Stevans reaction to form vinyl compounds, and as
intermediate in the Wolff-Kishner reaction, (Jaweria et al, 2021). Hydrazones can also be
synthesized by the Japp-Klingemann reaction (from β-ketoacids or β-ketoesters
and aryldiazonium salts). Hydrazones are among the useful compounds for drug design; they
are used as possible ligands for metal complexes, organocatalysis, and also for
the synthesis of heterocyclic compounds (Çakmak et al., 2021, Yapar et al., 2021). The
desirable characteristics of hydrazones include; the ease of preparation,
increased hydrolytic stability relative to imines, and a tendency toward
crystallinity (Bingul et al., 2020). Due to these favourable features, hydrazones have
been under study for a long time, but much of their basic chemistry remains
unexplored. Hydrazones are azomethines characterized by the presence of the
triatomic grouping >C=N-N<. They are differentiated from other members of
this class (imines, oximes, etc.) by the presence of the two interlinked
(–N–N–) nitrogen atoms. According to the
needs of a polydentate ligand, the group functionalities are increased by
condensation and substitution, (Mandal et al, 2021). Hydrazones are represented by the formulae given in Figure 1.1
(I and II).
I II
Figures 1.1 I and II: Synthetic
and generalized Structures of typical hydrazones
Where:
R1 and R2 = H, Alkyl, Ar, RCO, Ht (Heterocyclic Group), Y
= H, Alkyl, Ar, Ht, RCO X and X1 = H, Alkyl, Ar, Ht, Halogens, OR,
SR, CN, SO2R, NO2, NHNR R’, N = NR, COOR, CONR R’. The N, N'-dialkyl type
of hydrazones can be hydrolysed, reduced, and oxidized which leads to the
formation of amines by reduction of NN bond.
Figure 1.2: Benzophenone hydrazone

Figure 1.3: Acetone
hydrazine

Figure
1.4: Benzophenone (2,4-dinitrophenyl)hydrazone
In general, hydrazones can
undergo tautomerism between keto and enol forms (Figure 1.5) Coupling of
aryldiazonium salts with active hydrogen compounds is another route for the
synthesis of hydrazone Schiff base ligands (Rui and Junting,
2018).

Figure
1.5: Tautomerism of hydrazones
A quick survey of the structure
of a hydrazone Figures 1.1 to 1.4 reveals that they have;
i. Nucleophilic imine and
amino-type nitrogens,
ii. An imine carbon that has both
electrophilic and nucleophilic character,
iii. Configurational isomerism
stemming from the intrinsic nature of the C=N bond and
iv. In most cases an acidic N–H
proton (Abo 2018, Burlov, 2019).
These structural motifs give the
hydrazine group its physical and chemical properties, in addition to playing a crucial
part in determining the range of applications it can be involved in.

Figure 1.6: The Structural and functional diversity of the hydrazone
group
One of the salient features of
hydrazones is their high physiological activity (Jenna and Milkowski, 2019, Ruixue et al., 2022). Hydrazones possessing an azomethine proton (–NHN=CH–) constitute
an important class of compounds, they contain two connected nitrogen atoms of
different natures and a CN double bond that is conjugated with alone electron
pair of the terminal nitrogen atom. Extensive studies have revealed that the
lone pair on the trigonally hybridized nitrogen atom of the azomethine group is
responsible for the chemical and biological activity (Kaur and Kumar, 2021). Hydrazones can be synthesized in
the laboratory by heating the appropriate substituted hydrazines or hydrazides
with carbonyl compounds in various organic solvents like ethanol, methanol,
tetrahydrofuran, butanol and sometimes with glacial acetic acid or
ethanol-glacial acetic acid. Also, hydrazones can be synthesized by the
coupling of aryldiazonium salts with compounds containing active hydrogen (Swaminathan et al, 2021). They are also very effective
organic compounds with important biological activities and are a versatile
class of ligands that have been studied for a long time as potential
multifunctional ligands with various coordination modes (Shao and Aprahamian, 2020). The type of
coordination mode adopted by a hydrazone depends on different factors like
tautomerism, reaction conditions, stability of the complex formed and number
and nature of the substituents on hydrazone skeleton. In a similar dimension,
it is pertinent to infer that the importance of coordination complexes in our
day-to-day life is increasing due to their complex structures and interesting
magnetic, electronic, and optical properties. Ever since the importance of the
coordination phenomenon in biological processes was realized, lots of metals
containing macromolecules have been synthesized and studied to understand the
mechanism of complex biological reactions. This has resulted in the emergence
of an important branch of inorganic chemistry known as bioinorganic
chemistry. The living system is
partially supported by coordination compounds. For example, chlorophyll, the
pigment responsible for photosynthesis is a coordination compound of magnesium.
