Synthesis of a new sulfadimidine Schiff base and their nano complexes as potential anti-COVID-19 and anti-cancer activity.

The primary objective of this study was to describe the cytotoxicity on HEPG-2 cells and to study the COVID­19 activities of the novel H2L ligand and its Cr and Cu nano-complexes. As well as exploring the chemistry of the prepared nano-complexes. In this paper novel Schiff base, N-(4, 6-dimethyl pyrimidin-2-yl)-4-(((2-hydroxyl naphthalene-1-y l) methylene) amino) benzene-sulfonamidesulfonyl) amide has been synthesized. The novel Schiff base H2L is used to synthesize novel nano and micro-complexes with CrCl2.6H2O and CuCl2.2H2O. The prepared ligand and micro complexes were interpreted by different spectroscopic techniques. The nano-sized Cr and Cu complexes were synthesized in an environmentally friendly manner using Coriandrum sativum (CS) media extract in ethanol. The structure, morphologies and particle size of the nano-sized complexes were determined using FT-IR, TEM, and PXRD. The results showed that the nano-domain complexes are on the Sub-nano scale. Furthermore, using TGA, we studied the effect of heat on the size of newly prepared nano-complexes. Experimental data were supported by DFT calculations. The findings revealed that the metal complexes investigated are more stable than the free ligand H2L. The antitumor activity was examined before and after heating the nano-complexes at 200 °C. The results reveal the Cr nano complex, after heating, exhibited strong antitumor activity with IC50 value (3.349 µg/ml). The tested Cu nano-complex shows good DNA cleavage. The liver cancer and COVID19 proteins were examined using molecular docking to identify the potential binding energy of inhibitors.

Multi-target activity of copper complexes: Antibacterial, DNA binding, and molecular docking with SARS-CoV-2 receptor.

A series of pendant-armed mixed-ligand copper(II) complexes of the type [CuL1-3(diimine)] (1-6) have been synthesized by the reaction of pendant-armed ligands N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)benzamide (H2L1), N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-4-nitrobenzamide (H2L2) and N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-3,5-dinitrobenzamide (H2L3) with diimine = 2,2'-bipyridyl (bpy) or 1,10-phenanthroline (phen) in the presence of copper(II) chloride and analyzed using various spectroscopic methods. All the spectroscopic results support that the complexes adopt a pentagonal-bipyramidal shape around the copper ion. Gram-positive and Gram-negative bacteria were used to test all the complexes for antibacterial activity and all the complexes had greater potency against gram-negative pathogens. DNA-binding experiments of complexes with calf thymus DNA revealed a major-groove binding pattern, further supported by molecular docking studies. Complexes have significantly interacted with SARS-CoV-2 receptor via π-π, π-σ, π-alkyl, π-anion, π-cation, alkyl, hydrogen bond, van der Waals, and electrostatic interactions. The estimated binding energy and inhibition constant of these complexes are higher than standard drugs, chloroquine, and molnupiravir.

Synthesis, Crystal Structure, Theoretical Calculations, Antibacterial Activity, Electrochemical Behavior, and Molecular Docking of Ni(II) and Cu(II) Complexes with Pyridoxal-Semicarbazone.

New Ni (II) and Cu (II) complexes with pyridoxal-semicarbazone were synthesized and their structures were solved by X-ray crystallography. This analysis showed the bis-ligand octahedral structure of [Ni(PLSC-H)2]·H2O and the dimer octahedral structure of [Cu(PLSC)(SO4)(H2O)]2·2H2O. Hirshfeld surface analysis was employed to determine the most important intermolecular interactions in the crystallographic structures. The structures of both complexes were further examined using density functional theory and natural bond orbital analysis. The photocatalytic decomposition of methylene blue in the presence of both compounds was investigated. Both compounds were active toward E. coli and S. aureus, with a minimum inhibition concentration similar to that of chloramphenicol. The obtained complexes led to the formation of free radical species, as was demonstrated in an experiment with dichlorofluorescein-diacetate. It is postulated that this is the mechanistic pathway of the antibacterial and photocatalytic activities. Cyclic voltammograms of the compounds showed the peaks of the reduction of metal ions. A molecular docking study showed that the Ni(II) complex exhibited promising activity towards Janus kinase (JAK), as a potential therapy for inflammatory diseases, cancers, and immunologic disorders.

