1 Introduction

Diabetes mellitus (DM) is a complex and chronic metabolic disorder of numerous etiologies characterized by hyperglycaemia with abnormalities in protein, fat and carbohydrate metabolism resulting from defects in insulin action, insulin secretion or both [1, 2]. The global pervasiveness of diabetes had outstretched rampant proportions with the 10th edition of the IDF reporting a prevalence of 536 million people in 2021 and these figures would hit to 783 million people in 2045 [3, 4]. Devastating microvascular complications (retinopathy, nephropathy and neuropathy) and macrovascular complications (stroke and acute coronary syndromes) lead to increased mortality, kidney failure, blindness, nerve damage and an overall reduced quality of life in individuals with this disease [5]. There are two types of diabetes; insulin-dependent-DM (IDDM) and non-insulin-dependent-DM (NIDDM). Over 95% of total diabetic patients are currently diagnosed with NIDDM and it results from the interaction between environmental, behavioural and genetic risk factors [6, 7]. Current therapeutic strategies used in the treatment of diabetes involve the suppression of postprandial hyperglycaemia [8, 9]. Alpha-amylase is a calcium metalloenzyme which facilitates digestion by breaking down polysaccharide molecules into low molecular weight products such as maltose and glucose. Alpha-glucosidase, which is located in the brush border of the enterocytes of the jejunum and catalyses the hydrolysis of 1,4-α bonds of the unabsorbed disaccharides or oligosaccharides to monosaccharides such as glucose [10, 11]. Alpha-amylase and alpha-glucosidase are well-known therapeutic targets for the treatment and maintenance of elevated postprandial blood glucose levels [12,13,14]. By inhibiting these enzymes, glucose absorption is postponed, which reduces postprandial blood glucose (PPG) spikes and aids in better glycaemic management. Commercially available pharmacotherapy of the ailment includes the use of several oral antihyperglycemic medications such as biguanides (metformin), alpha-glucosidase inhibitors (acarbose, miglitol, voglibose), sulfonylureas (glipizide, gliclazide, glyburide, glimepiride), and thiazolidinediones (pioglitazone, rosiglitazone), each of which have their specific drawbacks [15, 16]. Therefore designing and developing more efficient drugs for the treatment of diabetes with lesser adverse effects is a highly challenging task for the global healthcare system.

1,2,4-Triazole core has been incorporated into a wide variety of therapeutically interesting drug candidates including antibacterial agents, sedatives, antifungal agents, central nervous system stimulants, antivirals, anti-inflammatories and antitumor agents [17,18,19,20,21,22]. The biological potential of triazole rings are in particular due to their ease to interact with various bio molecular targets, high solubility, rigidity and propensity for hydrogen bond formation [23]. 1,2,4-triazole based ligands have achieved considerable attention in recent years owing to their auxiliary N-donor atoms that produce mono, bi and tridentate binding sites thereby increasing the stability due to the chelate effect [18]. Imine ligand forming transition metal complexes with cobalt, copper, nickel, and zinc ions are exclusively studied due to their enormous biological applications, photochromic effects, enzyme inhibitory properties and their imperative role in catalysis [24, 25].

Considering the imperative role of 1,2,4-triazole based ligands in medicinal chemistry and the significance of metallodrugs as possible antidiabetic agents, we managed to synthesize transition metal complexes of the Schiff base ligand bearing 1,2,4-triazole motif and further evaluate their coordination behaviour and bioactivity. Additionally, DFT and molecular docking studies for all the compounds have been carried out.

2 Materials and Instrumentations

The chemicals used i.e., 5-nitrosalicyladehyde (98%), 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (97%), cobalt acetate tetrahydrate (98%), nickel acetate tetrahydrate (98%), copper acetate monohydrate (≥ 98%), zinc acetate dihydrate (≥ 98%) in the present work were procured from Sigma Aldrich company. For in vitro antidiabetic investigations, alpha-amylase from Bacillus subtilis and alpha-glucosidase from Saccharomyces cerevisiae were purchased from Sigma Aldrich. IR spectra were measured on a Perkin Elmer BX II spectrophotometer from 4000 to 400 cm−1 using KBr matrix. 1H and 13C NMR spectra of the ligand and the zinc complex were recorded at 300 K with a BRUKER AVANCE II (400 MHz) spectrometer. A SCIEX Triple TOF 5600 and 5600+/SCIEX mass spectrometer outfitted with an electrospray ionisation source was used to generate ESI-MS spectra in the m/z range of 100–1000. X-ray diffraction data of the complexes was recorded on a Rigaku table-top diffractometer. CHN analyses were performed using a Thermo Scientific FLASH 2000 elemental analyser. ESR spectrum of copper complex was obtained on a JES-FA200 spectrometer, by using TCNE as a field marker. Electronic spectra were recorded in DMSO on a Varian Cary-5000 spectrometer at 298 K. Morphological studies (SEM with EDAX) were carried out using the JEOL 7610F plus instrument. Using an SDT Q600 thermal analyser, TGA studies were performed in the temperature range of 25–1000 °C in a dynamic nitrogen atmosphere (30 mL/min) with a heating rate of 0.1–100 °C per min.

