Metal Complexes of Tridentate Schiff Base: Synthesis, Characterization, Biological Activity and Molecular Docking Studies with COVID-19 Protein Receptor

doi:10.21203/rs.3.rs-207632/v1

Mononuclear chelates of Cr(III), Mn(II), Fe(III), Ni(II), Cu(II), Zn(II) and Cd(II) resulting from new tridentate Schiff base ligand, 4-((1-(5-acetyl-2,4-dihydroxyphenyl)ethylidene)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, were synthesized and characterized via various spectroscopic methods. Metal to ligand ratio was found to be 1:1, which was revealed via elemental analysis. IR has sharp out that the coordination of the ligand towards the metal ions was carried out via NOO atoms. UV-Vis, ¹HNMR spectral data, molar conductance measurements, BET surface area, melting points and theoretically through density function theory were used such as characterizing techniques in supporting of further interpretation of the complexes structures. The complexes were octahedral except Cu(II) and Ni(II) complexes were tetrahedral as suggested through the magnetic moment measurement. The complexes were found to have surface area, pore volume and particle radius 23–176 m² g^− 1, 0.02–0.33 cc/g and 8.71–4.32 nm, respectively, as pointed out from BET measurement. Schiff base ligand and its metal complexes were tested in vitro to estimate their bactericidal activity opposed to Gram-negative and Gram-positive bacteria and antifungal organisms. In the recent incident of a novel coronavirus (SARS-CoV-2) spreads, antiviral drug detection is of most importance. MOE 2008 was used headed for screen potential drugs with molecular docking by the structural protein and non-structural protein sites of new coronavirus and the study was constructed to molecular docking without validation through MD simulations. Interactions with the main protease may play a key role in fighting against viruses.

Metal complexes

Schiff base ligand

spectroscopic analysis

Microbial and anticancer activity

molecular docking of COVID-19

density functional theory.

Table 1. Analytical and physical data of Schiff base ligand (H₂L) and its metal complexes.

Compound

(Molecular Formula)

Colour

(%yield)

M.p.

(°C)

% Found (Calcd.)

Λ_m

Ω^-1mol^-1cm²

µ_eff

(BM)

C

H

N

M

H₂L

orange

(92)

190

66.39

(66.42)

5.49

(5.53)

11.01

(11.07)

----

-----

----

[Cr(H₂L)(H₂O)₂Cl]Cl_2.2H₂O

yellow

(85)

>300

41.28

(41.34)

4.64

(4.76)

6.72

(6.89)

8.41

(8.53)

113

3.99

[Mn(H₂L)(H₂O)₂Cl]Cl.2H₂O

brown

(84)

206

43.18

(43.66)

4.99

(5.02)

7.20

(7.27)

9.39

(9.52)

63

5.41

[Fe(H₂L)(H₂O)₂Cl]Cl₂

brown

(83)

>300

43.37

(43.61)

4.29

(4.33)

7.19

(7.27)

9.56

(9.69)

103

5.28

[Ni(H₂L)(H₂O)]Cl₂.4H₂O

green

(80)

>300

42.01

(42.06)

5.07

(5.17)

7.00

(7.01)

9.71

(9.85)

107

4.39

[Cu(H₂L)Cl]Cl.2H₂O

Greenish blue

(86)

>300

45.73

(45.82)

4.43

(4.55)

7.22

(7.64)

11.18

(11.55)

74

2.8

[Zn(H₂L)(H₂O)Cl₂]2H₂O

Dark brown

(84)

169

43.83

(44.23)

4.63

(4.74)

7.30

(7.37)

11.37

(11.41)

24

Diamagnetic

[Cd(H₂L)(H₂O)Cl₂]

brown

(85)

158

43.25

(43.39)

3.78

(3.96)

7.21

(7.23)

19.19

(19.35)

9

Diamagnetic

Table 2. IR spectra of H₂L ligand and its metal complexes.