Spectro-electrochemical, fluorometric and biothermodynamic evaluation of pharmacologically active morpholine scaffold single crystal ligand and its metal(II) complexes: A comparative study on in-vitro and in-silico screening towards DNA/BSA/SARS-CoV-19.

A novel series of metal(II) complexes (1-5) [MII(L)2]{Where M = Cu (1), Co (2), Mn (3), Ni (4) and Zn (5)} constructed from 2-(4-morpholinobenzylideneamino)phenol Schiff base ligand (HL) in a 1:2 M ratio and the spectral and analytical results put forward square planar geometry. Spectro-electrochemical, hydrodynamic, gel electrophoresis, and DNA binding/cleavage results for all the compounds demonstrate that complex (1) had excellent DNA binding/cleavage properties compared to other compounds. The observation also suggests that test compounds could intercalate with DNA, and the biothermodynamic property more strongly supports the stabilizing of the double helix DNA with the complexes. BSA binding constant results show that complex (1) exposes the best binding property via a static mode, which is further confirmed by FRET calculations. The DFT calculations and docking results for all compounds towards DNA, BSA and SARS-CoV-19 main protease (3CLPro), reveal the binding energies were in the range of -7.8 to -9.4, -6.6 to -10.2 and - 6.1 - -8.2 kcal/mol for all test compounds respectively. In this case, complexes showed favorable binding energies compared to free ligand, which stimulates further studies aimed at validating the predicted activity as well as contributing to tackling the current and future viral pandemics. The in-vitro antioxidant, antimicrobial, and anticancer results for all compounds revealed that copper complex (1) has better activity compared to others. This might result in an effective anticancer drug for future research, which is especially promising since the observed experimental results for all cases were in close agreement with the theoretical calculations.

A new class of half-sandwich ruthenium complexes containing Biginelli hybrids: anticancer and anti-SARS-CoV-2 activities.

In order to discover new dual-active agents, a series of novel Biginelli hybrids (tetrahydropyrimidines) and their ruthenium(II) complexes were synthesized. Newly synthesized compounds were characterized by IR, NMR, and X-ray techniques and investigated for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549, A375, K562 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, two of them were chosen for analyzing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that the proportion of cells in G2/M phase was decreased following the increase of subG1 phase in all treatments. These results confirmed that cells treated with 5b and 5c were induced to undergo apoptotic death. The ruthenium complexes 5a-5d show significant inhibitory potency against SARS-CoV-2 Mpro. Therefore, molecule 5b has significance, while 5e possesses the lowest values of ΔGbind and Ki, which are comparable to cinanserin, and hydroxychloroquine. In addition, achieved results will open a new avenue in drug design for more research on the possible therapeutic applications of dual-active Biginelli-based drugs (anticancer-antiviral). Dual-active drugs based on the hybridization concept "one drug curing two diseases" could be a successful tactic in healing patients who have cancer and the virus SARS-CoV-2 at the same time.

Interactions of Co, Cu, and non-metal phthalocyanines with external structures of SARS-CoV-2 using docking and molecular dynamics.

