Evaluating the antidiabetes and antioxidant activities of halogenated Schiff bases derived from 4-(diethylamino)salicylaldehyde: in vitro antidiabetes, antioxidant and computational investigation | Scientific Reports

Scientific Reports volume 14, Article number: 27073 (2024) Cite this article

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Six Schiff bases with general name 5-(diethylamino)-2-(((halophenyl)imino)methyl)phenol (where halo = 4-fluoro (H1), 2-fluoro (H2), 2-bromo (H3), 4-bromo (H4), 4-chloro (H5) and 3-chloro-4-fluoro (H6)) were prepared by the condensation reaction between 4-(diethylamino)salicylaldehyde and suitable halogenated aromatic amines. The six halogenated Schiff bases were elucidated using different spectroscopic techniques and the structure of H3 and H6 were confirmed using single-crystal X-ray crystallography. The bond lengths of C7–N1, C7–C8 and C8–C9 obtained from structural analysis for both compounds depicted their enol-tautomeric characteristic form. The Hirshfeld analysis revealed that H‧‧‧H intermolecular contacts contributed most towards the Hirshfeld surfaces of both H3 (47.6%) and H6 (39.9%). Quantum chemical calculation studies showed that H1 and H2 have the highest and lowest energy band gap (∆E = 3.80 eV for H1 and ∆E = 3.73 eV for H2), depicting H2 and H1 as the most and least chemically reactive respectively among all the compounds. α-Amylase and α-glucosidase assay were used to evaluate the antidiabetes prowess of the synthesized compounds. All the compounds exhibited lower IC50 values than acarbose (reference drug) in α-amylase assay experiments and H5 with lowest IC50 value of 63.54 μM could be suggested to have the highest α-amylase inhibitory potential among the test samples. For α-glucosidase assay, H1–H6 displayed good antidiabetic potential. However, none of the compounds outshined acarbose with H6 having highest α-glucosidase inhibitory potential when compared to others i.e., IC50 of H6 = 60.89 μM and IC50 of acarbose = 51.42 μM. We measured the antioxidant potential of H1–H6 exploring 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and ferric reducing ability power (FRAP) assays. The DPPH as well as NO radical scavenging assay showed that all the compounds exhibited excellent antioxidant results with some of the compounds surpassing catechin (reference drug). Compound H5 with IC50 values of 30.32 mM and 31.73 mM outshined catechin with IC50 values of 31.17 mM and 140.62 mM for DPPH and NO assays respectively. All the compounds fell within the threshold of Lipinski’s Ro5 projecting them as orally bioavailable and less toxic future therapeutics.

Diabetes mellitus (DM) is known to be one of the deadly diseases posing a great threat to healthcare systems globally, most especially type 2 diabetes (non-insulin dependent)1,2. It’s reported cases are highly alarming in the past decades and even the world economy is being challenged by this disease. Type 2 diabetes (T2D) can be considered as a metabolic disorder caused by insulin resistance and low insulin level in the liver and peripheral tissue, associated to pancreatic defects3. It is a non-infectious disease with common symptoms such as excessive urination, high blood sugar, blurring vision as well as being very thirsty which later results into kidney failure, heart disease and even death if not managed properly4. If measures are not taken, it has been reported that, diabetes will be seventh leading cause of death by the year 20305. Inhibition of hydrolytic enzymes including pancreatic α-amylase together with intestinal α-glucosidase have been utilized over the years as treatment of diabetes6. α-Amylase enzymes break down glycosidic bonds of starch to liberate molecules of disaccharide as well as oligosaccharide and α-glycosidase acts on these molecules, hydrolyse them to glucose molecules which are being absorbed into the blood stream7,8. In the treatment of diabetes, drugs such as miglitol, voglibose and acarbose have shown promising antidiabetes prowess by inhibiting both α-amylase as well as α-glucosidase and they are commercially available. However, adverse effects associated with their use, including stomach pain, diarrhea, farting, and meteorism9,10 have been a great concern and therefore the need to develop antidiabetic drugs with little or no side effects without compromising effectiveness.

In the past years, scientists have been investigating the possibilities of antioxidant drugs to prevent or ameliorate diabetes, as free radicals have been linked to the causation of diabetes and other deadly diseases such as cancer, atherosclerosis, liver cirrhosis among others11. It is important to note that, free radicals are beneficial to the human body when generated in small quantities i.e. serves as defence against infectious diseases, induction of a mitogenic response among others12. However, they are very harmful at high concentrations and damage biological systems i.e. DNA, proteins as well as lipids and this is termed oxidative stress and nitrosative stress. Hence, the need to discover compounds which can counterbalance excess free radicals in the body and in turn avert deadly disease such as diabetes and the aforementioned ones.

Schiff bases have been reported to exhibit promising antidiabetes and antioxidant activities13,14,15. They have also been tested as antibacterial16, anticancer17, antifungal18, antiviral agents19 among others. The uniqueness in the medicinal properties of Schiff bases have been associated with the imine linkage as well as other heteroatoms present. Functional groups such as hydroxyl and phenyl groups have been reported to enhance free radical scavenging ability of drug molecules, thus improving their antioxidant properties20. Furthermore, the substitution of hydrogen with halogens i.e. fluorine has been documented to improve potency, physicochemical properties and DMPK parameters such as bioavailability21,22. In addition, halogen bonds play a significant role in enhancing affinity as well as selectivity in protein–ligand interaction. Thus, it can be projected that halogenated Schiff bases might bind strongly to α-amylase and α-glucosidase which in turn results in good antidiabetes activity23. We took all these factors into consideration (presence of hydroxyl & halogen groups) to design Schiff bases which we envisaged to exhibit effective antidiabetes and antioxidant properties. Though some of the compounds have been reported24,25, to the best of our knowledge no work has been done on the investigation of there in vitro antidiabetes and antioxidant potential. Herein, we report the in vitro antidiabetes and antioxidant potential of Schiff bases derived from 4-(diethylamino)salicylaldehyde and halogenated anilines. We also explore molecular docking studies to corroborate our experimental findings.

