A Computational Study of Structure and Reactivity of N-Substitued-4-Piperidones Curcumin Analogues and Their Radical Anions

Abstract

In this work, a computational study of a series of N-substitued-4-piperidones curcumin analogues is presented. The molecular structure of the neutral molecules and their radical anions, as well as their reactivity, are investigated. N-substituents include methyl and benzyl groups, while substituents on the aromatic rings cover electron-donor and electron-acceptor groups. Substitutions at the nitrogen atom do not significantly affect the geometry and frontier molecular orbitals (FMO) energies of these molecules. On the other hand, substituents on the aromatic rings modify the distribution of FMO. In addition, they influence the capability of these molecules to attach an additional electron, which was studied through adiabatic (AEA) and vertical electron affinities (VEA), as well as vertical detachment energy (VDE). To study electrophilic properties of these structures, local reactivity indices, such as Fukui (f + ) and Parr (P + ) functions, were calculated, and show the influence of the aromatic rings substituents on the reactivity of α,β-unsaturated ketones towards nucleophilic attack. This study has potential implications for the design of curcumin analogues based on a 4-piperidone core with desired reactivity.

Study of the Electrochemical Behavior of N-Substituted-4-Piperidones Curcumin Analogs: A Combined Experimental and Theoretical Approach

“…To obtain insights into the behavior observed for these two series of compounds, we studied the energy of frontier molecular orbitals. In previous works, theoretical calculations of some of these compounds had been carried out to study their reactivity and the behavior of their radical anions [ 16 ], as well as optical properties [ 28 ]. In our previous work [ 16 ], we obtained, at the B3LYP/6-31G(d) level, the energies of the frontier molecular orbitals of some compounds studied here ( C1 , C2 , C3 , C6 , C7 , and C8 ).…”

“…In previous works, theoretical calculations of some of these compounds had been carried out to study their reactivity and the behavior of their radical anions [ 16 ], as well as optical properties [ 28 ]. In our previous work [ 16 ], we obtained, at the B3LYP/6-31G(d) level, the energies of the frontier molecular orbitals of some compounds studied here ( C1 , C2 , C3 , C6 , C7 , and C8 ). Table 7 shows the values for HOMO and LUMO energies (E HOMO and E LUMO , respectively) and the HOMO–LUMO energy gap (GAP H-L ).…”

“…It has been proposed that compounds possessing a β-diketone moiety, as in the case of curcumin, are a substrate of liver aldo-keto reductases, which probably contribute to their rapid in vivo metabolism [ 12 , 14 , 15 ]. To avoid this drawback, multiple synthetic alternatives have been assayed, among which replacing the β-diketone moiety with a heterocyclic ring has shown to be effective [ 12 , 16 ]. Among the alternatives, synthetic analogs of curcumin possessing a 4-piperidone scaffold have shown high bioactivity, e.g., as anti-inflammatory and anticancer agents [ 17 , 18 , 19 , 20 , 21 ].…”

“…However, until now, the electrochemical behavior of N-substituted-4-piperidone curcumin analogs has not been reported, which seems relevant to study due to their interesting pharmacological properties, which have been suggested to be associated with the electron transfer process [ 13 ]. Besides our previous work on the reactivity of these compounds, only theoretical work dealing with the potential technological application for the non-linear optics of this type of curcuminoid can be found [ 16 , 28 ].…”

Synthesis and cholinesterase inhibitory activity studies of some piperidinone derivatives

“…The analytical results for the elements were within ±0.4% of the theoretical values. All final compounds were reported in the literature 16,[20][21][22] , but their AChE and BuChE activity results were reported for the first time with this study.…”