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Synthesis and Biological Study of Novel Schiff Base (1-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) methylene) hydrazine) Ligand and Metal Complexes

  • Nirmal R. Joshi1,
  • Sandip G. Mule1,
  • Vishnu A. Gore1,
  • Ravindra D. Suryawanshi2,
  • Ganesh T. Pawar2,
  • Saroj R. Bembalkar1,*  and
  • Rajendra P. Pawar2,* 
 Author information
Journal of Exploratory Research in Pharmacology 2022

doi: 10.14218/JERP.2022.00021

Abstract

Background and objectives

Hydrazone ligands along with their metal complexes exhibit important biological potential. Our objective was to synthesize new Schiff base ligands and their metal complexes which can act as vital drugs. Metal complexes of Zn(II), Ni(II), Cu(II), Mn(II), Co(II), Hg(II), Cd(II), Sn(II), Zr(II), and Fe(II) were synthesized from a novel Schiff base (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) ligand. The synthesized metal complexes were studied for antimicrobial, antimalarial, and anti-tubercular activity.

Methods

Schiff base hydrazone (1-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) methylene) hydrazine) ligand and metal complexes were synthesized using the condensation method. The ligand and metal complexes were characterized using analytical techniques.

Results

The synthesized ligand was found to be bidentate in nature. The stoichiometry of the metal ions to ligand was 1:2. Complexes of Co(II), Cu(II), Mn(II), and Cd(II) displayed excellent antimicrobial activity. The Mn(II) complex was active against M. Tuberculosis, while Cu(II) and Cd(II) exhibited excellent activity against malaria compared to standard drugs. The present work reports synthesis, characterization, and biological screening for antitubercular, antimicrobial, and antimalarial activity of metal complexes of bidentate (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) Schiff base ligands. Among the synthesized series of metal complexes, Cu(II) and Cd(II) complexes displayed excellent activity against malaria and moderate to good antimicrobial and anti-tubercular activity was observed for the synthesized metal complexes.

Conclusions

We report the synthesis of a new (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) Schiff base bidentate ligand and metal complexes. Metal complexes exhibit biological activities.

Keywords

Hydrazone, Ligand, Antimicrobial, Antitubercular, Antimalarial and metal complexes

Introduction

Hydrazones are compounds that have an azomethine group, such as CH=N–NH2 and are vital in applications of medicinal chemistry.1 Hydrazones are the condensation products of amines and carbonyl compounds. Hydrazone ligand and metal complexes are commonly used as analytical reagents, as well as for treatment of various diseases.2 In some chemical reactions, metal compounds of hydrazone are used as catalysts.3 A Schiff base ligand forms a coordinated complex with metal ions. This metal complex exhibits a reversible association of ions or atoms by weak coordinate covalent bond formation. Schiff bases are important due to their antimicrobial activity and are remarkable due to their stability and chelating properties.4 Schiff bases can be used for the production of novel drugs. Schiff base complexes with metal ions have interested chemists due to applications of imines for their antituberculosis, antibacterial, antifungal, antimalarial, and antiviral activity.5 Schiff bases and their metal complexes contain halogens that display antimicrobial activity.6

Herein, we report the synthesis and characterization of novel Schiff base hydrazone: (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) ligand. The ligand was prepared by condensing hydrazine hydrate and 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde. The synthesized ligand and its metal complexes were screened for antimicrobial, anti-tubercular, and antimalarial activities.

Materials and methods

All metal salts, solvents, and chemicals purchased were analytical reagent grade and did not require further purification.

Synthesis of [1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine] ligand (L2)

A mixture of 1 mmol of 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde (1) and 8 mmol of hydrazine hydrate (2) was refluxed in ethanol in the presence of 1-2 drops of concentrated sulfuric acid for 5 h. The reaction progress was monitored using thin layer chromatography (TLC) in ethyl acetate:n-hexane (1:4). Upon completion of the reaction, the reaction mixture was cooled and poured onto crushed ice. The resulting product (3) was filtered off, dried, and purified by recrystallization from ethanol (Figure 1).

Synthesis of [1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine] ligand.
Fig. 1  Synthesis of [1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine] ligand.

Synthesis of metal complexes

An ethanolic solution of metal salt (chlorides or nitrates) was mixed with an ethanolic ligand solution in a 2:1 (mmol) ratio. A slightly basic pH of the resulting reaction mixture was maintained with the addition of dilute ammonia, and the contents were refluxed for 6 h and the reaction was monitored using TLC in ethyl acetate: n-hexane as the mobile phase (1:4). After completion of the reaction, products were cooled, filtered off, dried (Figure 2), and confirmed using UV and IR spectra (Table 1).