Solvents such as ethanol, methanol, dichloromethane, hexane and glacial acetic acid utilized for this study were A.C.S. grade (purity ≥ 99.5%) and used as obtained without further purification. Reagents used are 4-(diethylamino)salicylaldehyde (98%), 1-amino-4-fluorobenzene (99%), 1-amino-2-fluorobenzene (≥ 99%), 1-amino-2-bromobenzene (98%), 1-amino-4-bromobenzene (97%), 1-amino-4-chlorobenzene (98%) and 3-chloro-4-fluoroaniline (98%). All chemicals were acquired from Merck.

1H and 13C NMR spectra for H1–H6 were recorded using a Bruker AvanceIII 600 MHz spectrometer at 25 ℃. Deuterated chloroform was used as a solvent to obtain the 1H NMR. and 13C NMR. data and peaks at δ 7.26 and δ 77.00 ppm are ascribed to residual d-chloroform. FT-IR spectra were obtained on a PerkinElmer Universal A.T.R. spectrum 100 FT-IR spectrometer. Mass spectra of the compounds were recorded using Waters Synapt G2 coupled to a Waters UPLC., ESI probe, ESI Positive, Cone Voltage 15 V and Shimadzu UV–Vis-NIR spectrophotometer was used to process the UV–Visible spectra.

The compounds H1 to H6 were prepared using an established procedure we previously reported26,27. Generally, appropriate mass of 4-(diethylamino)salicylaldehyde was dissolved in 30 ml of methanol in a 100 mL round-bottom flask and stirred vigorously to ensure all the compound is dissolved. To the resulting mixture, an equimolar amount of 1-amino-4-fluorobenzene (for H1), 1-amino-2-fluorobenzene (for H2), 1-amino-2-bromobenzene (for H3), 1-amino-4-bromobenzene (for H4), 1-amino-4-chlorobenzene (for H5) and 3-chloro-4-fluoroaniline (for H6) which was slightly in excess was added. Four to five drops of glacial acetic acid were added to speed up the reaction and the mixture was stirred at room temperature for 12 h. A rotary evaporator was used to remove methanol from the solutions to afford an orange crude product which was later washed with hexane to remove unreacted amines. The pure products were dried at room temperature and stored in a desiccator for further characterization and analysis.

The reaction of 4-(diethylamino)salicylaldehyde (0.30 g, 1.50 mmol) and 4-fluoroaniline (0.17 g, 1.50 mmol) in methanol furnished compound H1 as a yellow powder. Yield 0.39 g (85%). Melting point 86–87 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm): 1.21 (t, 6H, J = 7.1 Hz, CH2–CH3), 3.41 (q, 4H, J = 7.1 Hz, CH3–CH2), 6.91 (s, 1H, Ar–H), 6.25 (d, 1H, J = 8.8 Hz, Ar–H), 7.06 (t, 2H, J = 8.6 Hz, Ar–H), 7.15 (d, 1H, J = 8.8 Hz, Ar–H), 7.19 (t, 2H, J = 9.0, Ar–H), 8.38 (s, 1H, –CH = N), 13.55 (s, 1H, Ar–OH). 13C NMR (CDCl3, 150 MHz) δ (ppm): 12.70, 44.61, 97.76, 103.77, 108.99, 115.86, 116.01, 122.05, 122.10, 133.71, 145.33, 151.80, 159.99, 160.63, 161.61 and 163.75. IR υ (cm−1): (νC–H = 2954), (νC = N = 1605), (ν C = C = 1555), (νC–O = 1253) and (νC–F = 831). ESI–MS TOF, m/z of C17H19FN2O: [M + H]+ observed: 287.1556. MS Calc. analysis: 286.15 (100.0%), 287.15 (18.40%). UV–Vis (CHCl3, λmax, nm), 374 nm and 272 nm. Anal. Calc. for C17H19FN2O: C, 71.31, H, 6.69, N, 9.78. Found: C, 70.91, H, 6.02, N, 9.48.

The reaction of 4-(diethylamino)salicylaldehyde (0.30 g, 1.50 mmol) and 2-fluoroaniline (0.17 g, 1.50 mmol) in methanol furnished compound H2 as a yellow powder. Yield 0.38 g (80%). Melting point 91–92 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm): 1.20 (t, 6H, J = 7.1 Hz, CH2–CH3), 3.40 (q, 4H, J = 7.1 Hz, CH3–CH2), 6.20 (d, 1H, J = 2.5 Hz, Ar–H), 6.25 (d, 1H, J = 8.8 Hz, Ar–H), 7.14–7.10 (m, 3H, Ar–H), 7.15 (d, 1H, J = 8.7 Hz, Ar–H), 7.22 (m, 1H, Ar–H), 8.47 (s, 1H, –CH = N), 13.66 (S, 1H, Ar–OH). 13C NMR (CDCl3, 150 MHz) δ (ppm): 12.71, 44.64, 97.81, 103.84, 109.18, 116.25, 116.39, 121.01, 121.02, 124.45, 133.93, 136.99, 137.06, 152.06, 154.93, 156.58, 162.30, 162.32 and 164.09. ESI–MS TOF, m/z of C17H19FN2O: [M + H]+ observed: 287.1558. 15 MS Calc. analysis: 286.15 (100.0%), 287.15 (18.40%). IR υ (cm−1): (νC–H = 2969), (νC = N = 1620), (ν C = C = 1518), (νC–O = 1226) and (νC–F = 827). UV–Vis (CHCl3, λmax, nm), 378 nm and 271 nm. Anal. Calc. for C17H19FN2O: C, 71.31, H, 6.69, N, 9.78. Found: C, 72.98, H, 6.32, N, 9.58.

