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BY 4.0 license Open Access Published by De Gruyter Open Access November 20, 2023

Synthesis, Hirshfeld surface analysis, thermal, and selective α-glucosidase inhibitory studies of Schiff base transition metal complexes

  • Sadia Rehman EMAIL logo , Muhammad Ikram EMAIL logo , Adnan Khan EMAIL logo , Farzia , Rizwan Khan , Muhammad Naeem , Mutasem Omar Sinnokrot , Momin Khan , Abdullah F. AlAsmari , Fawaz Alasmari and Metab Alharbi
From the journal Open Chemistry


A synthesized Schiff base ligand 4-{(Z)-[(2-hydroxy-1-naphthyl)methylene]amino}-4-antipyrene (H-NAPP) was confirmed by single crystal diffraction analysis. The H-NAPP was crystalized in the P 21 21 21 space group and orthorhombic crystal system. The Schiff base ligand H-NAPP bears potential donor sites and therefore it was reacted with transition metal ions Co2+, Ni2+, Cu2+, and Zn2+ to yield respective metal complexes. All reaction products were investigated by elemental analyses and IR spectroscopic techniques. The combined spectroscopic characterizations revealed the distorted square planar geometries for all the synthesized metal complexes. The metal complexes were further studied for their thermal stabilities using TG techniques and proved to be thermally cleaved in the temperature range of 30–1,000°C in air. Pseudo-mirrored 2D fingerprint plots were used for the short interatomic interactions in the crystal structure. The major short interatomic interactions involve the hydrogen bonding which covers the Hirshfeld surfaces {H···H, O···H and C···H}. The ligand and complexes were investigated for a potential α-glucosidase inhibitory activity. While relatively inactive throughout, some notable differences were observed and, surprisingly, the ligand was found to be more active than its complexes.

1 Introduction

A variety of Schiff base molecules are produced by a combination of aldehydes and primary amines following different routes of synthesis [1,2,3]. The excellent coordination capabilities of Schiff bases, notably the –C═N– linkage pi-electron system, make them popular ligands. When these Schiff bases with a chiral moiety are complexed, a geometrical constriction is created; this characteristic is used to increase the catalytic activity of oxidation in transition metal complexes [3,4,5]. Complex formation may be accompanied by modifications in magnetic and electrochemical behaviour [6,7,8,9,10], which can be fine-tuned to improve a variety of applications, such as catalysis [11,12,13], pharmaceutical use [14,15,16,17,18], and laboratory reagents [5,19,20].

1- or 2-Hydroxy substituted iminium derivatives were used to coordinate metals as monoanionic and bidentate ligands via their N and O donor atoms. The improved α-glucosidase enzyme inhibition activity of transition metal complexes with such bidentate ligands was investigated.

In this context, one such example has been synthesized by reacting the synthesized Schiff base or imine derivative with copper(ii) acetate. The resulting complex was found to be soluble in common organic solvents like methanol, ethanol, dimethyl sulphoxide (DMSO), etc. Other metal(ii) acetates were also used to produce imine-containing metal complexes but after many unsuccessful attempts at crystal growth, we were unable to study them structurally.

The most fascinating advancement in the realm of supramolecular or coordination polymers is their most probable application in synthetic enzyme-type macromolecules [21,22,23,24]. Hence, our recent studies focused on the applications in enzyme inhibitory activities of all the synthesized compounds. Our focus on enzymatic studies diverted to α-glucosidase inhibition because of its role in augmenting diabetic conditions by the formation of glucose as depicted in Scheme 1.

Scheme 1 
               Conversion of different carbohydrates by α-amylase and α-glucosidase enzymes. ©Springer Nature [25].
Scheme 1

Conversion of different carbohydrates by α-amylase and α-glucosidase enzymes. ©Springer Nature [25].

