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


Analytical information

The CHNS contents, chemical system, melting factors, Colour and yields of the synthesized compounds are postulated in Desk 1. This illustrates the purity of the ligand and its complexes.

Desk 1 Elemental evaluation and bodily properties of the research compounds.

1H-NMR interpretations

The 1H NMR spectra of the synthesized H2L ligand had been detected in DMSO and D2O (Figs. S1 and S2). For H2L, The CH3 and OH protons alerts had been detected as a singlet at δ2.21 and 9.64 ppm, respectively. The imine (–CH=N) sign was noticed at δ 8.58 ppm37. The NH proton sign was noticed at δ 10.61 ppm38. The fragrant proton alerts of the H2L ligand had been detected between δ 7.24 and seven.91 ppm39. The sign at δ 2.51 ppm for DMSO-d6 37. The hydroxyl group sign has utterly disappeared upon the addition of D2O, indicating the purity of the ready ligand.

Molar conductivity evaluation

The molar conductance (Ωm) of the ready ligand H2L and its micro-complexes in 10–3 M DMSO answer lie within the 0.7 to five.35 Ohm−1 cm2 mol−1 vary (Desk 1), revealing the non-electrolytic nature of those compounds40.

IR spectra

Infrared spectral research of micro-complexes

The infrared spectra of the investigated ligand and its steel(II) Chelates are depicted in (Fig. 2A). The H2L ligand spectral exhibited absorption bands at 3200, 1384, and 1156 cm−1 that’s, respectively, assigned to υ(OH), υas(SO2) and υsy(SO2) teams. The synthesis of the H2L ligand is revealed by the imine sign of the ligand (C=N) at 1633 cm−1; nonetheless, within the Cr(II) and Cu(II) complexes, this sign shifted to 1607 and 1613 cm−1, suggesting that imine nitrogen is concerned in coordination41. The phenolic (O–H) of the H2L disappeared within the Cr(II) and Cu(II) complexes, exhibiting proton alternative throughout advanced formation. The three attribute peaks of υ(NH) at 3457, υas(SO2) at 1384 cm−1 and υsy(SO2) at 1156 cm−1 within the spectra of the Cr(II) and Cu(II) micro-complexes and their free ligand all seem on the identical place, excludes the coordination by means of the NH and SO2 teams42. The brand new bands within the IR spectra of the ready compounds at 520–528 and 570–573 cm−1 are ascribed to (M–N) and (M–O), respectively. Moreover, within the spectra of the Cr(II) advanced, the broadband close to 3477 may very well be attributed to the υ(OH2) (Desk 2).

Determine 2
figure 2

FT-IR spectra of H2L and its micro-complexes (A) and nano-complexes in CS media (B).

Desk 2 Important vibrational frequencies (cm−1) of H2L and its micro-complexes.

Infrared spectral research of nano-complexes

The FTIR spectra of the Cr and Cu nano-domain complexes generated in CS/EtOH media are given in (Fig. 2B), which reveals the binding modes of the Cr and Cu nano-domain complexes, that are corroborated by a change in band place of the nano-domain complexes when in comparison with the free ligand.

Mass spectral information

MS of the synthesized H2L and its Cr and Cu complexes are proven in (Fig. S3). The MS of H2L exhibited a molecular ion peak (m/z)=432.45, which is in good settlement with the proposed molecular weight (Fig. S3A). The proposed fragmentation sample of the H2L ligand was given in (Fig. 3). The mass spectrum of the Cr(II) and Cu(II) complexes displayed molecular ion peaks at m/z 968.27 and 518.92, respectively, approving the molecular weight and the existence of Cr and Cu isotope peaks at m/z 54 and 65, respectively (Fig. S3B, C).

Determine 3
figure 3

Steered MS fragmentation sample of Schiff base ligand.

X‑ray research

The X-ray diffraction sample is an analytical method that was used to study extra concerning the chemistry and crystallographic construction of the obtained Cr and Cu nano-complexes (Fig. 4). The crystalline section of the ready Cr and Cu nano-complexes in CS/EtOH media was revealed by their sharp and high-intensity diffraction peaks. The nano crystallite sizes of the Cr and Cu nano-complexes had been calculated utilizing the Scherrer system17,37,43, that are 42.5 and 39.2 nm, respectively, which lay contained in the vary of the nano-scale.

Determine 4
figure 4

XRD patterns of Cr and Cu nano-complexes in CS media.