Synthesis of metal complexes.
Fig. 2  Synthesis of metal complexes.
Table 1

Physical and analytical data of the synthesized ligand and complexes

CompoundMelting point (°C)Color
Ligand (L2)119–120Yellow
ZnL2258–260Yellowish Brown
CuL2239–240Yellowish Brown
NiL2>300Yellow
CoL2268–270Yellow
Mn L2>300Yellow
Hg L2279–280Yellow
CdL2263–265Yellow
SnL2>300Yellow
ZrL2279–280Yellow
FeL2>300Yellow

Characterization

[1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) methylene) hydrazine] L2:1HNMR (DMSO-d6) δ ppm: 8.34 (s, 1H, CH, hydrazide) 6.95 (s, 2H, NH2) δ 6.1 (m, 1H, CH, methine) 2.03 (s, 3H) 2.06 (s, 3H, CH3) 1.57 (d, 3H) 1.62 (d, 3H CH3) 7.51 (d, 2H, Ph), 7.67 (d, 2H, Ph) MS: m/z 295; FTIR: cm−1 3,385 (NH), 1,600 (C=N), 3,053 (CH-Ar), 1,529 (C-C Ar), 2,972 (CH-Aliphatic)

IR Spectral analysis

IR spectral data ν cm−1 for C-H, M-N, C=N of ligand, and metal complexes are reported in Table 2. The IR frequency band due to the N-H bond in the free ligand was shifted to a lower value in the spectra of all synthesized complexes, showing the involvement of an N-H group in the complexes.

Table 2

IR spectral interpretation of ligand and metal complexes

Compoundν cm−1 (C-H)ν cm−1 (M-N)ν cm−1 (C=N)ν cm−1 (N-H)
Ligand3,0531,6003,385
ZnL23,0644201,5312,966
CuL23,0624261,5312,970
NiL23,0594261,5272,873
CoL23,0644201,5312,906
Mn L23,0624261,5312,968
Hg L23,0624291,5292,968
CdL22,9804241,5272,665
SnL22,9744221,5272,974
ZrL23,0645671,5312,964
FeL23,0535161,5312,978

UV Spectral analysis of metal complexes

The λmax values observed in the UV spectra of the synthesized metal complexes are summarized in Table 3. The UV spectra of the complexes were recorded in DMSO.

Table 3

λmax value of the synthesized metal complexes

CompoundWavelength (λmax)
ZnL2256.50
CuL2205
NiL2206.50
CoL2205.50
Mn L2205.00
Hg L2204
CdL2203.4
SnL2229
ZrL2205
FeL2204.5

Biological activity

Antimicrobial study

The metal complexes were screened against four bacteria (S. Pyogenus MTCC 442, E. Coli MTCC 443, P. Aeruginosa MTCC 1688, and S. Aureus MTCC 96) and three fungal species (C. Albicans MTCC 227, A. Niger MTCC 282, and A. Clavatus MTCC 1323).

Antimicrobial activity was determined using the Broth dilution method.7 Mueller–Hinton agar nutrient medium was used. The Hinton Broth Method was used to grow microbes and dilute the microbe compound suspension for the test.

Solutions of synthesized compounds were made in DMSO solvent (control). The sample tubes were also incubated at 37°C overnight. The minimal inhibition concentration (MIC) for the control test microbes was recorded to study the antimicrobial potential of the synthesized compounds. The MIC values for the synthesized metal complexes compared with ampicillin, chloramphenicol, nystatin, and greseofulvin are summarized in Table 4.

Table 4

Antimicrobial results of metal complexes

CompoundMIC
Antibacterial Activity
Antifungal Activity
S.PYOGENUSS.AUREUSE.COLIP.AERUGINOSAA.NIGERA.CLAVATUSC.ALBICANS
ZnL2500500250500>1,000>1,000500
CuL21002501001001,0001,0001,000
NiL25005050250>1,000>1,000500
CoL210025012562.5500500500
Mn L25002501001001,0001,000250
Hg L2500500250250>1,000>1,000500
CdL22502001002505001,000250
SnL25002505005001,0001,000500
ZrL225012.525062.5>1,000>1,000250
FeL25005001002505001,0001,000
Ampicillin100250100
Chloramphenicol50505050
Nystatin100100100
Greseofulvin100100500

Antituberculosis activity

In vitro bacterial susceptibility tests were performed in bottles to determine antitubercular activity. Mycobacterium Tuberculosis (H37Rv strain) cultures were studied against the synthesized complexes.8

MIC values were determined for the antituberculosis activity. L.J inoculum nutrient medium (1 mg/mL) was used to grow the microorganisms. DMSO solvent was used to achieve the required concentration of test compounds. For primary and secondary screening, serial dilutions were prepared.

The MIC value was recorded as the highest dilution showing a minimum of 99% inhibition. MIC values of the synthesized compounds were recorded and compared with rifampicin and isoniazid as shown in Table 5.