The new coronavirus, SARS-CoV-2, caused the COVID-19 pandemic, characterized by its high rate of contamination, propagation capacity, and lethality rate. In this work, we approach the use of phthalocyanines as an inhibitor of SARS-CoV-2, as they present several interactive properties of the phthalocyanines (Pc) of Cobalt (CoPc), Copper (CuPc) and without a metal group (NoPc) can interact with SARS-CoV-2, showing potential be used as filtering by adsorption on paints on walls, masks, clothes, and air conditioning filters. Molecular modeling techniques through Molecular Docking and Molecular Dynamics were used, where the target was the external structures of the virus, but specifically the envelope protein, main protease, and Spike glycoprotein proteases. Using the g_MM-GBSA module and with it, the molecular docking studies show that the ligands have interaction characteristics capable of adsorbing the structures. Molecular dynamics provided information on the root-mean-square deviation of the atomic positions provided values between 1 and 2.5. The generalized Born implicit solvation model, Gibbs free energy, and solvent accessible surface area approach were used. Among the results obtained through molecular dynamics, it was noticed that interactions occur since Pc could bind to residues of the active site of macromolecules, demonstrating good interactions; in particular with CoPc. Molecular couplings and free energy showed that S-gly active site residues interacted strongly with phthalocyanines with values ​​of - 182.443 kJ/mol (CoPc), 158.954 kJ/mol (CuPc), and - 129.963 kJ/mol (NoPc). The interactions of Pc's with SARS-CoV-2 may predict some promising candidates for antagonists to the virus, which if confirmed through experimental approaches, may contribute to resolving the global crisis of the COVID-19 pandemic.

Biological Activity of Triazolopyrimidine Copper(II) Complexes Modulated by an Auxiliary N-N-Chelating Heterocycle Ligands.

Novel complexes of type [Cu(N-N)(dmtp)2(OH2)](ClO4)2·dmtp ((1) N-N: 2,2'-bipyridine; (2) L: 1,10-phenantroline and dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine) were designed in order to obtain biologically active compounds. Complexes were characterized as mononuclear species that crystallized in the space group P-1 of the triclinic system with a square pyramidal geometry around the copper (II). In addition to the antiproliferative effect on murine melanoma B16 cells, complex (1) exhibited low toxicity on normal BJ cells and did not affect membrane integrity. Complex (2) proved to be a more potent antimicrobial in comparison with (1), but both compounds were more active in comparison with dmtp-both against planktonic cells and biofilms. A stronger antimicrobial and antibiofilm effect was noticed against the Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). Both electron paramagnetic resonance (EPR) and Saccharomyces cerevisiae studies indicated that the complexes were scavengers rather than reactive oxygen species promoters. Their DNA intercalating capacity was evidenced by modifications in both absorption and fluorescence spectra. Furthermore, both complexes exhibited nuclease-like activity, which increased in the presence of hydrogen peroxide.

Antimicrobial and Anticancer Application of Silver(I) Dipeptide Complexes.

Three silver(I) dipeptide complexes [Ag(GlyGly)]n(NO3)n (AgGlyGly), [Ag2(GlyAla)(NO3)2]n (AgGlyAla) and [Ag2(HGlyAsp)(NO3)]n (AgGlyAsp) were prepared, investigated and characterized by vibrational spectroscopy (mid-IR), elemental and thermogravimetric analysis and mass spectrometry. For AgGlyGly, X-ray crystallography was also performed. Their stability in biological testing media was verified by time-dependent NMR measurements. Their in vitro antimicrobial activity was evaluated against selected pathogenic microorganisms. Moreover, the influence of silver(I) dipeptide complexes on microbial film formation was described. Further, the cytotoxicity of the complexes against selected cancer cells (BLM, MDA-MB-231, HeLa, HCT116, MCF-7 and Jurkat) and fibroblasts (BJ-5ta) using a colorimetric MTS assay was tested, and the selectivity index (SI) was identified. The mechanism of action of Ag(I) dipeptide complexes was elucidated and discussed by the study in terms of their binding affinity toward the CT DNA, the ability to cleave the DNA and the ability to influence numbers of cells within each cell cycle phase. The new silver(I) dipeptide complexes are able to bind into DNA by noncovalent interaction, and the topoisomerase I inhibition study showed that the studied complexes inhibit its activity at a concentration of 15 µM.

Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro.

Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with zinc demonstrate better clinical outcomes. The molecular targets and mechanistic details of the anti-coronaviral activity of zinc remain obscure. We show that zinc not only inhibits the SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of the Mpro-Zn2+ complex at 1.9 Å and provide the structural basis of viral replication inhibition. We show that Zn2+ coordinates with the catalytic dyad at the enzyme active site along with two previously unknown water molecules in a tetrahedral geometry to form a stable inhibited Mpro-Zn2+ complex. Further, the natural ionophore quercetin increases the anti-viral potency of Zn2+. As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Zn2+ mediated inhibition of Mpro may have wider implications.