Assignment	v(OH) phenolic and H₂O	v(C=N) azomethine	v(C=O) resorcinol	v(C=O) antipyrine	ρr(H₂O) and ρw(H₂O).	v(M-O)	v(M-N)
H₂L	3420br	1589m	1652br		------	---------	-
[Cr(H₂L)(H₂O)₂Cl]Cl_2.2H₂O	3424br,3148br	1531sh	1643m	1620s	757, 698	575	452
[Mn(H₂L)(H₂O)₂Cl]Cl.2H₂O	3428br,3192br	1560s	1636br		839, 666	578	421
[Fe(H₂L)(H₂O)₂Cl]Cl₂	3417br,3165br	1539m	1648sh	1595s	840, 692	546	453
[Ni(H₂L)(H₂O)]Cl₂.4H₂O	3429br	1550s	1626br		876, 720	591	443
[Cu(H₂L)Cl]Cl.2H₂O	3425br,3244br	1541sh	1630sh	1601s	836, 694	599	429
[Zn(H₂L)(H₂O)Cl₂]2H₂O	3439br,3264br	1579s	1651sh	1620s	840, 699	579	459
[Cd(H₂L)(H₂O)Cl₂]	3421br	1587m	1652sh	1630s	889, 696	590	448

sh = sharp, m = medium, br = broad, s = small, w = weak

Table 3. The different optimized and quantum chemical parameters of H₂L and its Cd(II) complex.

Bond lengths (Å)	H₂L	[Cd(H₂L)(H₂O)Cl₂]
C(1) - N(2)	1.46	1.47
C(1) - O(24)	1.25	1.33
N(2) - N(3)	1.41	1.43
N(2) - C(4)	1.47	1.47
N(3) - C(15)	1.47	1.47
N(3) - C(19)	1.50	1.49
C(25) - N(26)	1.46	1.50
N(26) - C(27)	1.31	1.31
C(29) - O(40)	1.43	1.45
C(34) - O(42)	1.43	1.43
O(40) -,H(41)	0.96	0.96
O(42)- H( 43)	0.96	0.96
C(44) - O(45)	1.26	1.26
Cd(50) - Cl(51)	------	2.40
Cd(50) - Cl(52)	----	2.40
Cd(50) - O(53)	----	3.11
O(40) - Cd(50)	----	3.06
N(26) - Cd(50)	----	3.06
O(24) - Cd(50)	----	3.08
Bond angles (^o)
O(24)- Cd(50)- O(40)	----	114
O(24) -Cd(50) - Cl(52)	----	89
N(26) - Cd(50) - Cl(52)	----	93
O(40) - Cd(50) - Cl(51)	----	90
O(40) - Cd(50) - O(53)	----	94
Cl(51) - Cd(50) - O(53)	----	86
The calculated quantum chemical parameters
E (a.u.)	-1270.99	-7705.93
Dipole moment (Debye)	4.60	13.75
E_HOMO (eV)	-5.51	-6.10
E_LUMO (eV)	-1.70	-2.30
Δ E (eV)	3.81	3.80
χ(eV)	-3.61	-4.20
η (eV)	1.91	1.90
σ (eV)^-1	0.52	0.53
Pi (eV)	3.61	4.20
S (eV)^-1	0.26	0.26
ω (eV)	3.41	4.64
∆N_max	1.89	-2.21

Table 4. Main calculated optical transition with composite ion in terms of molecular orbitals.

Compound

Transition

Excitation energy (ev)

λ_maxCalc.

(nm)

λ_maxexp.

(nm)

Oscillating strength

H₂L

HOMO → LUMO

3.39

366

395

0.147

[Cd(H₂L)Cl₂(H₂O)]

HOMO → LUMO

3.42

363

340

0.142

Table 5. Thermoanalytical results (TG and DTG) of Schiff base ligand (H₂L) and its metal complexes.

Complex

TG range

(°C)

DTG_max

(°C)

n*

Mass loss Total mass loss

Estim (Calcd) %

Assignment

Residues

H₂L

30-330

330-900

195, 255

400

2

1

37.69 (37.25)

60.17(62.75) 97.69 (100.00)

-Loss of C₁₀H₂₁.

-Loss of C₁₁N₃O₄.