SEM evaluation of micro-complexes

The morphologies and particle measurement of the Cr(II) and Cu(II) micro-complexes have been demonstrated by the scanning electron microscope (SEM). Determine 5 depicts the SEM images of the synthesized Cr(II) and Cu(II) Schiff base complexes. Within the pictograph, we noticed that the produced complexes are organized in an everyday matrix. This means that Cr(II) and Cu(II) complexes have homogeneous section materials. The Cr(II) advanced has a seashell-like form with a mean particle measurement of 8 µm. The pictures of the Cu (II) advanced show a spherical form with a mean particle measurement of 0.33 µm. This means that Cr(II) and Cu(II) complexes are discovered within the microdomain.

Determine 5
figure 5

SEM micrographs and particle measurement distribution curves for Cr(II) advanced (A) and Cu(II) advanced (B).

TEM measurement of nano-complexes

The transmission electron microscopy (TEM) method was used to look at the morphologies and particle measurement of the Cr and Cu nano-sized complexes produced in Coriandrum sativum (CS) media earlier than and after heating the nano-sized chelates at 200 °C for two h. The pictures of the Cr and Cu nano-complexes present that these complexes have a spherical form. Furthermore, the calculated histogram for the typical particle measurement of the ready nano-sized chelates earlier than heating was 3.85 and 16.42 nm (Sub-nano) for Cr and Cu nano-sized chelates, respectively. Whereas heating Cr and Cu nano-complexes to 200 °C resulted in particle sizes of two.05 nm and a couple of.72 nm (Sub-nano), respectively, it additionally signifies that the particle measurement of Cr and Cu nano-sized chelates decreases with rising temperature (Fig. 6).

Determine 6
figure 6

TEM footage and particle measurement distribution curves for Cr nano-complex (A & C) and Cu nano-complex (B & D) in CS media earlier than and after heating, respectively.

Thermal evaluation

Thermal evaluation of micro-complexes

The outcomes of thermogravimetric evaluation of mononuclear Cr(II) and Cu(II) complexes are collected in (Desk 3). The thermogram of Cr(II) advanced contains 4 decomposition steps. The load losses within the temperature vary of 45–317 °C are attributed to the elimination of 1 lattice H2O molecule, two coordinated H2O molecules and 2C6H8N2. Within the vary of 317–395 °C, the loss in weight corresponds to the lack of 2SO2 and 2C6H6. One other lack of 2C10H8 molecules happens at temperatures starting from 395 to 578 °C. At greater temperatures (578–736 °C), the discovered weight reduction related to this step could also be attributed to the lack of the 2HCN molecules. The thermal decomposition of the Cu(II) advanced has three principal degradation steps. The Cu(II) advanced reveals thermal stability as much as 400 °C, indicating that crystalline water molecules and coordinated water molecules don’t exist on this advanced. The primary stage of decomposition happens on the temperature vary of 41–451 °C, which corresponds to the elimination of 2C6H8N2. The elimination of 2C6H6, SO2 and HCN happen inside the temperature vary 451–702 °C adopted by the lack of 2C11H7NO inside the temperature vary 702–860 °C. In Cr(II) and Cu(II) complexes, the remaining residues are steel oxides. These outcomes are following the composition of the complexes. A consultant TG/DTA diagram is given in (Fig. S4A, B).

Desk 3 Thermogravimetric outcomes of steel complexes of the ligand H2L.

Thermal evaluation of nano-complexes

The present thermal evaluation methods purpose to amass extra concerning the chemistry of the Cr and Cu nano-complexes generated in CS/EtOH media by measuring the dimensions of the nano-complexes at every step of thermal heating to find out how the temperature influences the dimensions of the nano-complexes. The particle sizes of Cr and Cu nano-complexes had been calculated earlier than and after heating at 200 °C (Tables 4 and 5). After heating at 200 °C, the thermograms of Cr and Cu nano-complexes revealed a discount within the particle measurement at every of the thermal heating steps. The warmth remedy reduces the buildup of nano-complexes and thus reduces particles measurement. Cr and Cu nano-complexes are current in sub-nano buildings (Fig. S4C, F).

Desk 4 TGA steps and the particle measurement of Cr and Cu nanodomain of the ligand H2L earlier than heating.
Desk 5 TGA steps and the particle measurement of Cr and Cu nanodomain of the ligand H2L after heating.