Synthesis, Biological and In Silico Studies of a Tripodal Schiff Base Derived from 2,4,6-Triamino-1,3,5-triazine and Its Trinuclear Dy(III), Er(III), and Gd(III) Salen Capped Complexes.

A tripodal Schiff base ligand, 2,4,6-Tris(4-carboxybenzimino)-1,3,5-triazine (MT) and its trinuclear Dy(III), Er(III), and Gd(III) complexes were synthesized. These were characterized using UV-visible, IR, 1H, and 13C NMR spectroscopies, elemental analysis, and molar conductivity measurements. The spectral studies indicate that the ligand is hexadentate and coordinates to the Ln(III) ions through the oxygen atoms of the carboxylic group. The trinuclear complexes were characterized as being bridged by carboxylate anions to the Dy(III), Er(III), and Gd(III) salen centers and displaying a coordination number of six. Biological studies revealed that MT is more active against the test micro-organisms relative to the trinuclear complexes. Acute toxicity studies revealed that MT is safe and has a wide range of effective doses (ED50). In vivo antimalarial studies indicate that MT could serve as an effective antimalarial agent since it has parasitemia inhibition of 84.02% at 50 mg/kg and 65.81% at 25 mg/kg, close to the value (87.22%) of the standard drug-Artesunate. Molecular docking simulation studies on the compounds against SARS-CoV-2 (6Y84) and E. coli DNA gyrase (5MMN) revealed effective binding interactions through multiple bonding modes. The binding energy calculated for Er(III)MT-6Y84 and Er(III)MT-5MMN complexes showed active molecules with the ability to inhibit SARS-CoV-2 and E. coli DNA gyrase.

Selective Binding and Redox-Activity on Parallel G-Quadruplexes by Pegylated Naphthalene Diimide-Copper Complexes.

G-quadruplexes (G4s) are higher-order supramolecular structures, biologically important in the regulation of many key processes. Among all, the recent discoveries relating to RNA-G4s, including their potential involvement as antiviral targets against COVID-19, have triggered the ever-increasing need to develop selective molecules able to interact with parallel G4s. Naphthalene diimides (NDIs) are widely exploited as G4 ligands, being able to induce and strongly stabilize these structures. Sometimes, a reversible NDI-G4 interaction is also associated with an irreversible one, due to the cleavage and/or modification of G4s by functional-NDIs. This is the case of NDI-Cu-DETA, a copper(II) complex able to cleave G4s in the closest proximity to the target binding site. Herein, we present two original Cu(II)-NDI complexes, inspired by NDI-Cu-DETA, differently functionalized with 2-(2-aminoethoxy)ethanol side-chains, to selectively drive redox-catalyzed activity towards parallel G4s. The selective interaction toward parallel G4 topology, controlled by the presence of 2-(2-aminoethoxy)ethanol side chains, was already firmly demonstrated by us using core-extended NDIs. In the present study, the presence of protonable moieties and the copper(II) cavity, increases the binding affinity and specificity of these two NDIs for a telomeric RNA-G4. Once defined the copper coordination relationship and binding constants by competition titrations, ability in G4 stabilization, and ROS-induced cleavage were analyzed. The propensity in the stabilization of parallel topology was highlighted for both of the new compounds HP2Cu and PE2Cu. The results obtained are particularly promising, paving the way for the development of new selective functional ligands for binding and destructuring parallel G4s.

ReI Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS-CoV-2 Main Cysteine Protease.

Since its outbreak, the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has impacted the quality of life and cost hundreds-of-thousands of lives worldwide. Based on its global spread and mortality, there is an urgent need for novel treatments which can combat this disease. To date, the 3-chymotrypsin-like protease (3CLpro ), which is also known as the main protease, is considered among the most important pharmacological targets. The vast majority of investigated 3CLpro inhibitors are organic, non-covalent binders. Herein, the use of inorganic, coordinate covalent binders is proposed that can attenuate the activity of the protease. ReI tricarbonyl complexes were identified that demonstrate coordinate covalent enzymatic inhibition of 3CLpro . Preliminary studies indicate the selective inhibition of 3CLpro over several human proteases. This study presents the first example of metal complexes as inhibitors for the 3CLpro cysteine protease.

