ABSTRACT
INTRODUCTION: The formation of N-oxide degradants is a major concern in development of new drugs due to potential effects on a compound's pharmacological activity. Such effects include but are not limited to solubility, stability, toxicity, and efficacy. In addition, these chemical transformations can impact physicochemical properties that affect drug manufacturability. Hence identification and control of N-oxide transformations is of critical importance in the development of new therapeutics. OBJECTIVE: This study describes the development of an in-silico approach to identify N-oxide formation in APIs with respect to autoxidation. METHODS: Average Local Ionization Energy (ALIE) calculations were carried out using molecular modeling techniques and application of Density Functional Theory (DFT) at the B3LYP/6-31G(d,p) level of theory. A total of 257 nitrogen atoms and 15 different oxidizable nitrogen types were used in developing this method. RESULTS: The results show that ALIE could be reliably used to predict the most susceptible nitrogen for N-oxide formation. A risk scale was developed that rapidly categorizes nitrogen's oxidative vulnerabilities as small, medium, or high. CONCLUSIONS: The developed process presents a powerful tool to identify structural susceptibilities for N-oxidation as well as enabling rapid structure elucidation in resolving potential experimental ambiguities.
Subject(s)
Nitrogen , Oxides , Density Functional Theory , Models, Molecular , Oxidation-ReductionABSTRACT
This article represents the spectroscopic and computational studies of two new pyrazine compounds. In order to establish the structure and functional nature of the compounds, we have employed Fourier transformed infrared (FT-IR) and Raman spectra, nuclear magnetic resonance (NMR) spectra, and ultraviolet (UV) absorptions and have compared them with the simulated computational spectra and found that they are in the agreeable range. Simulated hyperpolarisability values are used to obtain the nonlinear optic (NLO) activity of the compound, to be used in organic electronic materials. The charge transfer and related properties was investigated by the simulation of electronic spectrum with time dependent density functional theory (TD-DFT). Natural transition orbitals (NTO) provides information about which region of the molecules are more involved in the electronic transitions and the charge transfer properties for the lowest energy excitation have been analyzed on the basis of electron density variation. Molecular dynamics simulations provide information about the behavior of the molecule in solutions. Frontier orbital analysis and study of various reactivity descriptors like ALIE and Fukui provided deep knowledge on the reactivity side. Molecular docking has been also performed to investigate the interaction between title molecules and exhibits inhibitory activity against Pseudomonas aeruginosa Enoyl-Acyl carrier protein reductase (Fabl).