Digital spectroscopy

The H2L Schiff base ligand reveals 4 absorption bands in DMF44. H2L Schiff base ligand displayed absorption bands at 386, 445, 468 and 539 nm, which can be assigned to π→π* transition of the benzene rings, n→π* of imine (C=N), n→π* of the phenolic group and charge-transfer (CT), respectively. The Cr(II) advanced revealed absorption bands at 334, 404, 434, 485 and 540 nm that may be attributed to π→π* transition of the benzene rings, n→π* of imine (C=N), n→π* of the phenolic group, cost switch CT (M→L) and 5Eg→5T2g(D) transition, respectively. These absorption bands resemble an octahedral geometry45. The spectrum of the Cu(II) advanced reveals three bands at 313, 364 and 412 nm, which will be attributed, respectively, to the π→π* transition of the benzene rings, n→π* of imine and phenolic teams. Furthermore, a broad band at 543 nm has been recorded for the 2T22E(D) transition. These digital bands resemble a tetrahedral geometry46,47. The digital spectrum of inexperienced synthesized nano-complexes revealed a model that’s related to the floor plasmon resonance (SPR) 48, confirming the discount course of and formation of nano-complexes. The Cr nano-complex reveals bands at 329, 381, 439 and 523 nm transitions, that are linked to π→π* transitions of the benzene rings, n→π* of imine and phenolic teams and 5Eg→5T2g(D) transitions, respectively. This means that the Cr nano-complex is an octahedral construction. The three bands within the spectrum of the Cu nano-complex detected at 364, 405 and 536 nm are attributed to n→π* of imine and phenolic teams and 2T22E(D) transitions, respectively, and recommend a tetrahedral geometry (Fig. S5) & (Desk 6).

Desk 6 UV–Seen spectra of H2L, its micro and nano-complexes.

EPR spectroscopy

The X-band EPR spectra of Cu(II) advanced had been recorded at room temperature (Fig. 7). The efficient geff-value of the noticed EPR spectrum of the ready Cu(II) advanced was decided and listed in (Desk 7). The investigated Cu(II) advanced is recommended to have tetrahedral geometry primarily based on the form of the noticed EPR alerts and geff-value. In keeping with the outcomes obtained, the g║ worth for the Cu(II) advanced is decrease than 2.3, revealing that the steel–ligand bonds are covalent. The geometric parameter G issue outlined as G=(g||–2.0023)/(g–2.0023), which is 0.355, means that the alternate interplay is detected within the Cu(II) advanced and the alternate interplay was operative between copper facilities within the current Cu(II) advanced49,50.

Determine 7
figure 7

EPR spectra of the usual (DPPH) (A) and CuL2 (B).

Desk 7 EPR parameters for Cu(II) advanced.

Molecular modeling

Geometry optimization of the H

2

L ligand

Determine 8 reveals the molecular optimization of the H2L through the use of the B3LYP technique and 6–311 + G(d,p) foundation units. The costs calculated from the natural-bond-orbital technique (NBO) are: O1(− 0.693), O2(− 0.953), O3(− 0.924), N1(− 0.531), N2(− 0.528), N3(− 0.891), N4(− 0.427) and S(2.357). Metallic ions coordinate to O3 and N4 atoms.

Determine 8
figure 8

Optimized buildings of H2L, dipole second vector, and the costs on energetic facilities of H2L.

Geometry optimization of the steel complexes

Complexes had been optimized utilizing the Gaussian 09 program, utilizing the DFT technique comprising the B3LYP/6-311G + (dp) degree of idea for all atoms besides steel ions and on the B3LYP/LANL2DZ degree of idea for steel ions. The computed theoretical infrared frequencies make sure the absence of imaginary frequencies.

Optimization of [CrL2(H2O)2].H2O

Determine 9A shows the molecular optimization of the advanced [CrL2(H2O)2].H2O because the lowest-energy configuration. The chromium steel ion is six-coordinated in an octahedral geometry, with atoms O3, N4, O4, and N5 having a dihedral angle of 0.730° (Desk 8). The gap between N4 and O1 within the ligand (3.715 Å) is lowered within the [CrL2(H2O)2].H2O advanced to 2.786 and a couple of.779 Å for N4–O3 and N5–O4, respectively, because of advanced formation. The costs calculated from the natural-bond-orbital technique (NBO) on the coordinated atoms are Cr (+ 0.506), O3 (− 0.616), O4 (− 0.619), N4 (− 0.468), N5 (− 0.461), O7 (− 0.873) and O8 (− 0.872).