The reaction of 4-(diethylamino)salicylaldehyde (0.30 g, 1.50 mmol) and 2-bromoaniline (0.27 g, 1.50 mmol) in methanol furnished compound H3 as a yellow powder. Yield 0.50 g (87%). Melting point 105–106 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm): 1.20 (t, 6H, J = 7.1 Hz, CH2–CH3), 3.41 (q, 4H, J = 7.1 Hz,, CH3–CH2), 6.26 (d, 1H, J = 8.8 Hz,, Ar–H), 7.04 (t, 1H, J = 7.4 Hz,, Ar–H), 7.19 (m, 2H, J = 9.1 Hz,, Ar–H), 7.32 (t, 1H, J = 7.4 Hz,, Ar–H), 7.63 (d, 1H, J = 9.4 Hz, Ar–H), 8.41 (s, 1H, –CH = N), 13.42 (s, 1H, Ar–OH). 13C NMR (CDCl3, 150 MHz) δ (ppm): 12.71, 44.68, 97.81, 103.92, 109.04, 118.69, 119.79, 126.42, 128.29, 133.12, 134.01, 147.32, 152.15, 160.92, and 163.93. IR υ (cm−1): (νC–H = 2965), (νC = N = 1631), (ν C = C = 1515), (νC–O = 1252) and (νC–Br = 805). ESI–MS TOF, m/z of C17H19BrN2O: [M + H]+observed: 347.0760, [M + 3H]+ observed: 349.0760. MS Calc. analysis: 346.07 (100.0%), 348.07 (18.40%), 347.07 (18.4%). UV–Vis (CHCl3, λmax, nm), 385 nm and 276 nm. Anal. Calc. for C17H19BrN2O: C, 58.80, H, 5.52, N, 8.07. Found: C, 59.32, H, 4.50, N, 7.98.

The reaction of 4-(diethylamino)salicylaldehyde (0.30 g, 1.50 mmol) and 4-bromoaniline (0.27 g, 1.50 mmol) in methanol furnished compound H4 as a yellow powder. Yield 0.46 g (81%). Melting point 102–103 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm): 1.20 (t, 6H, J = 7.1 Hz, CH2–CH3), 3.39 (q, 4H, J = 7.2 Hz, CH3–CH2), 6.18 (s, 1H, Ar–H), 6.23 (d, 1H, J = 8.7 Hz, Ar–H), 7.08 (d, 2H, J = 8.6 Hz, Ar–H), 7.13 (d, 1H, J = 8.8 Hz, Ar–H), 7.46 (d, 2H, J = 8.6 Hz, Ar–H), 8.36 (s, 1H, –CH = N), 13.52 (s, 1H, Ar–OH). 13C NMR (CDCl3, 150 MHz) δ (ppm): 12.70, 44.62, 97.70, 103.92, 108.97, 118.57, 122.49, 132.24, 133.90, 148.12, 152.00, 160.86, and 163.90. IR υ (cm−1): (νC–H = 2971), (νC = N = 1596), (ν C = C = 1514), (νC–O = 1092) and (νC–Br = 811). ESI–MS TOF, m/z of C17H19BrN2O: [M + H]+observed: 347.0760, [M + 3H]+ observed: 349.0760. MS Calc. analysis: 346.07 (100.0%), 348.07 (18.40%), 347.07 (18.4%). UV–Vis (CHCl3, λmax, nm), 381 nm and 273 nm. Anal. Calc. for C17H19BrN2O: C, 58.80, H, 5.52, N, 8.07. Found: C, 58.87, H, 4.69, N, 7.90.

The reaction of 4-(diethylamino)salicylaldehyde (0.30 g, 1.50 mmol) and 4-chloroaniline (0.20 g, 1.50 mmol) in methanol furnished compound H5 as a yellow powder. Yield 0.40 g (79%). Melting point 90–91 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm): 1.20 (t, 6H, J = 7.1 Hz, CH2–CH3), 3.40 (q, 4H, J = 7.1 Hz, CH3–CH2), 6.18 (s, 1H, Ar–H), 6.24 (d, 1H, J = 8.8 Hz, Ar–H), 7.14 (m, 3H, J = 8.8 Hz, Ar–H), 7.32 (d, 2H, J = 8.6 Hz, Ar–H), 8.39 (s, 1H, –CH = N), 13.53 (s, 1H, Ar–OH). 13C NMR (CDCl3, 150 MHz) δ (ppm): 12.70, 44.62, 97.71, 103.91, 108.96, 122.07, 129.29, 130.76, 133.88, 147.62, 151.98, 160.83, and 163.90. IR υ (cm−1): (νC–H = 2971), (νC = N = 1600), (ν C = C = 1514), (νC–O = 1240) and (νC–Cl = 812). ESI–MS TOF, m/z of C17H19ClN2O: [M + H]+ observed: 303.1260, [M + 3H]+ observed: 305.1239. MS Calc. analysis: 302.12 (100.0%), 304.12 (32.0%), 303.12 (18.4%). UV–Vis (CHCl3, λmax, nm), 381 nm and 273 nm. Anal. Calc. for C17H19ClN2O: C, 67.43, H, 6.32, N, 9.25. Found: C, 67.42, H, 5.45, N, 8.95.

