Crawford, P.W. (Philip W.)

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2011 - 20133

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    Cyclic voltammetric study of some anti-Chagas-active 1,4-dioxidoquinoxalin-2-yl ketone derivatives
    (Wiley, 2013-02) Devarapally, G. (Goutham); Aldana, I. (Ignacio); Torres, E. (Enrique); Monge, A. (Antonio); Moreno-de-Viguri, E. (Elsa); Peres-Silanes, S. (Silvia); Crawford, P.W. (Philip W.)
    The electrochemical properties of 24 1,4-dioxidoquinoxalin-2-yl ketone derivatives with varying degrees of anti-Chagas activity were investigated in the aprotic solvent dimethylformamide (DMF) by cyclic voltammetry and first-derivative cyclic voltammetry. For this group of compounds, the first reduction in DMF was either reversible or quasireversible and consistent with reduction of the N-oxide functionality to form the radical anion. The second reduction process for these compounds was irreversible under the conditions used. The reduction potentials correlated well with molecular structure. Substitution in the 3-, 6-, and 7- positions of the quinoxaline ring by electron-withdrawing substituents directly affected the ease of reduction and improved the biological activities of these compounds, whereas substitution by electron-donating groups had the opposite effect. The electrochemical results, when combined with previous work on their mechanism of action against Chagas disease and their measured anti-Chagas activities, indicated that the quinoxaline 1,4-dioxide system serves as a promising starting point for chemical modifications aimed at improving the T. cruzi activity via a possible bioreduction mechanism.
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    1,4-Di-N-oxide quinoxaline-2-carboxamide: Cyclic voltammetry and relationship between electrochemical behavior, structure and anti-tuberculosis activity
    (Elsevier, 2011) Aldana, I. (Ignacio); Ancizu, S. (Saioa); Torres, E. (Enrique); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Moreno-de-Viguri, E. (Elsa); Macharam, A. (Abinav); Gouravaram, S. (S.); Crawford, P.W. (Philip W.)
    To gain insight into the mechanism of action, the redox properties of 37 quinoxaline-2-carboxamide 1,4-di-N-oxides with varying degrees of anti-tuberculosis activity were studied in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. For all compounds studied, electrochemical reduction in DMF is consistent with the reduction of the N-oxide functionality to form a radical anion. The influence of molecular structure on reduction potential is addressed and it can be said that a general relationship exists between reduction potential and reported antimicrobial activity. For those compounds which have demonstrated promising biological activity, the more active the compound the less negative the reduction potential typically is. The results suggest the possible participation of charge transfer processes in the mechanism of action of quinoxaline di-N-oxides against tuberculosis and offer new insights into the design of future antitubercular drugs.
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    Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents
    (Elsevier, 2013-05-30) Devarapally, G. (Goutham); Aldana, I. (Ignacio); Torres, E. (Enrique); Gonzalez, M. (Mercedes); Varela, J. (Javier); Di-Maio, R. (Rossanna); Birriel, E. (Estefanía); Arbillaga, L. (Leire); Pérez-Silanes, S. (Silvia); Galiano, S. (Silvia); Monge, A. (Antonio); Moreno-de-Viguri, E. (Elsa); Cerecetto, H. (Hugo); Azqueta, A. (Amaya); Crawford, P.W. (Philip W.)
    As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-Noxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with fluoro groups at the 6- and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups,possessed a greater ease of reduction of the N-oxide groups