Determine 9
figure 9

The optimized buildings, dipole second vector, and the costs on energetic facilities of [CrL2(H2O)2].H2O (A), [CuL2] (B).

Desk 8 Bond lengths (Å) and bond angles (o) of optimized [CrL2(H2O)2].H2O.
Optimization of [CuL2]

Determine 9B reveals the molecular optimization of the advanced [CuL2] because the lowest-energy configuration. The copper steel ion is four-coordinated in a tetrahedral geometry (Desk 9). The gap between N4 and O1 within the ligand (3.715 Å) is lowered within the [CuL2] advanced to 2.913 and a couple of.821 Å for N4–O3 and N5–O4, respectively, because of advanced formation. The costs computed from the natural-bond-orbital technique (NBO) on the coordinated atoms are Cu (+ 0.893), O3(− 0.635), N4(− 0.602), O4(− 0.630) and N5(− 0.575).

Desk 9 Bond lengths (Å) and bond angles (o) of optimized CuL2.

HOMO/LUMO power analysis

An essential technique for analyzing the chemical conduct of ligands and complexes is HOMO/LUMO power analysis (Fig. 10). The power of the compound to amass electrons is expressed by the LUMO power, whereas its capability to donate electrons is expressed by the HOMO power. The overall energies of the Cr(II) and Cu(II) complexes are decrease than these of the free ligand, indicating that they’re extra secure. Along with the frontier molecular orbitals are utilized in estimation of different chemical parameters equivalent to dipole second, power hole (Eg), ionization potential (I), electronegativity (χ), Chemical hardness (η), Chemical softness (S), electrophilicity (ω), electron affinity (A), chemical potential (μ) are tabulated in (Desk 10). It was reported {that a} molecule with a excessive power hole (Eg) worth resulted in a tough molecule with low reactivity. CuL2 advanced has the next softness (S) worth, suggesting the next chemical reactivity.

Determine 10
figure 10

MO and their energies for, (H2L), complexes [CrL2(H2O)2].H2O and [CuL2]).

Desk 10 Calculated digital parameters of the ligand (H2L), complexes [CrL2(H2O)2].H2O and [CuL2]).

Electrostatic potential map (MEP)

The electrostatic potential mapping relies on the whole electron density floor, which shows electrostatic potential distribution, measurement, structural form and dipole moments. Determine 11 shows the MEP for the investigated ligand and its complexes. Pink, blue, yellow, and inexperienced shade zones on the MEP floor characterize, respectively, electron-rich, electron-poor, reasonably electron-poor, and impartial zones. Constructive potential zones are discovered over hydrogen atoms within the MEP, whereas detrimental potential areas are discovered over electronegative atoms (oxygen and nitrogen). The inexperienced area predominated within the MEP surfaces, akin to a possible midway between the 2 extremes of crimson and darkish blue shade.

Determine 11
figure 11

Molecular electrostatic potential (MEP) floor for H2Land complexes [CrL2(H2O)2].H2O and [CuL2]).

Antitumor exercise

The ligand H2L and its Cr and Cu nano-complexes ready in CS/EtOH media earlier than and after heating the nanodomain complexes at 200 °C had been measured towards a cell line (HepG-2) to determine in vitro antitumor effectivity (Fig. 12A) and in contrast with the cis-platin anticancer drug (IC50 ~ 1.714 μg/ml). The antitumor and growth-inhibitory results had been investigated through the use of the IC50 method, which estimates the focus of a drug that reduces cell lineout development by 50%. Compounds with IC50 values lower than 5.00 μg/ml, inside 5.00–10.00 μg/ml and between 10.00 and 25.00 μg/ml are thought-about robust, average, and delicate antitumor exercise, respectively51. The nano-sized Cr advanced, after heating at 200 °C, exhibited robust antitumor exercise with IC50 worth (3.349 μg/ml). The nano-sized Cr(II) advanced (earlier than heating) and Cu(II) advanced (earlier than and after heating) displayed average antitumor exercise, with IC50 values starting from 5.73 to 7.49 μg/ml, whereas the H2L ligand confirmed weak antitumor exercise, with IC50 worth of 25.6 μg/ml (Fig. 12B). The outcomes reveal that the nanodomain complexes generated in CS/EtOH media after heating at 200 °C have larger effectivity in comparison with the nano-complexes with out heating. This can be as a result of heating nano-complexes having the next capability to bind DNA than others examined as a consequence of their small particle measurement, which can be used extensively in financial anticancer research by specialists.

