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| A Study on Biological Activity of Copper (II) Complexes of Some Mannich Bases | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paper Id :
16909 Submission Date :
2022-12-03 Acceptance Date :
2022-12-21 Publication Date :
2022-12-24
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| Abstract |
The chemistry of thiazoles and their derivatives has attracted the attention of chemists, since they form a part of vitamin B1 and exhibit important biological activity in medicinal chemistry as anti-microbial, anti-inflammatory, anti-degenerative and anti-parasitic agent. Hence, some Copper (II) complexes of Mannich bases; p-hydroxybenzylidene-2-aminothiazole and p-hydroxybenzylidene-2-amino-6-methylpyridine have been tested and reported for the antimicrobial studies. It was indicated that most of the complexes exhibited higher antimicrobial activity against bacteria, E.coli and K.pneumoniae .
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| Keywords | Copper(II) Complexes, Antimicrobial Activities. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Introduction |
A number of in-vivo studies have indicated that heterocycles bearing nitrogen, sulphur and thiazole moieties constitute the core structure of a number of biologically interesting compounds1-3.They occur in nature in the form of alkaloids, vitamins, pigments and as constituents of plant and animal cells. The chemistry of thiazoles and their derivatives has attracted the attention of chemists, since they form a part of vitamin B1 and exhibit important biological activity in medicinal chemistry as anti-microbial4-6, anti-inflammatory7, anti-degenerative8 and anti-parasitic agent9.
Increasing knowledge of the biological activities of simple metal complexes guided many researchers to the development of promising chemotherapeutic compounds which target specific physiological or pathological processes. Many potential antitumoral agents have been investigated based on their anti-angiogenesis or proapoptotic behavior. These studies involve both designed and natural products in association with essential metal ions such as copper, cobalt and iron10-11. Biological activities of copper (II) complexes of many Mannich bases have been studied which showed antitumoral activities 12-14. In the present investigation, we have tried to establish bioinorganic relevance of some Mannich bases and their metal complexes in the form of antibacterial Studies.
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| Objective of study | Metal complexes of Mannich bases have played a central role in the development of coordination chemistry and have many applications in various fields. Copper (II) complexes of N, O and S donor ligands have drawn much attention in the last decade because of their immense biological applications5-6. Therefore, it was thought to synthesize some copper (II) complexes of Mannich bases prepared from p-hydroxybenzaldehyde, 2-aminothiazole and 2-amino-6-methylpyridine and check their antimicrobial acitivities. |
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| Review of Literature |
A survey of literature17-18 reveals that Mannich bases and their metal complexes have drawn the attraction of several bioinorganic chemists because of their versatile biological and pharmacological applications.
Synthesis and antibacterial properties of Mannich bases of some 3-substituted-4-(5-nitrofurfuryldene)amino-1,2,4-triazolo-5-thiones have been done by Kalluraya and coworker19. The antibacterial activity of the compounds were evaluated against both gram-positive and gram-negative bacteria. The results of the screening studies indicated that the titled compounds were highly active against gram-positive bacteria.
Havaldar et al.20 synthesized various Mannich bases by the reaction of bis
(4-hydroxyphenyl) (2-pyridyl)methane with secondary amine in the presence of formaldehyde. These compounds have been tested for their antibacterial activity. A series of 2,3-dihydro-2-oxo-1,3-disubstituted indoles were prepared by Ravichandran et al.21. The synthesized compounds were evaluated for their in-vivo antibacterial activity against pathogenic bacteria. The results showed that Mannich bases exhibited moderate antibacterial activity against B.subtilis and P. aeruginosa.
Pandeya and coworkers 22 synthesized Schiff and Mannich bases of isatin and their derivatives with triazole. The investigation of antimicrobial activity of the synthesized compounds was done by agar dilution method against twenty seven-pathogenic bacteria and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. Sridhar et al.23 synthesized a new series of corresponding N-Mannich bases by treating isatin with primary amines or hydrazines and formaldehyde. Most compounds were screened for antibacterial activity against seven gram-positive and seven gram-negative bacteria by disc diffusion technique.
