One-Electron Reduction Potentials: Calibration of Theoretical Protocols for Morita⁻Baylis⁻Hillman Nitroaromatic Compounds in Aprotic Media.

Amauri Francisco Da Silva,Mário Vasconcellos,Otávio Luís De Santana,Antonio João Da Silva Filho

doi:10.3390/molecules23092129

Amauri Francisco Da Silva, Mário Vasconcellos + Show 2 more

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https://doi.org/10.3390/molecules23092129

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Abstract

Nitroaromatic compounds—adducts of Morita–Baylis–Hillman (MBHA) reaction—have been applied in the treatment of malaria, leishmaniasis, and Chagas disease. The biological activity of these compounds is directly related to chemical reactivity in the environment, chemical structure of the compound, and reduction of the nitro group. Because of the last aspect, electrochemical methods are used to simulate the pharmacological activity of nitroaromatic compounds. In particular, previous studies have shown a correlation between the one-electron reduction potentials in aprotic medium (estimated by cyclic voltammetry) and antileishmanial activities (measured by the IC50) for a series of twelve MBHA. In the present work, two different computational protocols were calibrated to simulate the reduction potentials for this series of molecules with the aim of supporting the molecular modeling of new pharmacological compounds from the prediction of their reduction potentials. The results showed that it was possible to predict the experimental reduction potential for the calibration set with mean absolute errors of less than 25 mV (about 0.6 kcal·mol−1).

Highlights

Nitro compounds have been used against various diseases for over five decades [1,2,3,4,5] due to their wide range of pharmacological activity against bacteria [6,7], fungus [8], and tumors [9,10]as well as malaria, leishmaniasis, and Chagas disease [11,12,13,14]
This mechanism of oxidative stress, which is responsible for damage to biological membranes, proteins, and DNA molecules [20,21], is the main route of pharmacologic action of this class of compounds [22,23]. An indicative of this mechanism is the experimental observation of the relationship between the reduction potential and the pharmacological action of some nitro compounds, which can be used for modeling new bioactive compounds [24]
The calibration of two computational protocols to predict the one-electron reduction potentials in an aprotic medium was performed from a calibration set consisting of 12 molecules that exhibit antileishmaniasis activity

Summary

Introduction

Nitro compounds have been used against various diseases for over five decades [1,2,3,4,5] due to their wide range of pharmacological activity against bacteria [6,7], fungus [8], and tumors [9,10]as well as malaria, leishmaniasis, and Chagas disease [11,12,13,14]. The pharmacological mechanism of these compounds generally involves enzymatic bioreduction facilitated by the electron acceptor strength of the nitro group, leading to formation of free radicals with preferential toxicity for invading microorganisms [15,16,17,18,19] This mechanism of oxidative stress, which is responsible for damage to biological membranes, proteins, and DNA molecules [20,21], is the main route of pharmacologic action of this class of compounds [22,23]. Electrochemical studies were performed in aprotic media (N,N-dimethylformamide plus tetrabutylammonium perchlorate 0.1 mol·L−1 for supporting electrolyte) using cyclic voltammetry with a conventional three-electrode cell and Ag|AgCl,Cl−

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