Determine 12
figure 12

The cell viability of H2L and its nano-complexes ready in CS/EtOH media versus cisplatin drug (A). IC50 values of H2L and its nano-complexes (earlier than and after heating) on HepG-2 cell line (B).

DNA cleavage research

DNA interacts with nano-domain complexes in many various methods, and these interactions considerably have an effect on the construction and performance of DNA52. The Cu nano-domain advanced was investigated for its DNA cleavage exercise utilizing agarose gel electrophoresis, which was used with totally different and fixed concentrations of the copper nano-domain advanced with fixed and totally different concentrations of DNA, respectively, to find out whether or not the nano-domain Cu advanced ready in CS/EtOH media has any affect on DNA. In keeping with the outcomes, the Cu nano-domain advanced might cleave DNA at excessive concentrations (2 and 1 mg/ml) within the presence of a relentless focus of DNA and variable concentrations of the Cu nano-domain advanced (Fig. 13 lane 3,4); Moreover, when a set focus of Cu nano-domain advanced is current within the presence of various quantities of DNA, the Cu nano-domain advanced can cleave DNA at low concentrations of DNA (Fig. 13 lane 8]; beneath the experimental circumstances and full size photos (Figs. S6 and S7).

Determine 13
figure 13

Gel electrophoresis diagram illustrating the cleavage of DNA by Cu nano-complex after incubation at 37 °C for 1 h. Lane L- marker 1 kb DNA Ladder, lane 1 DNA management, lane 2 DNA + DMSO, lane 3: 400 ng DNA + 2 mg/ml of nano-complex, lane 4: 400 ng DNA + 1 mg/ml of nano-complex, lane 5: 400 ng DNA + 0.5 mg/ml of nano-complex, lane 6: DNA management, lane 7: DNA + DMSO, lane 8: 200 ng DNA + 1 mg/ml of nano-complex, lane 9: 400 ng DNA + 1 mg/ml of nano-complex, lane 10: 800 ng DNA + 1 mg/ml of nano-complex.

Molecular docking simulation with liver most cancers and COVID-19 protein receptors

The protein-drug affinities may very well be investigated by means of molecular docking interplay. The ligand H2L and its nano-scale Cu(II) and Cr(II) complexes had been docked with protein targets in liver most cancers, particularly the receptors of methionine adenosyl-transferases (PDB ID: 5A19) and COVID-19 principal protease viral protein (PDB ID: 6lu7). The binding free energies of ready compounds in case of (PDB ID: 5A19) are − 26.0, − 28.0, and − 39.0 kcal/mol whereas in case of (PDB ID: 6lu7) are − 8.0, − 23.3 and − 44.1 kcal/mol for H2L, CuL2 and [CrL2(H2O)2].H2O; respectively, (Tables 11 and 12). The stronger interplay displays extra detrimental binding power. Therefore, molecular interplay information present the very best binding affinity of the [CrL2(H2O)2].H2O in the direction of each receptors relative to different compounds. The 2- and three-dimensional plots of consultant docked buildings of H2L, [CrL2(H2O)2].H2O and CuL2 with the receptor’s energetic web site of the liver most cancers protein (PDB ID: 5A19) and COVID-19 principal protease viral protein (PDB ID: 6lu7) had been depicted in Figs. 14 and 15, respectively.

Desk 11 The Docking interactions discovered for H2L, [CrL2(H2O)2].H2O and CuL2 with the energetic websites of the receptor of liver most cancers protein (PDB ID: 5A19).
Desk 12 The Docking interactions discovered for H2L, CrL2(H2O)2 and CuL2 with the energetic websites of the receptor of COVID-19 principal protease viral protein (PDB ID: 6lu7).
Determine 14
figure 14

The 2- and three-dimensional plots of the interactions between H2L, [CrL2(H2O)2].H2O and CuL2 with the energetic web site of the receptor of liver most cancers protein (PDB ID: 5A19).

Determine 15
figure 15

The 2- and three-dimensional plots of the interactions between H2L, [CrL2(H2O)2].H2O and CuL2 with the energetic web site of the receptor of COVID-19 principal protease viral protein (PDB ID: 6lu7).

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