SYNTHESIS, CHARACTERIZATION, AND VIRTUAL SCREENING OF ANILINE HYDRAZONE AND ITS METAL COMPLEXES AGAINST SARS-COV-2 PROTEASE

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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) permeationThe 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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