Table 5

Anti-tubercular and antimalarial activity of metal complexes

CompoundAnti-tubercular activity against H37Rv (MIC µg/mL)Anti-malarial Activity (MEAN IC50 values)
ZnL21252.05 µg/mL
CuL25001.46 µg/mL
NiL22502.35 µg/mL
CoL22502.42 µg/mL
Mn L262.53.10 µg/mL
Hg L22502.61 µg/mL
CdL21251.68 µg/mL
SnL22501.87 µg/mL
ZrL22503.82 µg/mL
FeL25002.25 µg/mL
StandardIsoniazid 0.20 µg/mL, 99% inhibitionChloroquine IC50–0.020 µg/mL
StandardRifampicin 40 µg/mL, 99% inhibitionQuinine IC50–0.268 µg/mL

Antimalarial activity

The compounds were studied for antimalarial activity using the Rieckmann K.H. and co-worker’s method.9 An in vitro assay was used to evaluate antimalarial activity against Plasmodium falciparum; compound solutions were executed in 96 well microtiter plates.10 Culture medium RPMI 1640 was used to grow the P. Falciparum strain. Test compounds were diluted using DMSO and further dilutions were made with culture medium. Results of the antimalarial activity of the metal complexes are summarized in Table 5.

The MIC values and the results of antimalarial activity were compared with chloroquine and quinine.11

Results and discussion

A ligand (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) methylene) hydrazine) was synthesized from 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde and hydrazine hydrate and used for the preparation of metal complexes which were characterized using spectroscopic methods and further studied for antimicrobial, antituberculosis, and antimalarial properties. The metal complexes of Zn(II), Cu(II), Ni(II), Co(II), Mn(II), Hg(II), Sn(II), Cd(II), Zr(II), and Fe(II) resulted in a ligand : metal ratio of 2:1.

The band at 1,600 cm−1 in the IR spectrum can be attributed to the stretching of the C=N group.12 In cases of metal complexes, the spectral band that appeared at 420 cm−1 to 516 cm−1 is attributed to the presence of M-N bonds.13 The IR band at 2,974 cm−1 to 3,064 cm−1 corresponds to the C-H stretching frequency. The ligand behaves as bidentate, coordinating with the metal ion through two nitrogen atoms present in the structure of the ligand. The λmax values for metal complexes in the UV spectra were found in the range of 203 nm to 256 nm.14 the Zn(II) complex showed a λmax value at higher absorption.

The antimicrobial screening of metal complexes showed that Cu(II) and Co(II) were remarkably active against S. Pyogenus MTCC 442. The Cd(II) and Zr(II) complexes were active against S. Aureus MTCC 96. The Cu(II), Co(II), Mn(II), Cd(II), and Fe(II) complexes showed good activity against E. Coli MTCC 443, while Cu(II), Mn(II), and Zr(II) showed excellent activity against P. Aeruginosa MTCC 1688 compared to the standard drugs. Co(II) and Cd(II) were found to be active against A. Niger MTCC 282. Co(II) was found to be active against A. Clavatus MTCC 1323. Zn(II), Ni(II), Co(II), Mn(II), Hg(II), Cd(II), Sn(II), and Zr(II) showed good to excellent activity against the C. Albicans MTCC 227 fungus compared to standard drugs.

Mn(II) exhibited excellent antituberculosis activity against MTB (H37Rv strain). Zn(II) and Cd(II) were active against MTB compared to the standard drugs (rifampicin and isoniazid).

Cu(II) and Cd(II) metal complexes exhibited promising antimalarial activity while Zn(II), Co(II), Sn(II), Ni(II), Hg(II), and Fe(II) were active against malaria.

Future directions

Coordination chemistry has remained a useful field in search of bioactive agents. In the present work, we reported the synthesis and characterization of metal complexes of bidentate (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) Schiff base ligands and demonstrated that these complexes had antitubercular, antimicrobial, and antimalarial properties. Future studies will focus on identifying new similar Schiff base ligands and their metal complexes as potential entities for searching bioactive metal complexes.

Conclusions

In conclusion, the present work reports the synthesis, characterization, and antimicrobial activity of a series of metal complexes of bidentate (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) Schiff base ligands. The antitubercular, antimicrobial, and antimalarial activity of the synthesized metal complexes revealed good biological antimicrobial potential of Cu(II), Co(II), Mn(II), and Cd(II) complexes and the Mn(II) was remarkably active against MTB. The Cu(II) and Cd(II) displayed excellent activity against malaria compared to standard drugs, thus making the (1-((3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)methylene) hydrazine) Schiff base ligands useful entities in coordination chemistry.

Abbreviations

DMSO: 

dimethyl sulfoxide

IR: 

infra-red

MIC: 

minimal inhibition concentration

NMR: 

nuclear magnetic resonance

TLC: 

thin layer chromatography

UV: 

ultraviolet

Declarations

Acknowledgement

The authors thank Principal, Deogiri College, Aurangabad 431005 (MS), India for providing laboratory facilities.

Data sharing statement

No additional data are available.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.

Authors’ contributions

Contributed to study concept and design (NRJ), acquisition of the data (SGM), assay performance and data analysis (VAG), drafting of the manuscript (RDS, GTP), critical revision of the manuscript (SRB), supervision (RPP).

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Synthesis and Biological Study of Novel Schiff Base (1-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) methylene) hydrazine) Ligand and Metal Complexes

Nirmal R. Joshi, Sandip G. Mule, Vishnu A. Gore, Ravindra D. Suryawanshi, Ganesh T. Pawar, Saroj R. Bembalkar, Rajendra P. Pawar
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