A new series of
Heterocyclic Schiff base chemistry is one of the attractive and challenging fields in current medical science. Due to expanded range of applications, medicinal chemistry has grown actively into the most active research area. Heterocyclic Schiff base derivatives are the most extensively used organic compounds with broad range of applications used as pigments, dyes, catalysts, and intermediates in many organic reactions [
Heterocyclic tridentate Schiff base ligands, with a flexible atom, are better in comparison with bidentate ligand, and their chelating power makes them suitable ligands for stabilizing transition metals in various oxidation states and in wide range of catalytic transformations. They have been used extensively in biochemistry, material science, hydrometallurgy, catalysis and separation phenomena, and many of the biological processes [
Since DNA and genetic material contain all cellular information, the study of DNA interaction is a very important aspect at present. Interaction of small molecules with DNA has been investigated and it attracted more attention for the designing of more effective drugs which target to DNA. Classical and nonclassical intercalation and groove or electrostatic modes of binding have been studied by various interaction modes of drug-DNA [
In literature, an antioxidant activity evaluation of heterogeneous ring derivatives using hydrogen peroxide and DPPH radicals was reported free in various ways and many of these compounds act as good antioxidants. Thus, to know how these antioxidant compounds work is very essential [
So in this regard, we have tried to develop such types of heterocyclic derivatives which can bind easily with DNA and significant antioxidant to prevent damage caused by free radicals [
The compounds were synthesized according to the given protocol [
Yellow solid. Yield 73%, mp 238°C. IR spectrum, υ, cm−1: 1574 (HC=N), 2213 (-C≡N). 1H NMR (300 MHz, DMSO-d6)
Brown solid. Yield 65%, mp 214°C. IR spectrum, υ, cm−1: 1572 (-HC=N), 2212 (-C≡N). 1H NMR (300 MHz, DMSO-d6)
Yellow solid. Yield 69%, mp 264°C. IR spectrum, υ, cm−1: 1592 (-HC=N), 2210 (-C≡N). 1H NMR (300 MHz, DMSO-d6)
Brown solid. Yield 69%, mp 226°C. IR spectrum, υ, cm−1: 1598 (-HC=N), 2200 (-C≡N). 1H NMR (300 MHz, DMSO-d6)
Orange solid. Yield 74%, mp 276°C. IR spectrum, υ, cm−1: 1557 (–HC=N), 2208 (–C≡N). 1H NMR (300 MHz, DMSO-d6)
Pale yellow solid. Yield 64%, mp 246°C. IR spectrum, υ, cm−1: 1592 (-HC=N), 2215 (-C≡N). 1H NMR (300 MHz, DMSO-d6)
Yellow solid. Yield 60%, mp 193°C. IR spectrum, υ, cm−1: 1550 (-HC=N), 2214 (-C≡N). 1H NMR (300 MHz, DMSO-d6)
Yellow solid. Yield 67%, mp 195°C. IR spectrum, υ, cm−1: 1550 (–HC=N) 2212 (-C≡N). 1H NMR (300 MHz, DMSO-d6)
To study the DNA interaction with most potent compound, various spectroscopic techniques were employed and DPPH free radical and hydrogen peroxide were used to evaluate the antioxidant assay of the compounds according to our reported research work [
Synthetic route for the preparation of the Schiff bases
Synthesis of Schiff bases of
The stretching frequency due to –NH2 and –C=O of all the substituted amines and carbonyls disappears in the target compounds (
1H NMR spectra (DMSO-d6) at room temperature exhibited well-resolved signals. The signal due to –CH=N appears in the range of 8.5–9.5 ppm for the compounds corresponding to azomethine group which confirms the formation of Schiff bases. Moreover, a peak appears in 3.01–3.13 ppm range attributed to the –CH3 (6H) aliphatic for the compounds (
The electronic impact mass of Schiff bases of
The 1H NMR, 13C NMR, and mass spectra of compounds (
Electronic absorption spectroscopy is an essential tool which is applied for evaluating the binding way of DNA with the examined compounds and the extent of binding as well [
Absorption spectra of heterocyclic Schiff base derivatives
The optical tools provide substantial, but not sufficient, evidence to support the intercalative type of interaction between compounds and DNA. A hydrodynamic tool, like viscosity, that introduces large accuracy to any change in DNA length is probably the influential tool in order to evaluate the binding mode between tested compounds and DNA. The viscosity of DNA solutions is recorded using different dilutions of the compounds reported in this paper (compounds
Effects of increasing amounts of heterocyclic Schiff base derivatives (
The mechanism of interaction between compound and Ct-DNA was determined by fluorescence quenching studies. The fluorescence spectra of heterocyclic Schiff base derivatives
Fluorescence emission spectra of heterocyclic Schiff base derivatives
The binding constant
Electrochemical methods provide a useful complement in support of UV–visible and viscosity measurements methods. The electrochemical behavior of compounds was studied in Tris-buffer solution (5.0 mM Tris-HCl, 50 mM NaCl, pH 7.2) and an aqueous Ag/AgCl reference electrode with 3.0 M NaCl in saturated AgCl as the filling solution was used (Figure
Cyclic voltammogram of heterocyclic Schiff base derivatives
Circular dichroism (CD) spectroscopy has been performed for monitoring the structural variations occurred upon interaction of compounds and DNA. In the CD spectrum of Ct-DNA, two characteristic bands appear, one is a negative band at 249 nm and other is positive band at 277 nm corresponding to the helicity of B-DNA and due to
CD spectrum of Ct-DNA (5.5 × 10−5 M) in the absence and presence of heterocyclic Schiff base derivatives 3, 4, and 5 in 5 mM Tris buffer.