2.1 Synthesis of Schiff Base Ligand

The tridentate ligand (H2L1) was prepared by the condensation of 5-nitrosalicylaldehyde (0.835 g, 5 mmol) with equimolar amount 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (0.966 g, 5 mmol) in methanol. The mixture was refluxed for 6 h at room temperature [26, 27]. The resulting compound was filtered, washed with ethanol and dried overnight over fused CaCl2. The composition of synthesized compound was well supported by elemental analysis, 1H NMR, and FT-IR data measurements. The synthesis of ligand is illustrated in Scheme 1.

Scheme 1
scheme 1

Schematic pathway for the synthesis of ligand and its transition metal complexes

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2-(((3-mercapto-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl)imino)methyl)-4-nitrophenol (H2L1) (1) Light yellow, Yield: 85%, M.p.: 170–172 °C, Conductivity (Ω−1 cm2 mol−1) in DMF: 9.1. Anal. calcd (%): C: 49.12, H: 2.94, N: 24.55, found: C: 49.01, H: 2.91, N: 24.51. 1H NMR (400 MHz, DMSO) δ: 14.14 (s, 1H), 11.39 (s, 1H), 9.83 (s, 1H), 9.13 (s, 1H), 8.80 (d, J = 6.4 Hz, 1H), 8.45 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 13C NMR (100 MHz, DMSO) δ: 165.80, 161.07, 159.05, 156.19, 150.78, 148.13, 140.98, 136.10, 132.08, 129.46, 125.17, 124.04, 119.45, 115.97. HRMS: m/z calcd (M+H)+: 343.0608, found: 343.0612. FTIR (KBr, cm−1): 3306 (O–H), 2561 (S–H), 1614 (>C=N), 1078 (>N–N<).

2.2 Synthesis of the Transition Metal Complexes

In order to prepare metal(II) complexes (2-5), the metal precursors Co(CH3COO)2·4H2O (0.747 g, 3 mmol)/Ni(OCOCH3)2·4H2O (0.746 g, 3 mmol)/Cu(CH3COO)2·H2O (0.598 g, 3 mmol)/Zn(CH3COO)2·2H2O (0.658 g, 3 mmol) were added to a hot solution of the ligand (1.026 g, 3 mmol) in Methanol: DMF (1:1). The mixtures were stirred for 5–7 h at room temperature [28] and the resultant suspensions were filtered, washed thoroughly with ethanol, diethyl ether and dried over vacuum (Scheme 1).

[Co(L1)(H2O)3] (2) Yellow, Yield: 77%, M.p.: 220–222 °C, Conductivity (Ω−1 cm2 mol−1) in DMF: 14.1. Anal. calcd (%): C: 37.09, H: 3.11, N: 18.54, found: C: 37.01, H: 2.91, N: 18.51. HRMS: m/z calcd (M+H)+: 454.0101, found: 454.0104. FTIR (KBr, cm−1): 3410 (M–H2O), 1597 (>C=N), 1090 (>N–N<), 535 (M–O), 474 (M–N), 408 (M–S).

[Ni(L1)(H2O)3] (3) Yellow, Yield: 79%, M.p.: 228–234 °C, Conductivity (Ω−1 cm2 mol−1) in DMF: 15.2. Anal. calcd (%): C: 37.11, H: 3.11, N: 18.55, found: C: 37.11, H: 2.99, N: 18.59. HRMS: m/z calcd (M+H)+: 453.0122, found: 453.0128. FTIR (KBr, cm−1): 3402 (M–H2O), 1599 (>C=N), 1067 (>N–N<), 534 (M–O), 473 (M–N), 409 (M–S).