Also hemoglobin, the red pigment of blood which acts as an oxygen carrier is a
coordination compound of iron. They can have a wide variety of structures
depending on the metal ion, coordination number and denticity of the ligands
used. Diverse coordination compounds arise from interesting ligand systems
containing different donor sites. Coordination compounds also find extensive
applications in metallurgical processes, analytical and medicinal chemistry,
(Otuokere and Amadi, 2016, Otuokere et
al., 2017a, Otuokere et al., 2017b, Onyenze et al., 2016; Sokwaibe and Otuokere,
2016a; and Sokwaibe and Otuokere, 2016b). So the selection of ligands is most
important in determining the properties of coordination compounds. A ligand
system having electronegative atoms like nitrogen and oxygen increases the
denticity and thus enhances the coordination possibilities. The architectural
beauty of coordination compounds is due to the interesting ligand systems
containing different donor sites say ONO, NNO, NO and NNS. Among the
nitrogen-oxygen donor ligands, hydrazones possess a special place due to their
ease of synthesis, easily tunable electronic properties, denticity and
formation of a wide variety of complexes with chemical, structural, biological
and industrial importance (Dinda et al, 2020, Hou et al, 2021 and Liu et al, 2019). In coordination
chemistry, hydrazones find application as multidentate ligands forming chelates
with metals, usually from the transition series. Studies have shown that the
azomethine group having a lone pair of electrons in either an sp or sp2
hybridized orbital on trigonally hybridized nitrogen contributes to the
biological activities of the compounds. Many researchers have synthesized
several new hydrazones and their metal complexes because of their numerous
important properties. The d-block metal ions tend to form complexes. A series
of transition metal complexes with Schiff bases, and aromatic hydrazones (Aly
and Fathala, 2020, Davi et al, 2021, and Boulechfar et al, 2023) have been quite extensively investigated. The
chemistry of hydrazone complexes involving O, N, S donor ligands has received
special attention because of their coordination capability, their
pharmacological potentials and their uses in analytical chemistry as
metal-extracting agents. It has recently been shown that the metal complexes
are more potent and less toxic in many cases as compared to the parent
compound. The azomethine group in hydrazones is highly reactive, in the sense
that the two nitrogen atoms have nucleophilic nature and the carbon atom has
both electrophilic and nucleophilic nature.
1.2 SCOPE OF THE STUDY
Hydrazones and their transition metal complexes have been reported by
many kinds of literature to possess extraordinary pharmacological potential.
Many researchers have synthesized, characterize, and screened a quite number of
hydrazone complexes as potential drugs to combat different types of bacteria
and viruses, (Roghayeh et al, 2019, Ksendzova et
al, 2022, and Muhammad et al,
2022 and) . Activities in the present research
work therefore include; synthesizing, characterizing, and virtual screening a
novel hydrazone and its metal complexes as a potential antiviral drug for
SARS-CoV-2.
1.3 AIM AND
OBJECTIVES OF THE STUDY
This research work aims to synthesize, characterize
and screen an Aniline hydrazone and its metal complexes as potential inhibitors
against Sars-CoV-2 Protease.