The reaction of 4-(diethylamino)salicylaldehyde (0.30 g, 1.50 mmol) and 3-chloro-4-fluoroaniline (0.23 g, 1.50 mmol) in methanol furnished compound H6 as a yellow powder. Yield 0.42 g (79%). Melting point 113–114 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm): 1.21 (t, 6H, J = 7.1 Hz, CH2–CH3), 3.40 (q, 4H, J = 7.1 Hz, CH3–CH2), 6.19 (s, 1H, Ar–H), 6.25 (d, 1H, J = 8.7 Hz, Ar–H), 7.08 (s, 1H, Ar–H), 7.12 (d, 1H, J = 8.6 Hz, Ar–H), 7.15 (d, 1H, J = 8.8 Hz, Ar–H), 7.25 (d, 1H, J = 8.6 Hz, Ar–H), 8.35 (s, 1H, –CH = N), 13.26 (s, 1H, Ar–OH). 13C NMR (CDCl3, 150 MHz) δ (ppm): 12.69, 44.64, 97.63, 103.96, 108.81, 116.82, 120.70, 120.74, 121.32, 121.44, 122.42, 134.00, 146.17, 146.20, 152.05, 155.16, 156.80, 161.42, and 163.53. IR υ (cm−1): (νC–H = 2926), (νC = N = 1572), (ν C = C = 1515), (νC–O = 1247) and (νC–F = 833). ESI–MS TOF, m/z of C17H19ClFN2O: [M + H]+observed: 321.1168, [M + 3H]+ observed: 323.1141. MS Calc. analysis: 320.11 (100.0%), 322.11 (32.0%), 321.11 (18.4%). UV–Vis (CHCl3, λmax, nm), 380 nm and 273 nm. UV–Vis (CHCl3, λmax, nm), 380 nm and 273 nm. Anal. Calc. for C17H19ClFN2O: C, 63.65, H, 5.66, N, 8.73. Found: C, 63.65, H, 4.94, N, 8.49.

Single crystals appropriate for this analysis were obtained by slow evaporation of dichloromethane solution of H3 and H6. A suitable crystal with dimensions 0.320 × 0.080 × 0.064 mm3 and 0.227 × 0.189 × 0.077 mm3 for H3 and H6 were selected and mounted on a Bruker APEX II DUO CCD diffractometer with radiation (0.71073 Å) at room temperature. Using Olex228, the structure was solved with the SHELXT29 structure solution program using Intrinsic Phasing and refined with the olex2.refine30 refinement package using Gauss–Newton minimisation. Summarized crystallography data as well as structural parameters are presented in Table 1.

This enzyme assay for the chemical compounds was carried out via a slightly modified methodology of Olofinsan et al.31 and by utilizing p-nitrophenol glucopyranoside (pNPG) as the enzyme substrate. Solution of the compounds or the standard antidiabetic drug (acarbose) at 160 µl volume was equilibrated with 0.1 ml of 2 U/ml of α-glucosidase from yeast cells. After adding 50 µl of potassium phosphate buffer mixture (0.1 M, pH 6.8) to the enzyme/compound mixture, the solution was kept in an incubator for 12 min at 37 °C. The catalytic reaction of the enzyme started by adding 0.005 M of pNPG (35 µl) and was monitored for one minute before reading the optical density at 405 nm against a control experiment lacking the test samples.

This potential inhibitory effect for the compounds was investigated via Ibitoye et al.32 previous procedure with minor modification and using starch as the enzyme substrate. The reaction mixture contained 250 µl of each compound and 0.2 ml volume of pancreatic α-amylase in a test tube. Before twenty minutes of equilibration at 37 °C, 100 mM of pH 6.8 potassium phosphate solution was added. The catalytic reaction of the enzyme started by adding 0.2 ml starch soluble solution and was allowed to proceed for fifteen minutes before termination with 300 µl of DNSA reagent. After heating (100 °C) the test tube containing the solution mixture for eight minutes, 1 ml of distilled water was added before absorbance readings (540 nm) were taken when the solution was cooled to room temperature.

This antioxidant assay for the compound was done via Kurian et al.33 previous methodology. The reaction mixture contained 120 µl aliquot of phosphate buffered solution containing sodium nitroprusside (0.001 mM) and a solution of the synthesized compound or the antioxidant chemical standard. After equilibration at 25 °C for 120 min, 50 µl of Griess reagent was added for the formation of a pink chromogenic solution. Thereafter, the optical density of this coloured solution (546 nm) was measured against a blank solution containing a similar volume of distilled water instead of the tested compound.

The capacity of the chemical compounds to neutralize purple coloured 2,2′-diphenyl-1-picrylhydrazyl (DPPH) solution is evaluated by minor modification of Turkoglu et al.34 detailed procedure. The reaction mixture contained 0.06 ml equal volume of the test chemical solution and methanol solution of the free radical powder (300 µM). The set-up was transferred into a dark cupboard and allowed to incubate at room temperature for 45 min. The extent of the colour change in each sample well is then estimated after an absorbance reading is taken at 540 nm relative to a blank experiment containing a similar volume of distilled water instead of the sample solution.

The above property of the chemical compounds was evaluated by determining their ability to convert ferric ion with 3 + oxidation state to a ferrous state (Fe2+) via Tan and Chan’s35 experimental method. The reaction mixture contained 100 µl of 1% K3Fe (CN)6, 0.15 ml of the test chemical compound and 50 µl of potassium phosphate buffer (pH 6.6). After equilibration at 50 °C for 45 min, the solution was made acidic with TCA solution before 70 µl distilled water addition. Finally, 0.030 ml of ferric chloride solution 1 mg/ml was added prior to absorbance reading measurement at 700 nm. The % reducing power of the test compound was estimated from a quercetin standard curve graph.

GaussView v6.036 graphical interface program was explored to build the 3D model of H1–H6. Input files used for modelling these structures were created using this program and helps to visualize structures before and after calculations. The geometry optimization and calculations were carried out at B3LYP and basis set of 6-31G(d,p) for C, H, N and O atoms except for Br atom where CC-PVTZ-pp was used. All these were inclusive in the Gaussian 16 program package available on the Lengua cluster of the centre for high performance computing [CHPC, www.chpc.ac.za] Cape Town, South Africa.

This simulation analysis aimed to determine the synthesized compounds’ binding affinities with α-glucosidase and α-amylase enzymes. The Protein Data Bank website at https://www.rcsb.org/ was employed to retrieve the 3D structures of the carbohydrate digestive enzymes37,38 with the identification codes of 1B2Y and 3L4W for α-amylase and α-glucosidase respectively. The 2D structure of the chemical compounds imported into Avogadro software (http://avogadro.openmolecules.net/) was used to generate the 3D structure from protein active site molecular docking. The process employed for the preparation of ligand and enzyme molecules involved utilizing the method, according to Wang, Wang39. After docking these compounds at the protein catalytic site with the Autodock Vina (https://vina.scripps.edu/), the BIOVIA Discovery Studio40 application was utilized to present the molecular interactions of the protein–ligand complex generated.

