Combined Chemical, Biological and Theoretical DFT‐QTAIM Study of Potent Glycosidase Inhibitors Based on Quaternary Indolizinium Salts

Abstract

Six novel enantiopure epimeric indolizidinediols have been easily prepared in high yields by an effective and well‐established regioselective THF ring‐opening reaction as a key step. Quarternization of these species was also studied and comparison was made to the quaternizations of other substituted indolizidines. Importantly, a combined theoretical DFT‐QTAIM study has cast light on the various factors that explain the observed conformational selectivity. The inhibitory properties of the six synthesized indolizidines were then investigated against the recombinant Golgi α‐mannosidase‐IIb (dGMIIb) and lysosomal α‐mannosidase (dLM408), human homologues of Drosophila melanogaster. Among the tested compounds, two of them, 4a and 4b, exhibited a pH‐dependent inhibition of dGMIIb at the milimolar level (IC50 = 3.5 or 1.7 mM at pH 5.8 or 6.5, respectively) without affecting the activity of dLM408.

Fermi and Coulomb correlation effects upon the interacting quantum atoms energy partition

“…in which σ and τ have the same meaning that in equation (7), {ϕ p (r)} is the set of spatial molecular orbitals used to construct the Fock space of the system under consideration, k pσ represents the occupation number of spin orbital ϕ p (r)σ (s) in |HF and δ σ τ denotes the Kronecker delta. Equation ( 9) can be rewritten entirely in terms of expression (8), i.e., ,…”

“…These conditions have enabled QTAIM to address many different chemical processes and systems on the same footing [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] . In similar fashion, the IQA approach has recently been applied to the study of transition metal-ligand interactions [25][26][27] , bonding between electronegative atoms [28] , the transferability of different species inside oligopeptides [29] , the formation of water clusters [30,31] and the conformational arrangement of carboxylic acids [32] .…”

Comparisons between Crystallography Data and Theoretical Parameters and the Formation of Intramolecular Hydrogen Bonds: Benznidazole

“…The Quantum Theory of Atoms in Molecules (QTAIM) [17] represents a useful tool in studies of molecular stability and strength of chemical bonds [18], but is also widely applied in investigations of hydrogen bonds through the analysis of electronic density and its topological parameters [19]. According to some publications [20], the QTAIM approach has been also useful in studies of biological systems [21], mainly to characterize the intramolecular hydrogen bonds of compounds with biological activity [22]. In this sense, we are convinced that QTAIM can be decisive in our investigation not only regarding the intramolecular hydrogen bonds [23][24][25][26][27][28][29][30][31], but also to unveil the most stable conformation of benznidazole.…”

QTAIM and NCI analysis of intermolecular interactions in steroid ligands binding a cytochrome P450 enzyme – Beyond the most obvious interactions

“…Some experimental and docking modeling using homology model of CYP17 on inhibitory molecules against CYP17 were reported [12][13][14]. In addition, the Quantum Theory of Atoms in Molecules (QTAIM) has been recently used for topological analysis between ligands and target enzymes [15][16][17][18][19][20]. Important information about the type and strength (as function of charge density) of interatomic interactions involving ligand-enzyme atomic pairs were obtained from QTAIM which aimed to understand how some specific group functions (from ligands and residues) interact between themselves [16,17,20].…”

“…In addition, the Quantum Theory of Atoms in Molecules (QTAIM) has been recently used for topological analysis between ligands and target enzymes [15][16][17][18][19][20]. Important information about the type and strength (as function of charge density) of interatomic interactions involving ligand-enzyme atomic pairs were obtained from QTAIM which aimed to understand how some specific group functions (from ligands and residues) interact between themselves [16,17,20]. As a consequence, QTAIM proved to be an important tool for evaluation of molecular recognition giving new insights for designing new drugs.…”