The aim can be achieved through the following objectives:
1. To
synthesize an aniline hydrazone compound with the name: 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline
from 3-(2-nitrophenyl)prop-2-enal (2-nitrocinnamaldehyde) and 2,4-dinitophenylhydrazine (2,4-DNP)
2. To synthesize
the manganese, copper, vanadium, nickel, zinc, and iron, metal complexes of the
hydrazone.
3.To
characterize the compounds and suggest their possible structures.
4.To perform
molecular docking of the synthesized hydrazone and its metal complexes in the
NSP 1 of the SARS-CoV-2 protein.
5. To carry out the study of the protein-ligand interactions of the
docked hydrazone ligand and its metal complexes.
6. To perform the docking, and molecular dynamics of azithromycin
(PDB ID: 1YHQ) as an already exisiting drug of COVID-19 and compare the results
with the docking results of DNEAA ligand and its metal complexes.
6. To carry out a molecular dynamics study on the protein-ligand
interactions.
7. To carry out other virtual screenings which include; Toxicity tests,
druggability tests, and SWISSADME parameter analysis.
1.4
STATEMENT
OF THE PROBLEM
Microorganisms,
including bacteria and viruses, are both useful and dangerous to living
organisms, especially humans. The disastrous effects posed by these organisms
on society at large cannot be overlooked. This is because a wide range of
diseases and sicknesses arise from the infection of most bacteria, which are
co-dwelling with humans and animals. These diseases lead to the
under-performance of the mentioned targets and if not controlled can eventually
lead to their demise. In December 2019, a contagious disease caused by a strand
of severe acute respiratory syndrome, coronavirus 19, and known as SARS-COVID-19
was identified in Wuhan city of China. The regular reappearance of coronavirus
(CoV) outbreaks over the past 20 years has caused significant health
consequences and financial burdens worldwide. The most recent and still ongoing
novel CoV pandemic, caused by Severe Acute Respiratory Syndrome coronavirus 2
(SARS-CoV-2) has brought a range of devastating consequences. Due to the
exceptionally fast development of vaccines, the mortality rate of the virus has
been curbed to a significant extent. This disease led to a pandemic, which
ravaged the whole world and caused threats to both the economy and lives. Because of the ravaging effects of diseases caused
by these microorganisms, a quite number of approaches have been taken and are
also in progress as measures to combat these organisms and kick them out of the
system. Among the numerous ways of fighting these organisms, the use of
bioinorganic substances has proven to be the most efficient. Hydrazones and
their metal complexes have been reported as well to belong to the class of
bioinorganic compounds that yielded positive results in the fight against
deadly microorganisms. Some hydrazone
complexes of bivalent transition metal ions have been studied (Ramkisore et al, 2018, Masrat et al, 2023). The Ritonavir-boosted protease inhibitor PF-07321332
(Paxlovid) and various anti-SARS-CoV-2 monoclonal antibodies have been
authorised for use in the European Union for the treatment of COVID-19. Other
medications are currently being evaluated in clinical trials for the treatment
of COVID-19. All antivirals were more effective when administered early in the
disease course. There are also limitations that these antiviral agents are not
available to all patients due to drug–drug interactions and contraindications.
Therefore, the discovery of specific anti-viral drugs for SARS-CoV-2 is
urgently required. Given the essential role of nsp1 in the CoV life cycle, it
is regarded as an exploitable target for antiviral drug discovery. In this
research, therefore, it has been considered to be important to synthesize,
characterize and study some metal complexes of a new hydrazone and its metal
complexes and test their efficiencies towards the inhibition of the destructive
actions of SARS-CoV-2.
1.5 JUSTIFICATION OF THE STUDY
The limitations of vaccination
efficiency and applicability, coupled with the still high infection rate,
emphasize the urgent need for the discovery of safe and effective antivirals
against SARS-CoV-2 by suppressing its replication or attenuating its virulence.
Due to the remarkable advancement in the application of hydrazone compounds and
their metal complexes, a need has aroused for us to determine the potency of a
novel hydrazone compound and their metal complexes.
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