[Cu(L1)(H2O)3] (4) Yellow, Yield: 81%, M.p.: 218–227 °C, Conductivity (Ω−1 cm2 mol−1) in DMF: 15.9. Anal. calcd (%): C: 36.72, H: 3.08, N: 18.35, found: C: 36.71, H: 3.08, N: 18.29. HRMS: m/z calcd (M+H)+: 458.0064, found: 458.0058. FTIR (KBr, cm−1): 3391 (M–H2O), 1596 (>C=N), 1075 (>N–N<), 525 (M–O), 459 (M–N), 407 (M–S).

[Zn(L1)(H2O)3] (5) Yellow, Yield: 84%, M.p.: 210–219 °C, Conductivity (Ω−1 cm2 mol−1) in DMF: 16.2. Anal. calcd (%): C: 36.57, H: 3.07, N: 18.28, found: C: 36.51, H: 3.05, N: 18.23. 1H NMR (400 MHz, DMSO) δ: 10.24 (s, 1H), 9.18 (s, 1H), 8.94 (d, J = 7.4 Hz, 1H), 8.54 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 13C NMR (100 MHz, DMSO) δ: 166.57, 162.69, 159.31, 158.60, 150.89, 148.17, 141.43, 136.37, 132.88, 129.59, 125.25, 124.11, 119.78, 116.15. HRMS: m/z calcd (M+H)+: 459.0060, found: 459.0064. FTIR (KBr, cm−1): 3418 (M-H2O), 1598 (>C=N), 1069 (>N–N<), 529 (M–O), 467 (M–N), 406 (M–S).

2.3 Computational Methodology

2.3.1 Density Functional Theory Calculations

The Dell EMC PowerEdge r750xs GPU enabled high performance linux supercomputing machine with standalone version of Gaussian 16 [29] enabled programs were used to perform DFT calculations using the Gaussian 16 program package with the B3LYP hybrid functional [30, 31] and the standard 6-311++G basis set. The lower basis sets were used to optimize the geometries of the compounds in the gas phase. The geometry optimizations of these structures were performed out to determine the stationary states for each structure. The transition state structures were defined by the existence of one imaginary frequency in the frequency calculations. A distinguishing feature of transition state structures was the presence of one imaginary frequency in frequency computations. The energy values for the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), and the energy gap were calculated using the FMO analysis. The molecular structures were visualized using Gaussview 06. The electron affinity was related to LUMO and ionization potential was related to HOMO owing to their electron accepting and electron donating tendencies [32]. Global reactivity descriptors explain the overall stability and reactivity of a molecular system which include electronegativity, dipole moment, global hardness, global softness and electrophilicity index.

2.3.2 Molecular Docking

The structure of hit compounds were sketched and optimized in 2D and 3D using Chemsketch. The X-ray crystallographic structures of human pancreatic alpha-amylase (PDB id: 1BSI) [33] and alpha-glucosidase (PDB id: 5ZCC) [34] were retrieved from the protein data bank. After eliminating water molecules, cofactors and ions, hydrogen atoms were added. At pH 3.0, protonation and tautomeric states were altered. Computational investigations of docking were carried out using AutoDock and suitable binding conformations with the highest negative docking score corresponding to the lowest RMSD values were rooted out and investigated [35,36,37,38,39,40,41].

2.3.3 Biological Assay

The alpha-amylase and alpha-glucosidase inhibitory potential for the synthesized compounds was determined according to the protocol described by Xiao et al. [9, 42, 43].

3 Results and Discussion

3.1 Chemistry

Condensation of 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol with equimolar amount of the 5-nitrosalicylaldehyde, results to the formation of an important tridentate ligand (H2L1) in 85% yield in methanol. Treatment of the ligand (H2L1) with the corresponding metal acetates in a 1:1 M ratio under stirring condition led to the preparation of new metal chelates. The solid metal chelates formed were non-hygroscopic, stable at room temperature, moderately soluble in most of the organic solvents such as chloroform, acetonitrile, methanol and ethanol, but were completely soluble in DMSO and DMF. Attempts made to isolate single crystal of the produced compounds were not successful.

