Quantitative Structure—Activity Relationship for Cyclic Imide Derivatives of Protoporphyrinogen Oxidase Inhibitors: A Study of Quantum Chemical Descriptors from Density Functional Theory.

Abstract

This study examined the applicability of various density functional theory (DFT)-based descriptors, such as energy gap (ΔE) between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), weighted nucleophilic atomic frontier electron density (WNAFED, ), mean molecular polarizability (α), and net atomic charge (Qi), in quantitative structure−activity relationship (QSAR) studies on a class of important protoporphyrinogen oxidase (Protox) inhibitors including a series of cyclic imide derivatives with various heterocyclic rings and substituents. Our QSAR analysis using the quantum chemical descriptors calculated at the B3LYP/6-31G(d,p) level led to a useful explicit correlation relationship, i.e. pI50 = −5.7414 + 0.1424α − 0.0003α2 − 0.4546 + 0.2974QN•• (n=26, R2=0.87), showing that descriptors mean molecular polarizability, α, and WNAFED of a critical carbon atom and net atomic charge (Qi) in the molecules are most likely responsible for the in vitro biological acti...