Scheme 1 illustrates the synthetic pathway as well as the reaction conditions for H1 to H6. The compounds were prepared by reacting equimolar amounts of 4-(diethylamino)salicylaldehyde with the appropriate primary amines under suitable reaction conditions. The compounds were obtained as orange powders, and they are stable at room temperature. The compounds H1–H6 dissolved easily in solvents such as ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide and chloroform.

Synthesis of halogenated Schiff base H1–H6.

The 1H-NMR data for H1–H6 were obtained in d-chloroform and 2D NMR was used in assigning the peaks. The aliphatic protons for the compounds appeared within the range of 0 -3.50 ppm i.e., the peaks for methyl and methylene protons for H2 were observed at 1.21 ppm and 3.41 ppm respectively. The aromatic protons for all the compounds appeared as either doublets or triplets around 6.18–7.63 ppm and perfectly integrated to 7 protons except H6 which was integrated to 6 protons. The azomethine proton for all the compounds was observed as a singlet around 8.35–8.47 ppm. In the far downfield region of the spectra, a weak broad peak was observed, and this can be assigned to the proton of the –OH group. In the 13C-NMR spectra of H1–H6, the aliphatic carbons were observed between 12.70 and 44.68 ppm. The aromatic and azomethine carbons were observed around 99.76 and 164.09 ppm respectively. It is important to note that, due to the deshielding effect, the aromatic carbon in α-position to hydroxy, halogen (i.e. F), and nitrogen were observed at higher chemical shift relative to other aromatic carbons.

In the IR spectra of H1–H6, two major diagnostic vibrational bands were observed. These are ʋ(C–Hstr) as well as ʋ(C = Nstr) and they were observed around 2954–2971 cm−1 and 1596–1631 cm−1 respectively, which are very similar to those previously reported41,42,43. The expected ʋ(O–H) which ought to appear around 3100–3350 cm−1 in all the compounds was hardly noticeable due to the weak nature of the band which resulted from the intramolecular hydrogen bonding between the O–H and the nitrogen atom of the azomethine group44,45. Other noticeable vibrational bands around 1514–1555 cm−1 are attributed to –C = Cstr of aromatic ring while the ones around 1226–1253 cm−1 can be ascribed to ArC–Nstr.

The UV–Visible spectra of H1–H6 were obtained in dichloromethane and given in Fig. 1. Two major bands were observed, one intense and one less intense band. The less intense band appeared around 270–280 nm, and this can be attributed to n → π* due to azomethine functional group while the intense band appeared around 365–375 nm due to the aromatic moiety can be assigned to π → π*27. In the mass spectra of H1–H6, the molecular ion peak [M]+ could be seen. It appeared at 287.15, 287.15, 347.07, 347.07, 303.13, 323.12 for H1, H2, H3, H4, H5 and H6 respectively. The mass spectra of H3 and H4 displayed [M]+ and [M + 2]+ peaks with intensity of 1:1 due to the presence of one bromine atom while the one for H5 exhibited [M]+ and [M + 2]+ peaks with intensity of 3: 1 due to one chlorine atom46.

Electronic absorption spectra of H1–H6.

The single crystal used for the structural elucidation of H3 and H6 were obtained from the slow evaporation of dichloromethane solution of the respective compounds. H3 crystallizes as orthorhombic with space group of P212121 while H6 crystallizes as monoclinic with P21/n space group. Both compounds contain each molecule in their asymmetric unit has shown in Fig. 2. In these compounds, the bond lengths for C7–N1, C7–C8 and C8–C9 are 1.275(6) Å, 1.422(6) Å and 1.412(6) Å for H3; 1.284(2), 1.435(2) and 1.412(2) for H6 respectively (Table 2). It can be deduced from these bond lengths that, H3 and H6 crystallize in enol-tautomeric forms47. The bond length of the central double bond C7–N1 in H6 is longer than the one for H3 and this revealed that the enol character is prevalent in H3 more than H647. This bond also showed that both molecules adopted (E) configuration. The torsion angles of C6–N1–C7–C8 (for H3) and C5–N1–C7–C8 (for H6) are − 170.5(4)° and 177.7(1)° respectively and this depicts that the two-phenyl groups in both compounds are almost planar to each other. In addition, the torsion angle C13–C8–C7–N1 for H3 and H6 are 179.7(4)° and − 176.4(2)° respectively, which signifies that the phenyl ring with the hydroxyl group is coplanar with the azomethine functional group. A strong intramolecular O–H‧‧‧N bond was observed in both compounds, and this was created via azomethine nitrogen (–C = N) and hydroxyl oxygen (–OH). The bond lengths, bond/torsion angles are similar to those previously reported24,25.

Crystal structures of H3 and H6 with thermal ellipsoids drawn at 20% and 30% probability for H3 and H6 respectively. Hydrogen atoms have been omitted for clarity.