An attractive tool to investigate compound and DNA interactions for the planning and development of new drugs is molecular docking. Dodecamer sequence (B-DNA) is very abundant in natural DNA. The binding modes of compounds or a set of related compounds can bind in different modes to a specific binding site of DNA or a protein. This is especially evident from X-ray crystallographic structures of ligand-protein complexes. The availability of multiple binding modes of a ligand in a binding site may present an advantage in drug design when simultaneously optimizing several criteria [
Molecular docking study of heterocyclic Schiff base derivatives (
Compounds | Cluster run | ΔG (kcal/mol) |
|
|
|
|
Cluster RMSD (A) | Reference RMSD (A) | NB involved in bonding |
---|---|---|---|---|---|---|---|---|---|
1 | 40 | −7.77 | −7.77 | −7.83 | +1.67 | 0.00 |
0.00 | 32.344 | DC3, DG4 |
2 | 47 | −8.47 | −8.47 | −8.48 | +1.12 | 0.00 |
0.00 | 30.367 | DC3 |
3 | 9 | −7.79 | −8.31 | +0.03 | +0.84 | 2.05 |
0.00 | 26.531 | DG4, DA5 |
4 | 48 | −8.37 | −8.37 | −8.39 | +1.39 | 0.00 |
0.00 | 27.519 | DC3 |
5 | 4 | −8.46 | −8.46 | −8.48 | +1.12 | 0.00e + 00 | 0.00 | 26.745 | DA18 |
6 | 47 | −6.79 | −7.31 | −0.13 | +0.84 | 10.90 |
0.00 | 26.481 | DA5 |
7 | 52 | −7.32 | −8.62 | −0.13 | +1.39 | 4.51 |
0.00 | 26.810 | DA16, DA17 |
8 | 20 | −7.17 | −7.74 | −0.00 | +0.84 | 5.76 |
0.00 | 26.783 | DG4, DT20 |
Molecular docked model of the heterocyclic Schiff base derivatives 3 (a), 4 (b), and 5 (c) with DNA.
The
Antibacterial activity of heterocyclic Schiff base derivatives (
Control | MIC ( |
Lipophilicity | |||
---|---|---|---|---|---|
|
|
|
Log |
Clog |
|
1 | 200 | 200 | 200 | 3.40 | 3.23 |
2 | 150 | 200 | 150 | 2.67 | 2.98 |
3 | 125 | 150 | 125 | 4.42 | 4.26 |
4 | 50 | 75 | 50 | 3.83 | 4.02 |
5 | 50 | 50 | 75 | 3.84 | 4.08 |
6 | 125 | 150 | 150 | 4.52 | 4.33 |
7 | 125 | 125 | 125 | 2.96 | 3.17 |
8 | 50 | 75 | 75 | 3.93 | 4.09 |
Ofloxacin | 11 | 13.5 | — | — | — |
Ketoconazole | — | — | 13.5 | — | — |
2,2-Diphenyl-1-picryl-hydrazyl is a free radical which was used for the determination of antioxidant activity. It can accept electron or hydrogen from the compound and get reduced. After the incubation of one hour, colour was changed from violet to blue and absorbance was decreased. The absorbance at 517 nm was measured and IC50 values were calculated from the graph shown in Figure
DPPH free radical scavenging activity of the heterocyclic Schiff base derivatives (
Hydrogen peroxide was a very reactive species among all the oxygen-containing compounds employed for the investigation of antioxidant activity. UV-vis. spectrophotometer was used to monitor the capability of the target compound to scavenge the hydrogen peroxide. The IC50values of the compounds
Hydrogen peroxide scavenging activity of the heterocyclic Schiff base derivatives (
The experimental findings such as hypochromic effect, enhancement in the viscosity, and diminution in the peak current are the significant features of intercalation model. The
The data used to support the findings of this study are included within the article.
The authors declare that they have no conflicts of interest.
This research project was supported by a grant from the Research Center of the Female Scientific and Medical Colleges, Deanship of Scientific Research, King Saud University.
Figure S1: 1H NMR spectrum of compound 1. Figure S2: 13C NMR spectrum of compound 1. Figure S3: 1H NMR spectrum of compound 2. Figure S4: 13C NMR spectrum of compound 2. Figure S5: 1H NMR spectrum of compound 3. Figure S6: 13C NMR spectrum of compound 3. Figure S7: 1H NMR spectrum of compound 4. Figure S8: 13C NMR spectrum of compound 4. Figure S9: 1H NMR spectrum of compound 5. Figure S10: 13C NMR spectrum of compound 5. Figure S11: 1H NMR spectrum of compound 6. Figure S12: 13C NMR spectrum of compound 6. Figure S13: 1H NMR spectrum of compound 7. Figure S14: 13C NMR spectrum of compound 7. Figure S15: 1H NMR spectrum of compound 8. Figure S16: 13C NMR spectrum of compound 8. Figure S17: mass spectrum of compound 1. Figure S18: mass spectrum of compound 2. Figure S19: mass spectrum of compound 3. Figure S20: mass spectrum of compound 4. Figure S21: mass spectrum of compound 5. Figure S22: mass spectrum of compound 6. Figure S23: mass spectrum of compound 7. Figure S24: mass spectrum of compound 8. Table S1. Pharmacokinetic parameters important for good oral bioavailability of heterocyclic Schiff base derivatives (