Type II diabetes, a metabolic disease caused by insufficient insulin secretion, is associated with increased sugar levels in blood and ultimately in cells [26]. The most specific symptoms are frequent urination, increased thirst and hunger, hyperosmolar coma, and diabetic ketoacidosis. This disease mostly impairs the normal functioning of kidneys and heart, thereby increasing the chances of severe kidney and heart diseases up to failure of these organs. It can further affect vision and cause severe cognitive impairment [26]. The most recent data of 2019 revealed that around 463 million (8.8% of the total adult population worldwide) are suffering from diabetes. This number has increased from 382 million patients (about 8.3% of the total population of the world) as published in 2013. It has been predicted that it may become the leading cause of death in upcoming years if not treated adequately [27,28,29]. Regional statistics show that in China alone, 150 million people are suffering from diabetes. Similarly, in Canada, around 2.4 million people are diabetic. How alarming the situation is, is emphasized by the 1 million annual deaths caused by diabetes in India alone [26,27,28,29].

Therefore, inhibition of this enzyme may offer a feasible treatment for the diabetic condition. Notably, it has already been observed that control of postprandial hyperglycaemia can be achieved by inhibiting the glucosidase enzyme [30]. To date, there are a variety of drugs described as used for the inhibition of glucosidase such as miglitol, acarbose, and voglibose [31,32]. However, acarbose is excreted in faeces because of weak absorption; similarly, voglibose is excreted through stools while being absorbed only poorly and slowly. In contrast to acarbose and voglibose, miglitol is actually absorbed fully in the gut [33,34]. A substantial variety of Schiff bases have been synthesized which are distinct by their substitution patterns. Among these, anionic salicylaldehyde-derived Schiff base ligands are particularly prominent since they can at least partially balance the charge of the central metal ion in their complexes [35,36,37,38,39]. Salicylaldehyde-derived Schiff base ligands like H-QMP [39], CIMP and BIMP [38] have been observed to possess attractive anti-enzymatic activities. The aim of this study was, hence, to synthesize a related Schiff base ligand, 4-{(Z)-[(2-hydroxy-1-naphthyl)methylene]amino}-4-antipyrene (H-NAPP), by reacting 1-hydroxy-2-naphthaldehyde with 4-aminoantipyrine [37]. This known ligand and products from its reactions with divalent metal ions were investigated for their infrared (IR)-spectroscopic properties and elemental composition, and submitted to a study of their potential biological activity.

2 Experimental

2.1 Chemicals and reagents

All the chemicals like 4-aminoantipyrine, 1-hydroxy-2-naphthaldehyde, α-glucosidase (Saccharomyces cerevisiae), p-nitro-phenyl-α-d-glucopyranoside (p-NPG), PBS, NaCl, KCl, Na2HPO4, and KH2PO4 used in synthetic or biological manipulations were obtained from local Sigma Aldrich suppliers. The metal acetate salts were obtained from Riedal-de-Haen.

2.2 Instrumentation

The Varian Elementar II instrument was used for determining the elemental composition (experimental). Vario 6, Analytic Jena atomic absorption spectrophotometer, was used for determining the metal ion content. A PerkinElmer spectrophotometer version 10.4.00 with serial number 95120 made in Lliantrisant, UK, was used for recording the ATR spectra of all the samples. 1H-NMR and 13C-NMR spectra of the Schiff base ligand and zinc complex were recorded using a BRUKER advance III 400 spectrometer.

2.3 Crystal structure determination

A glass fibre was mounted with crystals of the ligand in innocuous paraffin oil. On an STOE-IPDS 2T diffractometer using graphite-monochromated Mo-K radiation (λ = 0.71073), data were collected at 170 K. Diffraction profile integration was done using the STOE program X-area, and numerical absorption adjustments were done using X-Shape and X-Red32. Dual space methods (SHELXT-2016) [40] were used to solve the structures, and full-matrix least-squares approaches (using the WingX GUI and SHELXL-2018 [41,42]) were used to enhance them. Anisotropic displacement parameters were refined for all non-hydrogen atoms. The hydrogen atoms were refined isotropically on calculated locations using a riding model, with their Uiso values constrained to 1.5 Ueq of their pivot atoms for terminal sp3 carbon atoms and 1.2 times for all other carbon atoms. The hydrogen atoms, except for the alcoholic H in the ligand, were refined isotropically on calculated positions. There are several known ligand structures, including those with the same cell characteristics and space groups. The additional information file contains crystallographic information, and the structure was sent to the CCDC via the CCDC-number 2129010 for H-NAPP; data may be requested from the Cambridge Crystallographic Data Centre via FAX (+44-1223-336-033), email (, or their online interface (at

2.4 TG-DTA analysis

Perkin Elmer’s TG/DTA Diamond model was used to record the TG-DTA thermograms of the synthetic compounds at a rate of 10°C per minute between 30 and 1,000°C in the presence of air. Samples of particular masses were placed in ceramic pan crucibles that were adjusted to the support of the platform, and proportional signals were computationally recorded. The plots of sample mass loss against temperature for TG and microvolts versus temperature for DTA were used to represent the results of mass changes with reference to the thermal decomposition of alumina.