3.2 FTIR

By carefully comparing the IR spectrum of the free ligand with those of its metal chelates, the mode of bonding in metal chelates can be facilely accomplished. The obtained outcomes were depicted in Figs. S1-S5 and Table T1 of the supplementary. The comparison demonstrated that the absorption band arising in the spectrum of the ligand at 1694 cm−1 was due to the azomethine group, which shifts to a slightly lower wavenumber by 15–20 cm−1 in the spectra of complexes, implying coordination to the metal centre via the azomethine nitrogen [44, 45]. Coordination of azomethine N to metal ions reduces the electron density of v(> C=N–) by back-bonding from metal to the π∗ orbital of the azomethine group. The IR spectrum of the ligand revealed a distinctive band at 3293 cm−1 due to v(O–H) stretching vibrations, which vanishes in complexes, thereby suggesting that the –OH group was involved in coordination with the metal atom via deprotonation [46]. Another protrusive band appearing in the ligand at 2579 cm−1 was due to the v(S–H) group, which gets disappeared in complexes thereby confirming the participation of sulphur in bonding. The phenolic oxygen, imino nitrogen and thiol sulphur coordination could also be confirmed by the emergence of weak bands located at lower wavenumbers i.e. 540–520, 476–445 and 410–406 cm−1, which may be designated to ν(M–O), ν(M–N) and ν(M-S) respectively [47, 48]. In complexes, absorption bands executing in the domain of 3337–3417 cm−1 was due to the presence of coordinated water molecules in the complexes [44]. Additionally, the coordination of water molecules is also supported by rocking and wagging modes of vibration of ν(–OH) at 722–780 cm−1 and 738–795 cm−1. Based on IR measurements, it can be concluded that the ligand behaves in a binegative tridentate manner and coordinates to the metal ions via deprotonated oxygen, azomethine nitrogen and deprotonated sulphur.

3.3 1H NMR

The NMR spectroscopy is a powerful method for detecting chemical species and forms of molecular interactions in complex materials. The NMR spectral analysis offered a comprehensive account that is deemed suitable for proton (1H) and carbon (13C) assignments. The 1H NMR spectra of ligand (1) and its zinc(II) complex (5) were recorded in DMSO-d6 solvent. The obtained results were summarized in Fig. S6 and S7 of the supplementary. In the spectrum of ligand, signals at δ 14.14 and 11.39 ppm corresponded to –SH [49] and –OH [50] proton attached to 1,2,4-triazole and aldehyde ring respectively. Another singlet at δ 9.83 ppm was attributed to proton of azomethine group, but in the zinc(II) complex, –HC=N– exhibited a signal at δ 10.24 ppm [51]. The disappearance of phenolic proton, thiol proton and shifting of –HC=N– signal (downfield) confirmed the coordination of phenolic oxygen, thiol sulphur and imine nitrogen to the metal ion [52]. In ligand, a singlet matching to one aromatic proton of the salicylaldehyde ring was discovered at δ 8.45 ppm, however the two remaining neighbouring aromatic protons of the salicylaldehyde ring were observed at δ 7.08 ppm and 7.98 ppm. In the complex, the signals due to aromatic protons of pyridine and aldehyde ring remained very less impacted by complexation, further confronting that these protons were not involved in complexation. The obtained results were in accordance with the literature reported values.

3.4 13C NMR

The 13C NMR spectra of synthesized Schiff base ligand (1) and its zinc(II) complex (5) were recorded in DMSO. The obtained spectra were depicted in Fig. S8 and S9 of the supplementary. The spectrum of Schiff base ligand exhibited a signal at δ 159.05 ppm which could be assigned to azomethine carbon. The azomethine (>C=N–) carbon shifted downfield upon complexation and its signal appeared at δ 159.31 ppm [53]. This deshielding signified that the azomethine nitrogen was involved in complexation with the metal atom. The signal of carbon attached to the hydroxyl group in the ligand was obtained at δ 165.80 ppm [54], which upon complexation shifted to δ 166.57 ppm, indicating the coordination of ligand via oxygen to the central metal atom. The peaks observed due to aromatic carbons of the Schiff base ligand remain unchanged in complexes, indicating their non-participation in bond formation with the central metal atom. 13C NMR spectral data helped to elucidate the proposed structures.

3.5 Mass Spectra

Mass spectrometry is an analytical technique for determining the mass to charge ratio of ions and to provide valuable information on how ligands and their metal complexes form. The obtained spectra are depicted in Figs. S10-S14 of the supplementary. The spectrum of ligand showed the molecular ion peak at m/z 343.0612 corresponding to C14H10N6O3S. The mass spectra of cobalt(II), nickel(II), copper(II) and zinc(II) complexes showed molecular ion peaks at m/z 454.0104, 453.0128, 458.0058 and 459.0064 respectively, due to [M+H]+ and these peaks corresponded very well with their molecular formulae [55].

