Synthesis, electronic structure calculations, and α-glucosidase inhibitions of some transition metal complexes containing pyridine derivatives

Coordination complexes are chemical compounds composed of a central metallic atom or ion, known as the coordination center, and surrounding ligands. Within a ligand, the atom that directly bonds to the central metal ion or atom is referred to as the donor atom. In a typical coordination complex, the metal ion is coordinated to multiple donor atoms, which may be identical or different in nature. A polydentate ligand is an ion or molecule that attaches to the central atom through several of its own atoms. Metal complexes play a crucial role in various fields, including agriculture, pharmaceuticals, and industrial chemistry. 2-Pyridinecarboxaldehyde (chemical formula: C6H5NO) is an organic compound of interest in coordination chemistry and pharmaceuticals. Pyridine aldehydes are typically synthesized through the oxidation of hydroxymethyl- or methylpyridines. Schiff bases are known to be medically significant and are widely employed in the design of pharmaceutical compounds. In coordination chemistry, Schiff bases play an important role and are commonly utilized. The imine group plays a prominent role in the formation of Schiff bases, which are known for their broad spectrum of biological activities. In addition to their extensive industrial applications, these compounds exhibit a wide range of physiological effects, including anti-inflammatory, antibacterial, antiproliferative, antifungal, antipyretic, and antiviral properties. α-Glucosidase is an enzyme that hydrolyzes polysaccharides and disaccharides into glucose for intestinal absorption. Inhibition of this enzyme postpones carbohydrate absorption after a meal and lowers postprandial glucose levels. Voglibose, acarbose, and miglitol are currently used as α-glucosidase inhibitors. Acarbose inhibits α-glucosidase in the intestine, competitively. That reduces the rate of glucose absorption through postponed carbohydrate digestion and prolonged digestion time. Therefore, these inhibitors are used in combination with other anti-diabetic agents. In theoretical calculations, the energies and wave functions obtained from the solutions of the electronic Schrödinger equation are not sufficient on their own for characterizing the materials under investigation. In such cases, it becomes necessary to compute additional quantities that provide a more comprehensive characterization of atomic and molecular systems. In particular, determining parameters such as ground-state molecular geometry optimization, vibrational frequencies, dipole moment, linear polarizability, and higher-order nonlinear polarizability, as well as electronic absorption wavelengths, oscillator strengths, and transition dipole moments for excited-state electronic transitions, is crucial for establishing connections with experimental results and assessing the agreement between theoretical and experimental data. Theoretical calculations hold particular significance as they allow for the investigation of structure–property relationships prior to detailed synthesis and experimental characterization, and they also provide insight into whether measurements are feasible. However, the reliability of various computational approaches can only be evaluated based on their consistency with experimental data.In this thesis, the complexes of N-(pyridin-2-ylmethylene)methanamine (L1) with isothiocyanate {[Mn(L1)2(NCS)2] (1), [Co(L1)2(NCS)2] (2), [Ni(L1)2(NCS)2] (3), [Cd(L1)2(NCS)2] (4), [Zn(L1)2(NCS)2] (5), [Cu(L1)2(NCS)2] (6), [Ag(L1)(NCS)2] (7), [Hg(L1)2(NCS)Cl] (8)} and with azide {[Mn(L1)2(N3)2] (9), [Ni(L1)2(N3)] (10), [Co2(L1)2(N3)2]·2H2O (11), [Cu2(L1)2(N3)3] (12), [Hg(L1)2(N3)·H2O] (13), [Cd(L1)2(N3)] (14), [Ag(L1)(N3)2·2H2O] (15), [Zn2(L1)2(N3)2Cl2.4H2O] (16)} were synthesized. Among the synthesized complexes, [Mn(L1)2(NCS)2] (1), [Co(L1)2(NCS)2] (2), and [Cd(L1)2(NCS)2] (4) were obtained as single crystals and their structures were elucidated using X-ray diffraction (XRD) analysis. The remaining complexes {[Ni(L1)2(NCS)2] (3), [Zn(L1)2(NCS)2] (5), [Cu(L1)2(NCS)2] (6), [Ag(L1)(NCS)2] (7), [Hg(L1)2(NCS)Cl] (8)}, and the azide-containing {[Mn(L1)2(N3)2] (9), [Ni(L1)2(N3)] (10), [Co2(L1)2(N3)2]·2H2O (11), [Cu2(L1)2(N3)3] (12), [Hg(L1)2(N3).H2O] (13), [Cd(L1)2(N3)] (14), [Ag(L1)(N3)2·2H2O] (15), [Zn2(L1)2(N3)2Cl2·4H₂O] (16)} were obtained as powder products and characterized using mass spectromery. Following structural determination, FT–IR spectra were recorded to investigate their vibrational