Correlation between electrochemical and theoretical studies on the leishmanicidal activity of twelve Morita-Baylis-Hillman adducts

Abstract

O processo de biorredução enzimática do grupo nitro é de grande importância para a ação molecular de nitrocompostos aromáticos biologicamente ativos. Os métodos eletroquímicos são considerados ferramentas úteis para a simulação de processos metabólicos in vivo. No presente trabalho, realizaram-se estudos eletroquímicos em meio aprótico (N,N-dimetilformamida (DMF) mais perclorato de tetrabutilamônio (TBAP) 0,1 mol L -1 ) utilizando-se as técnicas de voltametria cíclica (CV), de pulso diferencial (DPV) e de onda quadrada (SWV) de 12 adutos de Morita-Baylis-Hillman (MBHA) com atividade leishmanicida significativa. Para facilitar a análise, os adutos foram agrupados em quatro classes de acordo com a cadeia lateral. Os estudos de CV evidenciam duas ondas referentes à redução do grupo nitro e uma ou duas outras ondas (em potencial mais negativo) relativas à redução da função carbonila α,β-insaturada ou da olefina ativada por grupos nitrila. Adutos orto-substituídos apresentam maior facilidade de redução quando comparados aos demais isômeros (meta e para) em função, provavelmente, da ligação de hidrogênio entre o grupo nitro e a hidroxila benzílica, o que estabiliza mais o produto eletrogerado do que o composto de partida. Derivados orto também mostram uma maior atividade leishmanicida em comparação com seus isômeros em cada série. Estudos conformacionais usando HF/6-31+G(d)/PCM como nível de cálculo evidenciaram este efeito. Valores calculados de dureza molecular (N) e de cargas atômicas (Q N ) explicam corretamente os dados experimentais obtidos.Enzymatic bioreduction of nitro groups plays an important role on the activity of biologically active nitroaromatic compounds. Electrochemical methods are useful tools to simulate in vivo metabolic processes. This work presents electrochemical studies in aprotic media (N,N-dimethylformamide (DMF) plus tetrabutylammonium perchlorate (TBAP) 0.1 mol L -1 ) using cyclic voltammetry (CV), differential pulse voltammetry (DPV) and square wave voltammetry (SWV) of twelve Morita-Baylis-Hillman adducts (MBHA) with significant leishmanicidal activity. To facilitate the analysis, the molecules were grouped in four classes according to the side chain. CV studies show three up to four reduction waves, in which the first two waves are related to nitro group reduction. The other waves (presenting more negative potential) refer to the reduction of the α,β-unsaturated carbonyl or to the nitrile activated olefin side-chain. Ortho adducts present facilitated reduction in comparison to the other isomers (meta and para) possibly due to hydrogen bond formation between the benzylic-OH and the nitro group, which stabilizes the reduction product (anion radical nitro) more efficiently than the original compound. Ortho derivatives also present higher leishmanicidal activity upon comparison to the other derivatives of each class. Conformational studies using HF/6-31+G(d)/PCM as a calculation level highlight this effect. Molecular hardness (N) and atomic charges (Q N ) values corroborate the obtained expe...

Morita-Baylis-Hillman adduct showsin vitroactivity againstLeishmania (Viannia) braziliensisassociated with a reduction in IL-6 and IL-10 but independent of nitric oxide

“…The low ionization potential of HNAB can contribute to the generation of free radicals once inside the macrophages or the intracellular parasites (De Paiva et al 2012). The low ionization potential of HNAB can contribute to the generation of free radicals once inside the macrophages or the intracellular parasites (De Paiva et al 2012).…”

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

“…Biological antileishmaniasis activities (measured by the IC 50 ) for a series of 12 nitroaromatic compounds ( Figure 1 )—adducts of Morita–Baylis–Hillman (MBHA) reaction—have been previously reported by researchers [ 25 , 26 , 27 ]. For this series, 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 − (0.1 mol·L −1 ) as reference electrode at 25 °C (±2 °C).…”

“…All quantum chemistry calculations for a series of 12 MBHA with direct protocol were performed using the Gaussian 09 [ 61 ] software. Global minima for neutral species were determined at HF/6-31+G(d) level [ 25 ]. All structures in their neutral and reduced states were reoptimized with default convergence criteria at HF [ 62 ] level, and the effect of basis set size were tested with double and triple- zeta Pople’s basis adding progressively diffuse and polarization functions [ 63 ].…”

“…An indicative of this mechanism is the experimental observation of the relationship between the reduction potential and the pharmacological action of some nitro compounds (greater biological activity correlated with the least negative potential), which can be used for modeling new bioactive compounds [ 24 ]. For this reason, electrochemical methods are considered useful tools for simulation of metabolic processes in vivo [ 25 , 26 ].…”

“…The first cathodic peak ( E cp1 , values in parentheses in Figure 1 ) was related to the generation of stable nitro-anion radicals in a diffusion-controlled reversible system. A strong relationship between antileishmaniasis IC 50 and cathodic peak E cp1 values was observed when comparing the inter-series of MBHA compounds [ 25 , 26 ].…”