3.6 Electronic Spectra

The electronic spectra of the compounds were recorded in DMSO and the obtained results are summarized in Table 1 and Fig. S15 of the supplementary. The Schiff base ligand exhibits two strong bands at 36,400 and 27,540 cm−1 which were attributable to π → π* and n → π* transitions of aromatic ring. Three spin-allowed transitions i.e. 4T1g(F) → 4T1g(P), 4T1g(F) → 4A2g(F) and 4T1g(F) → 4T2g(F) in the electronic spectrum of Co(II) complex (2) were observed at 21,380, 16,310, and 9546 cm−1 respectively, thereby suggesting an octahedral framework for the cobalt complex. The cobalt complex was found to have a magnetic moment value of 4.86 BM. The spectrum of nickel(II) complex (3) showed three absorption bands at 23,507, 18,182, and 10,452 cm−1, which were attributed to the transitions 3A2g(F) → 3T1g(P), 3A2g(F) → 3T1g(F) and 3A2g(F) → 3T2g(F), respectively. The magnetic moment value of the nickel complex was estimated to be 2.91 BM. For copper(II) complex (4), an octahedral geometry with magnetic moment of 1.9 BM was suggested by two absorption bands at 24,782 and 13,760 cm−1, which were ascribed to the transitions 2B1g → 2E2g and 2B1g → 2A1g [56]. The electronic spectra of zinc complex (5) exhibit only one transition corresponding to ligand to metal charge transfer. Due to completely filled d-orbitals of zinc(II) ion, there was no possibility for d–d transitions. Also, zero magnetic moment value indicated diamagnetic nature of zinc(II) complexes.

Table 1 Electronic spectra of synthesized compounds
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3.7 Molar Conductivity

The molar conductance of the compounds (1–5) was measured in DMF at room temperature and it ranges from 9.1 to16.2 Ω−1 cm2 mol−1, indicating that the complexes behave as non-electrolytes [57].

3.8 Electron Spin Resonance Spectra

The ESR spectrum of copper(II) complex (4) was recorded in DMSO solvent at room temperature. From the ESR spectrum of Cu(II) complex (Fig. S15 of supplementary), the g value sequence and additional factors g║ = 2.35, g⊥ = 2.09, gavg = 2.176 and G = 3.96 were calculated. These values could be utilized to derive the ground state using the g tensor quantity principles. The values of g║, g⊥ and gavg in this particular configuration supported the formation of octahedral complexes [58]. Additionally, the value of g║ = 2.35 specified that this chelate contain mixed copper-nitrogen and copper-oxygen bonds. According to Hathway and Billing, if the value of G > 4.0 [59], then we could consider insignificant exchange interactions between Cu(II) centres in the solid state and if the value of G ˂ 4.0, then there would be considerable exchange interactions. Here, G value was found to be 3.96, indicating that exchange interactions were operative. The calculated magnetic moment for complex was found to be 1.89.

3.9 Thermogravimetric Analysis

Thermogravimetric study of the metal complexes has been performed within the temperature range of 22–990 °C and the obtained results are summarized in Table 2 and Fig. S16 of supplementary. Three phases of breakdown was observed in the nickel complex (3). In the first stage, water molecules started to disappear (calc. = 11.9%, obs. = 11.09%) [60]. In the subsequent stage, loss of C7H4N2O2 (calc. = 32.69%, obs. = 32.51%) fragment took place in the temperature range of 168–396 °C. The mass loss of 38.88 percent (calc. = 38.65%) was observed in third decomposition step which corresponded to loss of the organic moiety i.e. C7H4N4S in the temperature range of 396–691 °C leaving behind NiO as the residue.

Table 2 Thermogravimetric data of complexes
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figure b

Similar decomposition pattern was observed for Co(II), Cu(II) and Zn(II) metal complexes.

3.10 X-Ray Diffraction

To study the nature of synthesized materials whether crystalline or amorphous, XRD proves to be an indispensable tool. The XRD analyses were performed at a wavelength of 1.5406 Å in the 2θ range of 20–80° and the obtained difractograms are presented in Fig. 1. The peaks in ligand appears at 10.09°, 12.21°, 14.16°, 15.27°, 20.34°, 24.61°, 26.16°, 27.79°, 29.37°, 32.63°, 34.17° and 35.92°. The two characteristics peaks appearing at 2θ = 16.45° and 22.57°, authenticate the formation of azomethine linkage. The peaks in cobalt complex (2) arise at 12.29°, 13.92°, 16.97°, 23.49°, 24.53°, 27.29°, 31.17°, 36.73° and 38.51° angles. The peaks in nickel complex (3) were obtained at 12.97°, 13.42°, 18.98°, 21.96°, 26.57°, 27.61°, 31.37°, 32.34°, 34.69° and 38.51° angles. Copper complex (4) exhibited peaks at 12.79°, 18.97°, 21.99°, 23.56°, 25.99°, 28.79°, 32.36°, 37.49° and 39.41° angles. The peaks for zinc complex (5) appeared at 13.91°, 15.49°, 16.32°, 18.92°, 21.29°, 24.39°, 26.95°, 28.61° angles. The XRD pattern of ligand revealed numerous diffraction peaks which indicate its semi-crystalline nature [61], whereas the XRD patterns of metal complexes exhibited a predominance of amorphous nature. In addition, the diffraction pattern of ligand was significantly different from those of the metal complexes, thereby suggesting another evidence for complex formation. This can be attributed to the infrequent formation of solid frameworks during the accelerated precipitation process. In contrast, if the chelation process is rapid or if the resulting products are cooled immediately, then the generated compounds will predominantly precipitate in an amorphous state. Moreover, certain solids are formed inherently in amorphous state because their constituents lack the ability to form a suitable crystal lattice.