properties, and UV–Vis spectra were obtained to study electronic transitions and charge transfer interactions. The synthesized complexes were subjected to a comprehensive theoretical investigation at their optimized ground-state geometries using hybrid density functional theory (DFT), with their electronic absorption characteristics modeled through time-dependent DFT (TD-DFT). The comparison between computed and experimental data revealed a high degree of consistency. Essential electronic and optical features including dipole moment, polarizability, and both first- and second-order nonlinear optical (NLO) responses were explored in relation to structural parameters such as π-conjugation, electron delocalization, and substituent-driven charge redistribution. To evaluate electronic behavior, the energies of frontier orbitals (HOMO and LUMO) were computed, enabling the derivation of molecular reactivity descriptors like energy gap, chemical hardness and softness, and electronegativity. The roles of specific molecular orbitals in electronic transitions were elucidated with the aid of SWizard and chemissian softwares. In addition, Natural Bond Orbital (NBO) analysis was employed to unravel intra- and intermolecular interactions, revealing insights into bonding characteristics, charge delocalization, and interactions involving lone electron pairs on electronegative atoms and metal centers. Electrostatic potential surfaces, obtained through DFT calculations, provided further information on reactive regions within the molecular frameworks. Lastly, the α-glucosidase inhibition profiles of the complexes were evaluated, and molecular docking simulations were performed to clarify the binding mechanisms and structure–activity correlations underlying their biological function. For complexes 1–3, the experimentally obtained third-order nonlinear optical (NLO) susceptibilities (χ(3)) in the UV–Vis region in methanol exhibited maximum peaks at photon energies of 4.68, 4.21, and 5.25 eV, respectively, with approximately equal χ(3) values (χ(3) = 51.65 × 10-13, 51.42 × 10-13, and 51.42 × 10-13 esu). In this study, both the theoretical and experimental third-order NLO parameters indicate that complex 1 may be a promising candidate for the development of optoelectronic devices. Among complexes 4–8, complex 6, which exhibited an IC₅₀ value of 5.618 μM against α-glucosidase, can be considered a promising NLO material candidate based on its calculated β and γ parameters. Considering both the in vitro/docking and NLO results in the context of metal complexes with L1 and NCS ligands, it can be suggested that complex 8 (IC₅₀ = 0.2376 μM) represents a potential alternative drug candidate for type 2 diabetes mellitus (T2DM), while complex 6 appears to be a structurally viable NLO material candidate. For complex 9, the highest <γ(0;0,0,0)> value was obtained as 2216.40 × 10-36 esu at the CAM-B3LYP level, which is 147.76 times greater than that of p-nitroaniline (pNA, 15 × 10-36 esu) and 316.63 times greater than that of urea (7 × 10-36 esu). The β and γ results indicate that complexes 10 and 9 exhibit significant microscopic second- and third-order NLO properties, respectively. These findings are further supported by the χ(2) and χ(3) parameters. It was observed that the linear azide anion has an influence on the geometry, sign, and magnitude of γ in complex 10. For complexes 12–16, IC₅₀ values ranged from 0.2802±0.62 to 420.88±1.42 μM. Among them, complex 13 showed the highest α-glucosidase inhibitory activity, while complex 14 exhibited the lowest. In addition, complex 12 (1.562±0.83 μM) and complex 15 (1.274±0.32 μM) also showed effective IC₅₀ values. These results are supported by docking studies that reveal receptor–ligand interactions. Furthermore, molecular dynamics (MD) simulations conducted over 50 ns demonstrated that the compounds remained stable throughout the simulation period. Complexes 15 and 12 not only showed notable IC₅₀ values against α-glucosidase, but their β and γ results also confirmed their significant microscopic second- and third-order NLO characteristics, respectively. In conclusion, among the Schiff base–azide metal complexes studied, complex 13 may be proposed as a potential alternative anti-diabetic inhibitor for type 2 diabetes, while complexes 12 and 15 are promising candidates for NLO materials. Based on the results of molecular docking and in vitro studies, and considering structure–activity relationships, it can be concluded that metal complexes containing Cu, Ag, and Hg exhibit notable inhibitory properties against α-glucosidase.