Hirshfeld surface (HS) analysis of H3 and H6 was carried out to gain insight into the molecular interactions existing in the crystal packing systems of both compounds. HS is known to be the points where there is a balance between the contributions of electron density within the molecule and contribution from all other molecules in a crystal system. HS is crucial in the field of crystal engineering as it reveals data related to both strong and weak interactions within crystal systems48. HS mapped with dnorm properties and 2D fingerprint of all contacts, H…H together with C…H intermolecular contacts are generated using CrystalExplorer2149 and are given in Fig. 3. The mapped dnorm values for H3 and H6 are − 0.0357–1.2190 and − 0.1142–1.2331 respectively and values are visually encoded with red, blue and white colours on the Hirshfeld surfaces. Red depicts negative value in dnorm distribution and is ascribed to close contacts i.e. distance shorter than the sum of Van der Waal radii while blue colour depicts positive dnorm values and is assigned to longer contacts i.e. distance longer than the sum of Van der Waal radii. The white colour indicates zero dnorm value and signifies distance of contacts in relation to Van der Waal separation49,50. Report has it that, short intermolecular contacts play a vital role in stabilizing the crystal lattice, hence this section focuses on it. In H3, nineteen intermolecular contacts were found while it was twenty-two for H6. Among all these intermolecular contacts, H‧‧‧H contacts contributed most towards the Hirshfeld surfaces of both H3 (47.6%) and H6 (39.9%). The HS analysis also displayed significant quantity of C‧‧‧H contacts, 11.6% and 15.1% for H3 and H6 respectively. Intermolecular C–H․․․π interaction were reciprocal H‧‧‧C contacts and they contribute 12.5% and 9.4% for H3 and H6 respectively. Other substantial intermolecular contacts are Br‧‧‧H (8.1%), H‧‧‧Br (4.5%) as well as O‧‧‧H (3.1%) for H3 and Cl‧‧‧H (7.7%), F‧‧‧H (5.2%), together with H‧‧‧Cl (4.9%) for H6.

dnorm generated over the Hirshfeld surface as well as the fingerprint plots of the intermolecular contacts displaying their contribution towards the Hirshfeld surface of H3 and H6.

Quantum chemical descriptors obtained from DFT calculations or other computational methods are parameters used to gain insight into the electronic, reactivity, stability and geometry properties of molecules most especially organic compounds51. Calculated quantum parameters are given in Table 3 and all parameters are measured in electron volts (eV). Energies of lowest unoccupied molecular orbital (ELUMO) and highest occupied molecular orbital (EHOMO) are the fundamental parameters52 utilized to calculate other parameters (∆E = band energy gap, A = electron affinity, I = ionization potential, η = global hardness, σ = global softness, Cp = chemical potential, χ = electronegativity) using the equations below:

Chemical reactivity is a measure using ∆E parameter and the smaller the ∆E of a molecule, the more reactive it is. As seen in Fig. 4, H2 has the lowest ∆E, hence the most chemically reactive while H1 has the highest ∆E, thus the least chemically reactive50. Global softness quantifies how swiftly electron cloud of molecules deforms or polarizes to react to small chemical perturbations. H2 and H4 have the highest global softness, and this depicts that, they are the more reactive relative to others. Global hardness is the reciprocal of global softness (Eq. 5) and it measures the resistance of molecule to chemical perturbations. H1 with the highest global hardness (η = 1.90 eV) and this affirms its least reactivity among all the compounds. Nucleophilic properties of the compounds can be measured from the ionization potential values which were deduced from HOMO distribution. As seen in Table 3, H2 and H6 have the smallest and highest IP respectively. Electronegativity values measure the electron attraction power of molecules and H6 with χ value of 3.37 eV has the highest electronegativity compared to other compounds. This could be associated to the presence of two halogen atoms (F and Cl) in H6 while others have one halogen atom. Electron affinity value is derived from LUMO energy, and it quantifies the energy released when an electron is added to a neutral molecule. H6 and H1 have the highest and least electron affinity values respectively. Chemical potential is expressed mathematically as the negative form of electronegativity, and it is the change in free energy of a system with respect to change in number of molecules added to the system. Cp could be related to chemical reactivity i.e. Cp is directly proportional to reactivity6. Thus, H6 with a Cp value of -3.37 eV would be the most chemically reactive when compared to other ones.

LUMO and HOMO plots for (a) H1–H3, (b) H4–H6.

To gain insight into how charges are distributed in H1–H6, molecular electrostatic potential surfaces maps are generated and given in supplementary material (Fig. S25). In MEPS map, the colour ranges from red to blue based on their electrostatic potentials. The red and blue region indicate site for electrophilicity and nucleophilicity respectively while colours such as orange and yellow region depicts site with partially negative charge and lightly an electron-rich site respectively53. In all the compounds, the red region is located around the hydroxyl (–OH) group and this signifies the site which is electron-rich, which indicates the location from which nucleophilic attack might take place. Orange colour was observed around the halogen atoms in H1–H6, and this depicts an area with partially negative charge. Generally, the blue region was observed very close to diethylamino group, a location which is moreso electrophilic.

α-Amylase is a vital enzyme present in human saliva as well as the pancreas and it is liable for the cleavage of malto-oligasaccharides to maltose, a substrate for intestinal α-glucosidase54. Inhibition of α-amylase has been explored as a therapeutic measure to control postprandial hyperglycemia55. Compounds H1–H6 were examined for their α-amylase inhibitory prowess by evaluating their IC50, which quantifies inhibitors potential. The data in Table 4 revealed that all the compounds displayed inhibitory biological effects on the α-amylase carbohydrate digestive enzyme. At 50 µM, compounds H1 and H4 had higher significant activities that superseded those of other compounds and acarbose, suggesting a clinically promising antidiabetic drug. However, at 200–400 µM concentration, all the synthesized chemical samples displayed higher enzyme inhibition, suggesting their superior effectiveness than acarbose. Interestingly, the fact that H5 had more excellent activity at 100–400 µM with a low IC50 value of 63.54 µM may suggest the compound’s higher efficacy relative to the other chemicals. For this assay, we observed that, compounds with the halogen atom at the para position exhibited better activity than those in which the halogen atom is positioned at the ortho position, with H3 and H4 exceptional. Report has shown that, bromine atom is essential in the structures of α-amylase inhibitory compounds, hence their presence as one of the main parts of the structure of future α-amylase inhibitors56. Besides H5 (with chlorine at para position), H3 as well as H4 having bromine atom in their structure, displayed excellent α-amylase inhibition potential compared to other compounds and acarbose, confirming the significant role of bromine atom in α-amylase inhibition. Generally, as the concentrations of the test compounds increases, the percentage α-amylase inhibitory activity also increases (Fig. 5).

Compound H1–H6 inhibitory effect on α-amylase in comparison with acarbose standard. Data = mean ± SD; n = 3.