............

[Cr(H₂L)(H₂O)₂ Cl]Cl_2.2H₂O

30-120

120-900

66

218,700, 810

13

5.64 (5.90)

69,70 (71.31) 75.34 (77.21)

-Loss of 2H₂O.

-Loss of 1.5Cl_2, 2H₂O and C₁₆H₂₂N₃O_2.5.

¹/₂Cr₂O₃+ 5C

[Mn(H₂L)(H₂O)₂Cl]Cl.2H₂O

30-375

375-900

71, 125, 155

379, 812

3

2

34.50 (34.81)

41.62 (42.43) 76.12 (77.24)

-Loss of Cl₂,4H₂O, C₄H₁₀.

-Loss of C₁₂H₁₁N₃O₃.

MnO +5C

[Fe(H₂L)(H₂O)₂Cl]Cl₂

30-900

139, 204

2

78.15 (77.78) 78.15 (77.78)

-Loss of 1.5Cl₂, 2H₂O and C₁₇H₂₁N₃O_2.5.

¹/₂Fe₂O₃+ 4C

[Ni(H₂L)(H₂O)]Cl₂.4H₂O

30-250

250-900

73, 157

183, 424

2

27.29 (26.87)

50.91 (50.74) 78.2 (77.61)

-Loss of 5H₂O, Cl₂.

-Loss of C₁₆H₂₁N₃O_3.

NiO + 5C

[Cu(H₂L)Cl]Cl.2H₂O

30-135

135-900

68

169, 270, 550

1

3

6.56 (6.55)

69.02 (70.19) 75.58 (76.74)

-Loss of 2H₂O.

-Loss of Cl_2,C₁₇H₂₁N₃O₃.

CuO + 4C

[Zn(H₂L)(H₂O)Cl₂]2H₂O

30-180

180-365

365-900

61, 155

178, 285

464, 800

2

9.47 (9.48)

19.77 (20.89)

43.44 (42.65) 72.68 (73.02)

-Loss of 3H₂O.

-Loss of Cl_2,3CH₄

-Loss of C₁₂H₁₉N₃O₃

ZnO + 6C

[Cd(H₂L)(H₂O)Cl₂]

30-160

160-245

245-480

480-900

132

217

268

561, 833

1

2

3.65 (3.10)

11.83 (12.22)

24.70 (24.45)

33.30 (32.03) 73.48 (71.80)

-Loss of H₂O.

Loss of Cl₂.

-Loss of C₁₀H ₂₁.

-Loss of C₇N₃O_3.

CdO + 3C

* n =number of decomposition steps.

Table 6. BET surface area and band gaps of metal chelates.

Samples	S_BET (m²/g)	Pore volume (cc/g)	Average Particle radius (nm)	BET surface area (m² g^-1)	Band gap energy (eV)	Average Pore Size (nm)
[Cr(H₂L)(H₂O)₂Cl]Cl_2.2H₂O	119	0.20	7.75	176	3.41	2.28
[Mn(H₂L)(H₂O)₂Cl]Cl.2H₂O	90	0.15	4.32	118	3.41	2.57
[Fe(H₂L)(H₂O)₂Cl]Cl₂	13	0.02	5.83	23	3.68	1.95
[Ni(H₂L)(H₂O)]Cl₂.4H₂O	51	0.09	5.32	95	3.14	2.02
[Cu(H₂L)Cl]Cl.2H₂O	79	0.14	8.71	156	3.44	1.73
[Zn(H₂L)(H₂O)Cl₂]2H₂O	200	0.33	6.10	83	3.69	7.85
[Cd(H₂L)(H₂O)Cl₂]	77	0.13	7.96	63	3.66	4.08

Due to technical limitations, table 7 is only available as a download in the Supplemental Files section.