Metal Complexes as Antiviral Agents for SARS-CoV-2.

The severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2), the infectious agent responsible for COVID-19 - has caused more than 2.5 million deaths worldwide and triggered a global pandemic. Even with successful vaccines being delivered, there is an urgent need for novel treatments to combat SARS-CoV-2, and other emerging viral diseases. While several organic small molecule drug candidates are in development, some effort has also been devoted towards the application of metal complexes as potential antiviral agents against SARS-CoV-2. Herein, the metal complexes that have been reported to show antiviral activity against SARS-CoV-2 or one of its target proteins are described and their proposed mechanisms of action are discussed.

Supramolecular Cylinders Target Bulge Structures in the 5' UTR of the RNA Genome of SARS-CoV-2 and Inhibit Viral Replication*.

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.

Quercetin/Zinc complex and stem cells: A new drug therapy to ameliorate glycometabolic control and pulmonary dysfunction in diabetes mellitus: Structural characterization and genetic studies.

Medicinal uses and applications of metals and their complexes are of increasing clinical and commercial importance. The ligation behavior of quercetin (Q), which is a flavonoid, and its Zn (II) (Q/Zn) complex were studied and characterized based on elemental analysis, molar conductance, Fourier-transform infrared (FTIR) spectra, electronic spectra, proton nuclear magnetic resonance (1H-NMR), thermogravimetric analysis, and transmission electron microscopy (TEM). FTIR spectral data revealed that Q acts as a bidentate ligand (chelating ligand) through carbonyl C(4) = O oxygen and phenolic C(3)-OH oxygen in conjugation with Zn. Electronic, FTIR, and 1H-NMR spectral data revealed that the Q/Zn complex has a distorted octahedral geometry, with the following chemical formula: [Zn(Q)(NO3)(H2O)2].5H2O. Diabetes was induced by streptozotocin (STZ) injection. A total of 70 male albino rats were divided into seven groups: control, diabetic untreated group and diabetic groups treated with either MSCs and/or Q and/or Q/Zn or their combination. Serum insulin, glucose, C-peptide, glycosylated hemoglobin, lipid profile, and enzymatic and non-enzymatic antioxidant levels were determined. Pancreatic and lung histology and TEM for pancreatic tissues in addition to gene expression of both SOD and CAT in pulmonary tissues were evaluated. MSCs in combination with Q/Zn therapy exhibited potent protective effects against STZ induced hyperglycemia and suppressed oxidative stress, genotoxicity, glycometabolic disturbances, and structural alterations. Engrafted MSCs were found inside pancreatic tissue at the end of the experiment. In conclusion, Q/Zn with MSC therapy produced a synergistic effect against oxidative stress and genotoxicity and can be considered potential ameliorative therapy against diabetes with pulmonary dysfunction, which may benefit against COVID-19.

Molecular designing, crystal structure determination and in silico screening of copper(II) complexes bearing 8-hydroxyquinoline derivatives as anti-COVID-19.

The pandemic by COVID-19 is hampering everything on the earth including physical and mental health, daily life and global economy. At the moment, there are no defined drugs, while few vaccines are available in the market to combat SARS-CoV-2. Several organic molecules were designed and tested against the virus but they did not show promising activity. In this work we designed two copper complexes from the ligands analogues with chloroquine and hydroxychloroquine. Both the ligands and complexes were well characterized by using various spectroscopic, thermal and X-ray diffraction techniques. Both the complexes as well as ligands were screened through in silico method with the chloroquine and hydroxychloroquine which essentially proved pivotal for successful understanding towards the target protein and their mechanism of action. The results indicated that the balanced hydrophobic and polar groups in the complexes favor their binding in the active site of the viral ADP-ribose-1 monophosphatase enzyme over the parent organic molecules.