Fig. 1
figure 1

The XRD patterns of A Ligand, and B–D Complexes 2–4

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3.11 SEM and EDAX

The SEM images (Fig. 2A–D) showed that ligand had a rough surface with semi-crystalline nature before the modifications; however after the formation of metal complexes, the surface features were completely changed to amorphous, thereby providing additional evidence that required modifications was achieved. The metal complexes were analysed via EDAX profile (Fig. 3A–D) alongside with SEM images to quantitatively measure the elemental composition of prepared materials. The EDAX micrographs of complexes revealed successful insertion of metal ions in the respective samples [62].

Fig. 2
figure 2

The typical SEM (scanning electron microscopy) images of A Ligand, and B–D Complexes 2–4

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Fig. 3
figure 3

EDAX micrographs of A Ligand, and B–D Complexes 2–4

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3.12 Density Functional Theory Studies

To gain insight into the structural parameters of synthesized compounds (1–5), density functional theory (DFT) computations have been performed. The ligand has been improved in order to study the geometrical and electrochemical factors that can regulate electron transfer. The fully optimised structures of compounds are presented in Figs. S17–S21 of the supplementary. The bond lengths and bond angles of examined compounds are listed in Table T2 of supplementary. The ligand functioned in a tridentate manner and coordinates to the metal centre through the imine-N, hydroxy-O and thiol-S donor atoms. Coordination of ligand to the metal ions shortens the bond lengths in compounds (2–5) i.e. C2-S1 (1.43–1.46°) and C14-O4 (1.36–1.40°) as compared to ligand. Also, the M-O4 (2.07–2.09°) bond length was shorter than the M-S1 (2.30–2.35°) in complexes. The calculated angles for the metal complexes lie in the range S1-M-N4 (91.29–92.41°), S1-M-O1 (77.49–85.40°), S1-M-O2 (89.70–97.58°), S1-M-O3 (163.38–170.30°), S1-M-O4 (92.35–95.84°), N4-M-O1 (99.57–105.24°), N4-M-O2 (163.38–170.66°), N4-M-O3 (88.61–99.23°) and N4-M-O4 (84.67–98.13°), thereby suggesting an octahedral environment around the central metal atom in the complexes.

3.12.1 Quantum Chemical Descriptors Study

The conceptual quantum chemical descriptors have been used for determination of biological and chemical reactivities. The parameters i.e. energy of HOMO (EHOMO), energy of LUMO (ELUMO), Egap between the LUMO and HOMO, hardness (η), dipole moment, global softness (S), electrophilicity indices (ω) were selected for this study. The HOMO–LUMO gap defines the electronic characteristics of a stable molecule. The ability of electrons to migrate from occupied orbitals to vacant orbitals was frequently reflected in orbital distribution analysis, which provides a fundamental foundation for evaluating the chemical reactivity, selectivity, and stability of compounds [63, 64]. The energy of HOMO–LUMO and band gap (ΔE) of compounds (1–5) is depicted in Fig. 4. The phenolic ring has highly filled molecular orbitals, whereas the triazole and pyridine ring orbitals were vacant. The HOMO energy indicates the molecule’s nucleophilic site, whereas the LUMO energy indicates the molecule’s electrophilic site. The energy band gap (ΔE) between the two orbitals shows the chemical stability of the molecule; the smaller the energy gap, the simpler it is to excite the molecule [65]. The HOMO orbital is primarily an electron donor, whereas the LUMO orbital is primarily an electron acceptor. The computed ΔE values were relatively low i.e.0.04371922 (1), 0.02513350 (2), 0.010439 (3), 0.03951043 (4) and 0.0.03610343 eV (5) respectively; low ΔE values were accompanied by significant reactivity and stability [66, 67].