2.5 α-Glucosidase inhibitory assay

An improved approach from Rouzbehan et al. [43] was used to determine the α-glucosidase activity. In a nutshell, 210 µL of reaction mixtures was added to each well (20 µL of the sample that was serially diluted with DMSO, 20 µL of α-glucosidase enzyme, 130 µL of PBS, and 40 µL of substrate p-NPG). The blank included only 210 µL of DMSO, while the control contained 20 µL DMSO + 20 µL α-glucosidase enzyme + 130 µL PBS + 40 µL α-PNPG. Five serial dilutions of 20 µL of each sample in DMSO were performed. Following the addition of 20 µL of the α-glucosidase enzyme, 130 µL of phosphate buffer (pH 6.8) was added. p-NPG (40 µL) was added and incubated for 15 min at 37°C. A 405 nm ELISA Plate Reader was used to measure the absorbance. The IC50 value for the α-glucosidase inhibitory assay was obtained. The benchmark chosen was acarbose and the experiments were performed in triplicate.

2.6 Synthesis of H-NAPP

The synthetic procedure along with spectroscopic characterizations has been reported in our earlier study [37].

2.7 Synthesis of M-NAPP where M = Co2+, Ni2+, Cu2+, and Zn2+ introduced as acetates

About 0.2929 mmol or 0.1 g of the ligand (H-NAPP) was mixed with 0.5858 mmol of the divalent metals ion acetate {[M(CH3COO)2], where M = Co(ii), Ni(ii), Cu(ii), and Zn(ii)} salts in a minimum amount of dried methanol and the mixture was stirred for 6–8 h at room temperature. For Ni-NAPPP and Zn-NAPP adducts, the mixtures were refluxed for 3–4 h at 100°C. After metal complex or adduct formation, they were filtered off and washed with dry n-hexane (Scheme 2):

Scheme 2 
                  Synthetic scheme of metal complexes.
Scheme 2

Synthetic scheme of metal complexes.

2.7.1 Cobalt complex with H-NAPP [Co-NAPP]

Colour: light brown, m.p.: 210–215°C, IR (cm−1): 3057.96(w), 1643.82(m), 1588.72(m), 1530.48(w), 1488.31(w), 1477.33(w), 1428.71(s), 1388.34(m), 1335(s), 1279.03(w), 1247.81(s), 1167.31(w), 1150.04(m), 1130.40(m), 1067.30(m), 1047.89(w), 1022.80(w), 972.04(w), 941.39(m), 920.07(m), 900(s), 880.46(s), 836.50(s), 763.39(s), 750.33(s), 702.85(s), 680.01(w), 666.24(w), 629.54(m), 585.76(s), 570.93(m), 530.32(m), 500(s). Elemental analyses: Calc. C(67.83%), H(4.34%), Co(7.92%), N(11.30%) Found. C(66.98%), H(5.47%), Co(08.03%), N(11.21%).

2.7.2 Nickel complex with H-NAPP [Ni-NAPP]

Colour: sea green, m.p. : 240°C, IR (cm−1): 3055.87(w), 1639.57(s), 1619.53(s), 1588.04(s), 1568.62(s), 1478.93(w), 1453.53(s), 1420.70(s), 1396.21(s), 1333.94(s), 1304.31(m), 1281.22(s), 1249.44(s), 1185.23(m), 1138.73(m), 1087.17(s), 1047.92(w), 1031.78(w), 958.36(w), 881.87(s), 858.72(m), 822.14(S), 775.84(m), 761.63(m), 745.31(S), 723.56(m), 699.47(S), 680.91(s), 637.97(s), 622.00(m), 583.49(S), 542.97(s), 507.55(m), 481.34(s). Elemental analyses: Calc. C(67.85%), H(4.34%), N(11.30%), Ni(7.89%) Found. C(67.31%), H(4.41%), N(08.23%), Ni(11.98%).