Inhibition of α-glucosidase enzymes is one of the important assays used in the development of novel antidiabetic drugs. It is one of the carbohydrate-hydrolysing enzymes, which if inhibited, could prolong carbohydrate digestion time, resulting in drastic reduction of glucose intake in the body system10. The ability of H1–H6 to limit the catalytic activities of α-glucosidase is presented in Fig. 6 and this revealed that, their activity is dose dependent. Amongst the synthesized chemicals, compound H6 had the highest inhibitory effects at 50–200 µM concentrations. Though the enzyme inhibitory capacities of all the compounds were nearly in the same range of acarbose at 400 µM, the 60.89 µM IC50 of H6, as compared to those of the other compounds as seen in Table 4, could reveal a better inhibitory potential on this specific enzyme physiological activity. This could probably be due to the presence of two electron-withdrawing atoms (Cl & F) which enhance the lipophilicity of H6 compared to other compounds with one halogen atom. Thus, enhancing lipid solubility and metabolic stability which in turn increase biological activity57. The presence of these two halogen atoms might also be responsible for H6 forming more halogen and/or hydrogen bonds, that help in the number of interactions with α-glucosidase compared to other compounds, thereby enhancing activity57.

Compound H1–H6 inhibitory effect on α-glucosidase in comparison with acarbose standard. Data = mean ± SD; n = 3.

Molecular docking is a crucial computational tool used to study the interaction between drug and protein target of a causing disease. This is to gain insight into the conformation of the ligand within the constraints of a receptor binding site of protein target and accurately predict the binding energy between them58. It has been extensively explored in designing of novel drugs and in pharmaceutical industries. The binding energies of H1–H6 with protein targets are given in Table 5 while the 2D diagram of the interaction between protein crystal structure of both the α-amylase and α-glucosidase with H6 are given in Fig. 7 and the ones for H1–H5 are given in the supplementary material. Asides H4 and H5, all other compounds exhibited higher binding energies than acarbose against α-amylase enzymes while against α-glucosidase, all the compounds displayed higher binding energies than acarbose. This suggests that the reported compounds could be lead molecular candidates against the inhibition of α-glucosidase and α-amylase, hence future antidiabetic therapeutics. The results for the molecular studies corroborate well with the experimental findings for α-amylase while a general trend was not observed for α-glucosidase. Among all the synthesized compounds, H6 exhibited the highest binding energies against the two targeted proteins when compared to other compounds and even outshined acarbose. H6 displayed hydrogen bonding with active site of amino residue (LYS200, ILE 235 and ASP3000) of α-amylase together with other interactions such as alkyl, pi-alkyl and van der Waals (Fig. 7a). These interactions were also observed in α-glucosidase-H6 complex with the addition of pi-pi stacked, pi-sulphur, pi-anion and unfavourable bump (Fig. 7b). Most of the interactions were also observed in α-glucosidase-acarbose and α-amylase-acarbose complexes except alkyl, pi-alkyl, pi-pi stacked and pi-sulphur. The receptor- compounds interactions for other compounds can be found in supplementary material (Figs. S25 and S26).

2D diagram of receptor-compound interaction between a(i) α-amylase and acarbose, a(ii) α-amylase and H6, b(i) α-glucosidase and acarbose, b(ii) α-glucosidase and H6.

DPPH has an odd electron in its structure and yet quite stable. The ability of compounds to scavenge this odd electron in DPPH structure is mainly determined by their electron radical and hydrogen donating capability, which in turn quantifies their antioxidant potential59. The data in Fig. 8 presents the extent to which the synthesized compound donates electrons to the DPPH free radical. At the highest test concentration (400 µM), compounds H1 and H5 showed higher antioxidant properties than catechin and the rest of the test compounds. While their biological activities at this concentration slightly different, the lower IC50 of H1 (30.06 µM) in Table 6 suggests its superior capacity to H5 (IC50 = 30.32 µM). As observed in the α-amylase assay, the compounds with a halogen atom in the para position, scavenge free radicals better than those whose halogen atom is positioned in the ortho position, with the exception of H3 and H4.

DPPH free radical reducing properties of compound H1–H6 in comparison with catechin standard. Data = mean ± SD; n = 3.

The excessive production of nitric oxide radicals in the body results in the nitrosylation reaction, which tends to alter the functions of protein and even harm them. Though at lower concentrations, nitric oxide radicals play a crucial physiological role in processes such as defence mechanism, smooth muscle relaxation, and blood pressure regulations60. Thus, the need to control its concentration in the body system by developing compounds that could assist in mopping excess nitric oxide radicals. Aside from H3, all the compounds displayed higher nitric oxide radical scavenging ability than catechin (Table 6). While H3 and catechin were almost similar to each other at 50 µM (Fig. 9), their activities at this experimental concentration were lower than those of the other test compounds. Amongst the test samples, compound H5 has higher activities at 100–400 µM and lower IC50 (31.73 µM) in Table 6 indicates nitric oxide scavenging properties with better potency compared to the other compounds and the reference (Catechin IC50 = 140.62 µM).

Compound H1–H6 nitric oxide scavenging activities in comparison with catechin standard. Data = mean ± SD; n = 3.

FRAP assay is one of the frequently used techniques explored to measure the antioxidant capability of synthetic and natural compounds. It quantifies the potential of test compounds to reduce Fe(III) to Fe(II), which in turn reflects their tendency to donate electrons and mop free radicals. The reduction of Fe(III) to Fe(II) during this experiment is affirmed by colour change, usually from yellow to blue6. Figure 10 shows the reductive properties of the test compounds. At concentrations 50–200 µM, there were considerable differences between the ferric-reducing capacities of the compounds. Although compound H5 at 400 µM had higher activities than the other synthesized samples but lower than catechin at all concentration. Generally, all the compounds displayed poor ferric reducing power ability.

Compound H1–H6 reducing properties in comparison with catechin standard. Data = mean ± SD; n = 3.