Fig. 4
figure 4

B3LYP/6-311++G calculated contour plots of HOMO and LUMO for A Ligand, and B–E Complexes 2–5

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The global indices of chemical reactivity are shown in Table 3. Complex 3 depicts better results as compared to other compounds with lowest (ΔE), hardness (η), and global softness (S). The potential reactivity of compounds was indicated by the minimum hardness and maximum softness values. Global electrophilicity indices (ω) can be used to assess the electrophilic power of compounds. As a result, the electrophilicity index of an electrophilic molecule is high. The electrophilicity indices of complex 3 appear to be quite high. Because of the positively charged coordinating metal, the complexes have a low electronegativity power (χ).

Table 3 Density functional theory calculations of compounds along with other descriptors
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3.12.2 Molecular Electrostatic Potential Profiles

The MESP is a significant metric that is related to the charge distribution and is highly useful in comprehending coordination sites and hydrogen bonding interactions. The B3LYP method with the 6-311++G basis set was used to calculate the mapped surface of compounds (1–5). The maps of studied compounds are presented in Fig. 5. The map of ligand clearly shows that the negative areas are localized over the electronegative site, whereas the positive regions are localized over the electropositive site [68]. The negative areas are mostly located around the oxygen atom of the O–H group (deep red/yellow) and nitrogen atoms of the imine group, while majority of the positive charge is concentrated around the hydrogen and carbon atoms, and most positive areas (blue/green) are seen around the hydrogen atom of phenolic O–H group and the carbon atoms of imine group. Ligand contains four potential coordination sites and is coordinated to the central metal through NOS donor atoms. The three water molecules were also coordinated to central metal with O as the donor atom. As a result, the metal ions are present in the octahedral arrangement surrounded by six donor atoms. Different colours depict different values of the electrostatic potential at the surface. The potential increases in the order: blue > green > yellow > orange > red [69].

Fig. 5
figure 5

Mesp profile map of A Ligand and B–E Complexes 2–5

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3.13 Antidiabetic Assay

The biological effects of the synthesized compounds were evaluated in vitro against two enzymes i.e. alpha-amylase and alpha-glucosidase. The inhibitory effect was measured in terms of IC50 (µmol/mL). The calculated IC50 values for the compounds are depicted in Fig. 6. Acarbose was acting as standard drug for the experiment. Metal complexes were found to effectively inhibit the enzymes as compared to ligand.

Fig. 6
figure 6

Graph representing alpha-amylase and alpha-glucosidase inhibitory potential of compounds

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3.13.1 Alpha-Amylase Inhibition Assay

In this study, compounds were tested for inhibition against alpha-amylase. From the in vitro examinations, no hypoglycaemic activity was observed for ligand 1 (IC50 = 2.46 ± 0.048 µmol/mL), while highest activity was observed for nickel complex 3 with IC50 value of 1.71 ± 0.044 µmol/mL, very approximate to the standard Acarbose whose IC50 value was found to be 1.70 ± 0.029 µmol/mL. Complex 2 having IC50 value of 1.73 ± 0.040 µmol/mL was found to be moderately active. Complex 4 appeared to be moderately potent with IC50 value of 1.89 ± 0.043 µmol/mL. Complex 5 showed significant inhibitory potential with 1.72 ± 0.035 µmol/mL as IC50 value. For alpha-amylase, IC50 value of compounds followed the order: Acarbose > 3 > 5 > 2 > 4 > 1. The obtained results suggested that nickel complex could work effectively against alpha-amylase as compared to the other complexes and variation in potential was due to the nature of metal ions [70]. Furthermore, the enhanced activity of metal complexes may be due to synergistic interactions of the ligand to the metal ions in a certain environment, thereby leading to enhanced absorption at the surface of enzymes and a better inhibition.

3.13.2 Alpha-Glucosidase Inhibition Assay

Alpha-glucosidase inhibitory assay of the synthesized compounds was done according to the protocol provided by Xiao et al. 1,2,4-Triazole based complexes were utilized as hypoglycaemic agents which effectively reduced the absorption and formation of glucose in the intestine. As a result, suppression of postprandial hyperglycaemia was observed. The ligand exhibits very less inhibition with 4.32 ± 0.033 µmol/mL as IC50 value. The IC50 value obtained for copper complex (4) was 3.25 ± 0.05 µmol/mL which was very close to standard Acarbose (IC50 = 3.24 ± 0.021 µmol/mL). Complex 5 displayed IC50 value of 3.30 ± 0.04 µmol/mL for enzyme alpha-glucosidase. With moderate inhibition, an IC50 value of 3.69 ± 0.045 µmol/mL was observed for complex 3. Complex 2 exhibited very less inhibition for enzyme with IC50 value of 3.81 ± 0.051 µmol/mL. The inhibition of compounds followed the trend: Acarbose > 4 > 5 > 3 > 2 > 1. The higher activity of copper complex might be due to the fact that it bonded to allosteric or active site of alpha-glucosidase and established various hydrophobic and hydrogen interactions, thus leading to stabilization of inhibitors [71, 72].