2.7.3 Copper complex of H-NAPP [Cu(NAPP)OAc]

The synthesis and characterization are given in our earlier study [37]

2.7.4 Zinc complex with H-NAPP [Zn-NAPP]

Colour: light orange, m.p.: 182–186°C, IR (cm−1): 3053.20(w), 1636.74(s), 1619.68(w), 1590(s), 1557.64(w), 1488.42(w), 1453.28(s), 1430(w), 1356(s), 1311.93(s) 1248.33(w), 1185.60(s), 1141.12(s), 1086.71(w), 1050.99(w), 1020.02(s), 951.98(m), 912.13(w), 856.81(m), 820.93(S), 774.84(s), 763.07(m), 743.12(S), 722.37(w), 700.25(S), 638.30(w), 621.48(S), 582.32(S), 536.21(m), 505.63(m), 481.58(s). Elemental analyses: Calcd C(67.25%), H(4.30%), N(11.20%), Zn(8.72%); found: C(67.55%), H(4.76%), N(11.01%), Zn(9.23%).

3 Results and discussion

The Schiff base ligand H-NAPP was prepared as shown in Scheme 3.

Scheme 3 
               Synthesis of the H-NAPP Schiff base ligand.
Scheme 3

Synthesis of the H-NAPP Schiff base ligand.

The anionic Schiff base ligand is an NOO-type of donor ligand; therefore, its coordination behavior was also studied.

3.1 Crystal studies

The Schiff base H-NAPP has also been characterized by single crystal diffraction analysis. The single crystal of the ligand was grown from the concentrated methanolic solution of the Schiff base ligand. The H-NAPP Schiff base ligand was crystalized in the P 21 21 21 space group [44]. The molecular structure and the packing pattern of the ligand are shown in Figure 1, whereas the crystal data are given in the supplementary information. The Schiff base linkage C12–N3 is 1.288(15) Å long, comparatively shorter than similar bond lengths as found in H-HMAC zwitterionic Schiff base ligand (C9–N8 = 1.291(7) Å) [36].

Figure 1 
                  (a) The ORTEP plot and (b) crystal packing diagram of the H-NAPP Schiff base ligand.
Figure 1

(a) The ORTEP plot and (b) crystal packing diagram of the H-NAPP Schiff base ligand.

A considerable decrease was observed in the relative amounts of the light atoms in their elemental analyses supporting the reactions between transition metal salts and the ligand, at least in the formation of a complex between the ligand and transition metal cation. The melting temperatures were also observed designating the formation of a metal complex (see Section 2).

3.2 Infrared studies

After assessing the IR spectra of the metal complexes, a shift in the characteristic bands of the ligand has been observed. The cobalt(ii) NAPP pair exhibits a medium sharp peak around 1,643 cm–1. This peak is shifted by about 7 cm–1 in comparison to the free Schiff base ligand to higher wavenumbers. This suggests that the lactonic carbonyl oxygen bond has an increased strength upon reaction with the transition metal salt instead of a decreased one, which would have been the result of C═O coordination to Co2+. The –HC═N stretching frequency is shifted by a small increment. The –OH peak is completely absent in the spectrum of the complex. It can be concluded that at least some kind of complex must have formed (absence of O–H bands), and possibly the ligand coordinates with cobalt(ii), which decreases resonance effects in the ligand and thereby stabilizes the C═O double bond (i.e. or impairs its participation in the resonance of the molecule). If proper coordination does indeed take place, it is most likely that –OH and –HC═N moieties are involved in bonding [45].

In the nickel(ii) NAPP combination, the carbonyl frequency of the lactone oxygen is displaced to 1,639 cm–1, i.e. again to higher wavenumbers. The effect is minimal, though. The HC═N stretching frequency is obtained at the same position as in the free ligand. Notably, a weak band around 3,055 cm–1 appears, which is tentatively assigned to an N–H frequency, which would arise from the vibration caused by intramolecular hydrogen bonding due to OH and HC═N moieties. Overall, there is no clear indication that a complex has formed, while the ligand is transformed by the reaction, at least to some extent.