Raman and Ravichandran24 synthesized solid complexes of Mannich base N-(-piperidinobenzyl)isonicotinamide (PBN) with copper(II), cobalt(II), nickel(II) and zinc(II) metal ions. These compounds were evaluated for their antibacterial activity against gram-positive bacteria S.aureus and gram-negative bacteria E.coli. The metal complexes were more active than the free PBN ligand. The transition metal complexes of azo dye ligand derived from sulphanilamide and substituted p-cresol were prepared by Vidya and Joshi25. Some metal complexes of above mentioned ligand had antimicrobial activity.
In the interest of the above study, we are reporting the antibacterial study of the newly synthesized Mannich bases derived from 2-aminothiazole/2-amino-6-methylpyridine with p-hydroxybenzyldehyde and their copper(II) complexes on the following bacteria
(i) Escherichia coli
(ii) Klebsiella pneumoniae
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| Methodology | Although a number of methods with their own limitations and disadvantages have been cited to study the biological activities of potentially active compounds, out of them some methods are :-
1. Filter paper disc method [26]
2. Turbidimetric methods [27]
3. Determination of mean death time [28]
4. The end point or extinction time determination [29].
5. Determination of percentage inhibition and minimum inhibitory concentration (MIC) by agar diffusion methods [30]
In present work, the activities of the synthesized compounds were evaluated by filter paper disc method. The main aim of this investigation was to study the change in activity with the variation in structure of the molecule.
Overnight culture of E.coli and Kleibsiella pneumoniae were used as test organism for antibacterial study. The Mueller-Hinton’s agar medium was used as the culture medium for the bacterial activity.
The method in general is carried out in the following steps :
(i) Sterilization of culture media
(ii) Preparation of culture media
(iii) Sterilization of culture media
(iv) Preparation of solution of test compounds
(v) Determination of inhibition zones
(i) STERILIZATION OF CULTURE MEDIA :
All the glassware such as test tube, measuring cylinder, beakers, conical flask, pipettes etc. were thoroughly cleaned and sterilized in an autoclave at 1210C temperature 15 pounds pressure for 20 minutes.
(ii) PREPARATION OF CULTURE MEDIA :
It is well known that protein rich material is the best medium for bacteria and it should be almost neutral (pH=7) in nature. In this present investigation, for antibacterial studies we used Mueller-Hinton’s agar medium.
(iii) STERILIZATION OF CULTURE MEDIA :
Sterilization process of culture media was made by moist heat sterilization in an autoclave at 1210C temperature under 15 pounds pressure for about 20 minutes.
(iv) PREPARATION OF SOLUTION OF MANNICH BASE AND METAL CHELATES:
For preparing solutions of different concentration (i.e.-750 ppm, 500 ppm and 250 ppm, w/v) dimethylsulphoxide (DMSO) were used as a solvent. The calculated weight of test compounds: MB1, MB2 and metal complexes of these Mannich bases were dissolved separately in suitable volume of DMSO in the concentrations mentioned above.