Table 8. Anticancer effects of Schiff base ligand and its metal complexes in terms of % Cell Inhibition at 100 µg/ml concentration.

samples	% Cell Inhibition	Surviving fraction (MCF7)					IC ₅₀ (µg/ml)
samples	% Cell Inhibition	0.0	5.0	12.5	25	50	IC ₅₀ (µg/ml)
H₂L	64						-----
[Cr(H₂L)(H₂O)₂Cl]Cl_2.2H₂O	64						-----
[Mn(H₂L)(H₂O)₂Cl]Cl.2H₂O	72	1	0.85	0.73	0.51	0.33	26
[Fe(H₂L)(H₂O)₂Cl]Cl₂	75	1	0.88	0.71	0.64	0.25	33
[Ni(H₂L)(H₂O)]Cl₂.4H₂O	75	1	0.88	0.81	0.62	0.3	34
[Cu(H₂L)Cl]Cl.2H₂O	70	1	1	0.73	0.33	0.31	19.6
[Zn(H₂L)(H₂O)Cl₂]2H₂O	67						-----
[Cd(H₂L)(H₂O)Cl₂]	64						-----

Table 9. Energy values obtained in docking calculations of H₂L and its metal complexes with to Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor UAW247 (6XBH).

COMPOUND	moiety	Receptor site	Interaction	Distance (A^ο)	E (kcal/mol)
Ligand H₂L	O 16	OE2 GLU 166	H-donor	2.88	-2.5
	C2 26	SD MET 165	H-donor	3.45	-1.1
	5-ring	NE2 GLN 189	pi-H	3.36	-0.9
[Cr(H₂L)(H₂O)₂Cl]Cl_2.2H₂O	O15	O THR 24	H-donor	3.09	-1.0
	O54	SD MET 49	H-donor	3.38	-28.6
	6-ring	CG2 THR 25	pi-H	4.55	-0.7
[Mn(H₂L)(H₂O)₂Cl]Cl.2H₂O	O 22	SD MET 165	H-donor	4.03	-0.4
	CL45 49	SD MET 49	H-donor	3.47	-3.1
	O46 50	SD MET 49	H-donor	3.07	-0.9
	O 54	OG1 THR 25	H-donor	2.70	-1.4
	CL45 49	NE2 GLN 189	H-acceptor	3.77	-3.3
	5-ring	CG2 THR 25	pi-H	3.92	-0.7
	6-ring	5-ring HIS 41	pi-pi	3.64	-0.0
[Fe(H₂L)(H₂O)₂Cl]Cl_2.	O 15	O GLU 166	H-donor	2.86	-5.0
[Fe(H₂L)(H₂O)₂Cl]Cl_2.	O 54	OD1 ASN 142	H-donor	2.91	-3.6
[Ni(H₂L)(H₂O)]Cl₂.4H₂O	O 50	SD MET 49	H-donor	3.31	-4.9
[Cu(H₂L)Cl]Cl.2H₂O	O 15	O ASP 187	H-donor	2.88	-2.9
	CL 50	CG GLN 189	H-acceptor	3.34	-0.8
	CL 50	NE2 GLN 189	H-acceptor	3.08	-3.0
[Zn(H₂L)(H₂O)Cl₂]2H₂O	CL45 49	CA ASN 142	H-acceptor	4.24	-0.6
	CL46 50	CA ASN 142	H-acceptor	4.03	-0.9
	CL46 50	N GLY 143	H-acceptor	3.06	-8.0
	CL46 50	N CYS 145	H-acceptor	4.27	-1.9
	CL46 50	SG CYS 145	H-acceptor	3.60	-0.9
	6-ring	N GLU 166	pi-H	4.80	-0.7
[Cd(H₂L)(H₂O)Cl₂]	O 15	SD MET 165	H-donor	3.51	-2.6
	CL45 49	SG CYS 145	H-donor	3.92	-3.8
	CL45 49	CA MET 165	H-acceptor	3.48	-2.2
	CL45 49	N GLU 166	H-acceptor	4.16	-1.1
	CL46 50	N GLU 166	H-acceptor	3.34	-6.5
	CL46 50	CB GLU 166	H-acceptor	3.64	-0.8

Table7.jpg

Metal Complexes of Tridentate Schiff Base: Synthesis, Characterization, Biological Activity and Molecular Docking Studies with COVID-19 Protein Receptor

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