The IR spectrum of the Cu-NAPP complex revealed a clear displacement of the lactone vibration from the 1,636 cm–1 region in the free ligand to 1,623 cm–1 in the Cu-NAPP complex. This clearly indicates a weakening of the C═O double bond due to the coordination of copper(ii) by the C═O oxygen. Along with it, the HC═N stretching frequency has also been displaced to 1,556 cm–1, clearly indicating the coordination through this site. Acetate ions acting as counter ions also appeared around 1,358 cm–1. The IR data clearly indicate that in Cu-NAPP, the alcoholate moiety, the C═O oxygen, and the H–C═N group coordinate copper, with the likelihood of an additional interaction with oxygen from acetate [37].

The IR spectrum of the zinc(ii) NAPP pair is similar to those of cobalt(ii) and nickel(ii). The –OH stretching band is completely absent from the spectrum, confirming deprotonation. The band at 3,053 cm–1 is tentatively assigned to an N–H vibration similar to the Ni-NAPP combination. The lactone vibration is observed at 1,638 cm–1 as in the free ligand, suggesting an absence of any interaction of the C═O moiety with the metal ion. Rest is like the other metal–ligand combinations.

3.3 UV/visible studies

Further, confirmation was carried out by UV/visible analyses in the region of 300–850 nm. The UV spectrum of Co-NAPP shows a strong absorption band at 460 nm, which was assigned to the 2A2g→2B1g transition. Similarly, a shoulder absorption peak at 370 nm was also observed, which was assigned to the 2A22A1 forbidden transition. The crystal field splitting parameters reveal a high value of 2.73 eV, responsible for the splitting of dyz and dxy orbitals. Therefore, the complex may be assigned to distorted square planar geometry.

The Ni-NAPP also revealed an absorption peak at 470 nm, assigned to the 1A1g→1A2g charge transfer transition. The CFSE value of 2.65 eV is almost similar to the Co-NAPP, and therefore assigned the same geometry. The absorption in the Cu-NAPP complex appeared as a single curve at 360 nm, assigned to the 2E→2T transition. From the absorption studies, it can be concluded that the pi electrons from phenolate ions are pushed to the metal centre, which are accommodated in dπ* orbitals. The electrons from the –C═N moiety also cause some weak absorptions. Therefore, in the NAPP-derived Schiff base metal complexes, both phenolate oxygen group and azomethine are involved in bonding. Zn-NAPP was also presumed to be distorted square planar in the predicted geometry.

3.4 Hirshfeld surface analysis

The intermolecular interactions in the crystals of H-NAPP can be verified by studying the Hirshfeld surface analysis. Intermolecular interactions are of immense importance in studying enzymatic interactions of the test compound and the active sites. Stronger intermolecular interactions in the crystal lattice are shown as red patches on the d norm surface plot. The computation of the d norm surface plot is done by measuring the d e (external) and d i (internal) distances to the nearby atoms.

The Hirshfeld surface area of the HNAPP ligand covers an area of 403.66 Å2 and spreads over the 447.21 Å3 volume. The iso value was found to be 0.5 with 0.701 globularity. The scaled-coloured patched index of H-NAPP can be seen in Figure 2, whereas the quantitative and predicted 2D fingerprint plot may be seen in Figure 3. The short atomic contacts H···H = 45.8%, C···C = 1.8%, C···H = 19.1%, C···N = 0.9%, and H···O = 6.1% suggest that the major supports are from H···H, C···H, and H···O compared to the other atomic interactions.

Figure 2 
                  The d
                     norm plot decorated Hirshfeld surfaces in different directions of the H-NAPP lattice.
Figure 2

The d norm plot decorated Hirshfeld surfaces in different directions of the H-NAPP lattice.

Figure 3 
                  2D fingerprint plots of short intermolecular interactions with their associate contributions to the HS in the crystal lattice of H-NAPP: (a) all atoms interactions, (b) H···H, (c) C···H/H···C, (d) N···H/H···N, and (e) O···H/H···O.
Figure 3

2D fingerprint plots of short intermolecular interactions with their associate contributions to the HS in the crystal lattice of H-NAPP: (a) all atoms interactions, (b) H···H, (c) C···H/H···C, (d) N···H/H···N, and (e) O···H/H···O.