(v) DETERMINATION OF INHIBITION ZONE:
The obtained results of the inhibition zone of Mannich bases and their metal complexes in 750, 500 and 250ppm concentrations are presented in Table:-1 and 2. |
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| Result and Discussion |
A comparative study of the
Mannich base and their metal complexes indicates that most of the metal
complexes exhibit higher antimicrobial activity against Escherichia coli and
Kleibsiella pneumoniae than that of the free Mannich bases. The increase in the
antimicrobial activity of the metal complexes is due to the effect of metal
ions on the normal cell processes. Such increased activity of the metal
complexes can be explained on the basis of “Overtone’s concept”[31].According to Overtone’s
concept of cell permeability, the lipid membrane that surrounds the cell favors
the passage of only lipid-soluble materials in which liposolubility is an
important factor which controls the antimicrobial activity. On chelation the
polarity of the metal ion will be reduced[32] to a greater extent due to the
overlap of the ligand orbital and partial sharing of positive charge of the
metal ion donor groups. Further, it increases the delocalization of p-electrons
over the whole chelate ring and enhances the lipophilicity of the
complexes[33]. This increased lipophilicity enhances the penetration of the
complexes into lipid membrane and blocks the metal binding sites in enzymes of
micro-organisms. These complexes also disturb the respiration process of the
cell and thus block the synthesis of proteins, which restricts the further
growth of the organism.The study showed that MB1
(C10H10N2OS) have good antibacterial activity against E.coli and Kleibsiella
pneumoniae at all concentrations i.e. 250, 500 and 750 ppm but MB2 (C13H14N2O)
was found to be inactive against E.coli and Kleibsiella pneumoniae at these
concentration ranges.The antibacterial activity
revealed that both the ligands and their cobalt (II) and copper (II) complexes
shown weak to good activity. Cobalt (II) complexes of MB1 exhibited good
antibacterial activity against E.coli at 750 ppm while copper (II) complexes of
same ligand showed active and moderate activity against Kleibsiella pneumoniae
at different concentration levels. Cobalt (II) and copper (II) complexes of MB2
showed moderate to good activity against E.coli and Kleibsiella pneumoniae at
different concentration ranges.The inhibition zones shown
by ligands and their metal complexes are depicted in photographs (Fig.:8a and
8b & Table:1 and 2. On the basis of above result, it was observed that,
compared to the ligands and metal salts, the complexes exhibited enhanced
antibacterial activity, which is due to the synergistic effect that increases
the lipophilicity of the complexes. Chelation decreases the polarity of the
metal ions, which further leads to the enhancement of complex’s lipophilicity.
Since the micro-organism cell is surrounded by a lipid membrane which favors
the passage of lipid soluble materials, increased lopophilicities allows the
penetration of complex into and through the membrane and deactivates the active
enzyme sites of the micro-organism34. Table-1Antibacterial Activity Data
Against Escherichia Coli (Inhibition of radial growth in mm)
TABLE-2 |
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|
S.No. |
Compounds |
Concentration
(ppm) |
||
|
250 |
500 |
750 |
||
|
1 |
DMSO |
- |
- |
- |
|
2 |
L1 |
6.0 |
8.0 |
8.0 |
|
2.1 |
Cu(L1)2.Cl2 |
- |
- |
- |
|
2.2 |
Cu(L1)2.(OAc)2 |
- |
- |
- |
|
2.3 |
Cu(L1)2.(NO3)2 |
- |
- |
5.0 |
|
2.4 |
Cu(L1)2.SO4 |
5.0 |
5.0 |
6.0 |
|
3 |
L2 |
- |
- |
- |
|
3.1 |
Cu(L2)2.Cl2 |
- |
- |
- |
|
3.2 |
Cu(L2)2.(OAc)2 |
- |
- |
- |
|
3.3 |
Cu(L2)2.(NO3)2 |
- |
- |
- |
|
3.4 |
Cu(L2)2.SO4 |
- |
- |
- |
On the basis of above studies, it is revealed that the Mannich base and their metal complexes indicated that most of the metal complexes exhibit higher antimicrobial activity against Escherichia coli and Kleibsiella pneumoniae than that of the free Mannich bases.We observed that the complexes exhibited enhanced antibacterial activity, which is due to the synergistic effect that increases the lipophilicity of the complexes. Chelation decreases the polarity of the metal ions, which further leads to the enhancement of complex’s lipophilicity. Since the micro-organism cell is surrounded by a lipid membrane which favors the passage of lipid soluble materials, increased lopophilicities allows the penetration of complex into and through the membrane and deactivates the active enzyme sites of the micro-organism.
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