Novel PEPPSI-type N-heterocyclic carbene palladium(II) complexes: Synthesis, characterization, in silico studies and enzyme inhibitory properties against some metabolic enzymes

In this study, a series of PEPPSI-type N-heterocyclic carbene palladium(II) complexes 3a-e were synthesized using amine functionalized benzimidazolium salts 2a-e as N-heterocyclic carbene precursors. These complexes were characterized by FT-IR, 1H NMR and 13C NMR spectroscopy, elemental analysis and mass spectrometry. Also, the molecular and crystal structure of 3b has been determined by the single-crystal X-ray diffraction method. According to the structural analysis, the geometry of the palladium center of the complex adopts a slightly distorted square planar environment. The benzimidazolium salts 2a-e and their palladium(II) complexes 3a-e were screened for human carbonic anhydrase I, II (hCAs I and II), and alpha-glycosidase inhibitory activities. Results indicated that all the synthetic compounds exhibited potent inhibitory activities against all targets as compared to the standard inhibitors, revealed by IC50 values. Ki values of 2a-e and 3a-e for hCA I, hCA II, and alpha-glycosidase enzymes were obtained in the ranges 1.17 +/- 0.11-65.50 +/- 8.20 mu M, 1.02 +/- 0.08-57.60 +/- 6.41 mu M, and 118.86 +/- 11.92-509.21 +/- 26.61 nM, respectively. Besides these, molecular docking calculations of potent compounds 2b, 2d, 2e, 3a, 3b, 3c and 3e towards human carbonic anhydrase I (hCA I), human carbonic anhydrase II (hCA II), and alpha-glycosidase (alpha-Gly) were presented using AutoDock 4. Among the compounds discussed, compounds 3c, 3a, 2e and 2b have the best binding affinity for alpha-Gly (-9.87,-9.77,-9.04 and-8.63 kcal/mol); compounds 3e, 3b, 2d and 2e turn out to have the second-best binding affinity (-8.80,-8.74,-8.39 and-7.57 kcal/mol) against hCA II. Lastly, compounds showing the lowest binding affinity for hCA I enzyme are 3e, 3b, 2d and 2e, respectively. These findings show that especially NHC-palladium(II) complexes 3a-e are more active for all three enzyme structures than their N-heterocyclic carbene precursors 2a-e and may be potential candidates for the discovery and development of effective inhibitors for the related enzymes in the future.

Automated summary

In this study, a series of PEPPSI-type N-heterocyclic carbene palladium(II) complexes 3a-e were synthesized using amine functionalized benzimidazolium salts 2a-e as N-heterocyclic carbene precursors. These complexes were characterized and their inhibitory activities against hCAs I, II, and alpha-glycosidase enzymes were evaluated. Molecular docking calculations were performed to determine their binding affinities. The NHC-palladium(II) complexes 3a-e showed higher inhibitory activities and binding affinities compared to the N-heterocyclic carbene precursors 2a-e.