3.14 Molecular Docking

3.14.1 Alpha-Amylase Enzyme

Complex 5 was recognized with a docking score of − 9.3 kcal/mol. A total of 4 H-bond interactions were identified with the backbone amino acids Gln63, Asp197, Glu233, Asp300 and Gln168. Some of the residues presented in the hydrophobic form were Trp58, Trp59, Tyr62, Leu162, Leu165, Ala198 and Ile235. Complex 4 established strong hydrogen bond interactions with amino acids such as Gln63, Asp197 and Glu233, as well as with cluster residues such as Trp58, Trp59, Tyr62, Leu162, Leu165, Ala98 and Ile235 which are involved in strong hydrophobic interactions. Complex 2 and 3, which have a predicted binding energy of − 8.6 kcal/mol, forms hydrogen bonds with Thr163 and Asp300, as well as with cluster residues like Trp59, Tyr62, Leu162, Leu165, Ala198 and Ile235 that have strong hydrophobic contacts. Ligand (Binding energy − 7.3 kcal/mol) makes hydrogen bonds with Gln63 and with cluster residues including Trp58, Trp59, Tyr62, Tyr151, Leu162, Leu165 and Ile235, which were engaged in strong hydrophobic contacts. The binding interactions of compounds (1–5) are depicted in Fig. 7A–F.

Fig. 7
figure 7

The molecular interactions and binding mode of A–E Compounds 1–5 and F Acarbose (Element ball and stick structure) inside alpha-amylase (cyan structure) (Color figure online)

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3.14.2 Alpha-Glucosidase Enzyme

Complex 4 was acknowledged with the lowest docking score of − 7.7 kcal/mol. A total of 3 H-bond interactions were identified with the backbone amino acids Asn333, Asn371 and Lys373. Some of the residues presented in the hydrophobic form were Trp288 and Trp407. Complex 5 formed three hydrogen bonds with Asn333, Asn371 and Lys373 as well as several hydrophobic interactions with amino acids such as Trp288 and Trp407. Complex 3 with a binding energy of − 7.4 kcal/mol established strong hydrogen bond interactions with Asn333. Complex 2 created strong hydrophobic contacts with Leu287, Trp288, Leu296 and Ile329 in the active site of alpha-glucosidase with a binding energy of − 7.3 kcal/mol. The development of new hydrophobic contacts with Trp288, Pro295, Leu296, Phe335, Ala339, Pro508 and Try547 residues yielded binding energy of − 6.7 kcal/mol for ligand 1. The binding interactions of compounds (1–5) are depicted in Fig. 8A–F.

Fig. 8
figure 8

The molecular interactions and binding mode of A–E Compounds 1–5 and F Acarbose (Element ball and stick structure) inside alpha-glucosidase (maroon structure) (Color figure online)

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4 Conclusions

The cobalt(II), nickel(II), copper(II) and zinc(II) complexes of tridentate Schiff base ligand were synthesized. Spectral and physico-analytical techniques such as NMR, HRMS, FTIR, XRD, ESR, TGA, SEM and EDAX studies combined with elemental analyses were utilized to structurally explore the synthesized compounds. The complexes present an octahedral structure with the metal atom linked by azomethine nitrogen, deprotonated sulphur, deprotonated oxygen and three coordinated water molecules. Thermal degradation studies confirmed the existence of three water molecules. DFT (density functional theory) calculations at the B3LYP level using a 6-311++G basis set were done to determine the biological accessibility and thermodynamic stability of the synthesized compounds. In enzyme inhibition study, the complexes showed improved potential as compared to parent ligand and especially the complex 3 against alpha-amylase and complex 4 against alpha-glucosidase were found to be effective inhibitors. Furthermore, molecular docking studies were conducted in order to validate the wet lab experiments and to identify the active binding sites of the synthesized compounds with those of the target protein. Overall, the present study expanded a new vision towards the development of triazole based metal complexes as antidiabetic agents.