3.5 Thermal studies of Schiff base metal complexes

All four synthesized complexes or adducts were studied for their thermal degradation within the temperature range of 30–1,000°C. The thermal curves of the metal complexes or adducts are shown in Figure 4. The ligand H-NAPP decomposes in a single step of degradation, and no residue is left behind. The ligand most likely decomposes into carbon dioxide, carbon monoxide, H2O, and nitrogen oxide species, as shown in Scheme 4. The transition metal complexes/adducts of the H-NAPP ligand decompose in two steps of degradation leaving behind the metal oxides as residues. The Co-NAPP adduct starts decomposing at 205°C, and this first step of decomposition ends at 215°C. The second step of decomposition is initiated at 216°C and ends at 430°C. The third stage of degradation is covered from 431 to 470°C. Beyond 470°C, only CoO was observed as a residue.

Figure 4 
                  TG and DTG curves of metal adducts with the H-NAPP Schiff base ligand.
Figure 4

TG and DTG curves of metal adducts with the H-NAPP Schiff base ligand.

Scheme 4 
                  Thermal degradation of H-NAPP and its metal adducts.
Scheme 4

Thermal degradation of H-NAPP and its metal adducts.

C43H36N7O4nCO x + H2O + nNOx

M(C43H36N7O4)nnCO x + H2O + nNOx + MO↓

Similarly, the temperature windows for each step of degradation and the corresponding moieties are shown in Table 1. Overall, the stability for all the synthesized metal complexes/adducts appears to vary in the order Zn-NAPP > Ni-NAPP > Cu-NAPP > Co-NAPP. This indicates that at least for zinc and nickel, some type of actual coordination takes place since their combinations with the ligand appear to be more stable than the copper complex, which was proven to bear real coordinative ligand–metal bonds.

Table 1

Thermoanalytical data of metal adducts with H-NAPP

Compounds Stage of degradation TG temperature range (°C) % Mass loss Moieties released
Co-NAPP 1st 30–430 67.21
2nd 431–470 13.11
>470 Residue CoO
Ni-NAPP 1st 30–392 32.78
2nd 393–650 55.73
>650 Residue NiO
Cu-NAPP First 30–360 36.66
Second 360–560 18.33
Third 560–640 12.50
>640 Residue CuO
Zn-NAPP First 30–455 50.00
Second 455–660 41.02
>660 Residue ZnO

3.6 Enzyme inhibitory studies

In the realms of pharmaceuticals and disease therapy, the design of an enzyme inhibitor is recognized as being of paramount importance. Drugs with clearly defined effects can be created because of the substrate specificity of enzymes, which may only recognize a single molecular location. Metals serve as cofactors in many enzymes, which are essential for their structural stability and catalytic activity. Therefore, medications made with metal are quite important. Enzymes with accessible active site pockets or channels seem to be natural candidates for inorganic medicines. α-Glucosidase inhibitors (AGIs) are considered antihyperglycaemic medications because they inhibit intestinal α-glucosidase enzymes in a competitive and reversible manner. Therefore, postprandial blood glucose spikes are diminished and glucose absorption is slowed down. As a result, better glycaemic management is made possible [46]. At present, few AGIs have been selected as anti-glucosidase medicines, such as 1-deoxynojirimycin and voglibose [31]. However, due to their side effects, a search for better anti-glucosidase drugs is continuing constantly.

The synthesized Schiff base ligand (H-NAPP) and its metal complexes or adducts were tested for their α-glucosidase inhibitory activities. The results are summarized in Table 2. Surprisingly, only the free ligand and its copper complex were found to be active against α-glucosidase. This supports the findings of the IR study, i.e. only for copper coordination, three obvious donor sites could be verified, and for the other three metals, something different may occur. The adducts between the same ligand and cobalt(ii), nickel(ii), and zinc(ii) were only marginally active giving substantially lower percent inhibitory values. IC50 values could not even be determined for a lack of activity. Possibly, in contrast to copper(ii), the other three metals bind the ligand in a position that is responsible for its biological activity, thereby blocking it. Or, the interaction between transition metals and ligand force the latter into an inactive conformation. The data obtained through this study, unfortunately, do not allow for a respective in-depth analysis.