In this section, the oral bioavailability and drug-likeness of H1–H6 were predetermined by predicting the physicochemical and pharmacokinetics properties of these compounds using SwissADME61, a web-based tool reliable for small organic molecules. The estimated ADME results are given in Table 7 and compared with the standard Lipinski’s rule of five (Ro5). This is to measure the level of their compliance or violation with the standard values, since potential drug candidates are expected to fall within the range or deviate minimally from standard. Molecular Weight (MW) is one of the factors which affect absorption and cellular uptake of drug molecules, and it directly influences its bioavailability. A drug molecule with small MW could be easily transported to target biomolecules in turn increasing concentration at the epithelium surface and enhance absorption62. According to Lipinski’s Ro5, the acceptable MW for potential candidates is ˂ 500 g/mol and herein, all the synthesized compounds MW are within the acceptable range. This poses them to be orally active and bioavailable. The estimated lipophilic (LogP) and solubility (LogS) for H1–H6 as seen in Table 7 revealed that, they all fall within the range of acceptable values. This finding implies that, all the compounds exhibited good absorption and permeability, indicating their easiness to be transported to cellular target sites. Topological surface area (TPSA) takes into consideration polar atoms on the surface of compounds i.e. nitrogen, oxygen as well as their added hydrogen and it is used in estimating the bioavailability of drug molecules in terms of their transportation across lipid bilayer membrane i.e. blood–brain barrier (BBB). The lower the TPSA values the easier they are transported through lipid bilayer membrane. H1–H6 had low TPSA value and also fell within acceptable standard of Lipinski’s Ro5 buttressing their potential as promising drug candidates. Based on the predicted values for rotatable bonds (RotBs), hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD), all the compounds are predictively orally bioavailable and active. The gastrointestinal (G.I.) absorption capacity of H1–H6 is high, and this further established their bioavailability. They all showed the tendency to pass through the blood–brain barrier (B.B.B.). The ability of a potential drug candidate to bind or not to bind P-glycoprotein (P-gp substrate) is also a critical stage in drug discovery as P-gp reduces the bioavailability of drugs63. Interestingly, all the synthesized compounds are not Pg-substrates affirming their potential as a good drug candidate. The rate at which H1–H6 can penetrate across stratum corneum of the skin is in the order of H5 < H6 < (H3 and H4) < (H1 and H2). All the predicted pharmacokinetics and physicochemical parameters for H1–H6 depict the oral bioavailability of these compounds and pose them to be less toxic. The excellent antidiabetes and antioxidant properties displayed by some of these compounds coupled with their promising bioavailability showed the possibility to be a new source for potential drug candidates to combat diabetes and free radical causing diseases, most especially after further optimization.

Six halogenated Schiff bases derived from 4-(diethylamino)salicylaldehyde and aromatic amines were prepared and characterized using UV–Visible, FT-IR, NMR as well as mass spectrometry methods while the purity of the compounds were ascertained using elemental analysis. Structural analysis revealed that H3 and H6 crystallizes as enol-tautomeric forms, and it is more pronounced in H3 than H6. The H‧‧‧H intermolecular contacts contributed most towards the Hirshfeld surfaces relative to other force contacts. DFT studies showed that, H2 and H1 have lowest energy band gap (most chemically reactive) and highest energy band gap (least chemically reactive) respectively. In vitro α-amylase inhibitory potential studies showed that all the compounds exhibited better activity than acarbose while for α-glucosidase assay, none of the compounds outshined acarbose but they all displayed promising activity. DPPH, NO and FRAP assays were used to measure the antioxidant capacity of H1–H6 and the results showed that H1 and H5 scavenge DPPH free radicals better than catechin while all the compounds’ asides H3 scavenge nitric oxide radical than the reference drug. All the compounds did not violate the Lipinski’s Ro5, and this poses them to be good drug candidates for future therapeutics most especially after further studies.

All data generated or analysed during this study are included in this published article and its supplementary information files.

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The authors acknowledged the funding from the National Research Foundation (N.R.F.), Stellenbosch University, Matieland, 7602, South Africa. The first author is a recipient of the postdoctoral fellowship award of the N.R.F. at Stellenbosch University, Matieland, South Africa. The authors are also grateful to the South Africa Centre for High-Performance Computing, CHPC [www.chpc.ac.za] for resources.

Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland, 7602, South Africa

Segun D. Oladipo & Robert C. Luckay

Department of Chemical Sciences, Olabisi Onabanjo University, P.M.B 2002, Ago-Iwoye, Nigeria

Segun D. Oladipo

Department of Biochemistry, Faculty of Natural and Applied Sciences, Nile University of Nigeria, Abuja, Nigeria

Kolawole A. Olofinsan

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Conceptualization, S.D.O. and RCL; methodology; S.D.O., K.A.O, and RCL.; software, S.D.O., K.A.O., and RCL validation, S.D.O., K.A.O., and R.C.L.; formal analysis; S.D.O., K.A.O., and RCL; resources’ RCL.; data curation, S.D.O., K.A.O., and RCL.; writing original draft preparation; S.D.O. and K.A.O.,; writing review and editing, S.D.O, K.A.O., and RCL., visualization, S.D.O and R.C.L., supervision, R.C.L., project administration, R.C.L., funding acquisition, S.D.O and R.C.L.

Correspondence to Segun D. Oladipo or Robert C. Luckay.

The authors declare no competing interests.

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Oladipo, S.D., Luckay, R.C. & Olofinsan, K.A. Evaluating the antidiabetes and antioxidant activities of halogenated Schiff bases derived from 4-(diethylamino)salicylaldehyde: in vitro antidiabetes, antioxidant and computational investigation. Sci Rep 14, 27073 (2024). https://doi.org/10.1038/s41598-024-78460-w

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Received: 24 June 2024

Accepted: 30 October 2024

Published: 07 November 2024

DOI: https://doi.org/10.1038/s41598-024-78460-w

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