Table 2

In vitro α-glucosidase inhibition assay

Compounds Concentration (μM)a IC50 (μM ± SEM)
H-NAPP 0.5 1.473 ± 0.001
Co-NAPP 0.5
Ni-NAPP 0.5
Cu-NAPP 0.5 3.705 ± 0.001
Zn-NAPP 0.5
Standard 0.5 94.42 ± 11.60

aThe concentrations of cobalt(ii), nickel(ii), and zinc(ii) complexes are estimated based on the assumption that their composition mirrors that of the copper(ii) complex.

Previously a copper–picolinic acid complex has also been tested for α-glucosidase inhibitory activities [47]. It was observed that copper complexes impart similar effects on the α-glucosidase enzyme as observed for Acarbose or other drugs. After clinical applications, more specific copper-based AGIs may be designed. In the best-case scenario, the copper complex may not cause side effects as acarbose. Previously, it has been suggested that copper complexes inhibited α-glucosidase activities in the epithelium of the small intestine and hence decreased disaccharide digestion [47]. The same explanation may possibly be applied to the observed inhibitory activity of the Cu-NAPP complex in this study.

4 Conclusion

The monoanionic ONO type, possibly tridentate ligand H-NAPP, is the Schiff base ligand. The molecular and chemical structures of the ligand had been conclusively determined from a crystal structure. The transition metal complexes were produced by complexing the NAPP ligand with the metal ions Co2+, Ni2+, Cu2+, and Zn2+, respectively. The copper(ii) complex’s ligand coordination through azomethine, hydroxyl, and lactone carbonyl moieties were identified. Between the two coordination monomers of the Cu-NAPP complex, a bridging acetate group was also discovered. This information makes up the initial structural analysis of a complex containing this specific ligand. The thermal stabilities of all the synthesized metal complexes were studied in air. It was found that the Zn-NAPP adduct is most stable followed by Ni-NAPP. The Co–NAPP complex was the least stable of the four compounds. Moderate glucosidase inhibition activities were only found for the free ligand and its copper(ii) complex. The other three complexes, surprisingly, were entirely inactive.


The authors acknowledge the Abdul Wali Khan University Mardan, Pakistan, for providing financial assistance from research innovation funds.

  1. Funding information: Authors are thankful to researchers supporting project number (RSP2023R235), King Saud University, Riyadh, Saudi Arabia and Higher Education Commission Pakistan {NRPU sponsored project no. Ref No. 20-14898/NRPU/R&D/HEC/2021-2020}.

  2. Author contributions: Conceptualization, Sadia Rehman; data curation, Muhammad Ikram, Adnan Khan, Mutasem Sinnokrot, Farzia Farzia, Rizwan Khan, and Muhammad Naeem; formal analysis, Adnan Khan, Mutasem Sinnokrot, Muhammad Naeem, and Carola Schulzke; funding acquisition, Muhammad Ikram; investigation, Muhammad Ikram and Sadia Rehman; methodology, Farzia and Rizwan Khan; project administration, Muhammad Ikram, Adnan Khan, and Sadia Rehman; resources, Muhammad Ikram, Momin Khan, and Adnan Khan; Software, Rizwan Khan and Adnan Khan; supervision, Sadia Rehman and Muhammad Naeem; validation, Muhammad Ikram and Sadia Rehman; visualization, Sadia Rehman; writing – original draft, Muhammad Ikram, Sadia Rehman, Mutasem Sinnokrot, Abdullah F. AlAsmari, Fawaz Alasmari, and Metab Alharbi; writing – review and editing, Muhammad Ikram, Mutasem Sinnokrot, Momin Khan, Abdullah F. AlAsmari, Fawaz Alasmari, and Metab Alharbi.

  3. Conflict of interest: The authors declare no conflict of interest.

  4. Ethical approval: This research is not related to either human or animal use.

  5. Data availability statement: All data generated or analysed during this study are included in this published article (and its supplementary information files). The structure was submitted to the CCDC. Data can be obtained free of charge from the Cambridge Crystallographic Data Centre by FAX (+44-1223-336-033), email (, or their web interface (at by quoting the CCDC-number 2129010 for H-NAPP.


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Received: 2023-08-05
Revised: 2023-10-10
Accepted: 2023-10-26
Published Online: 2023-11-20

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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