DFT/PCM, QTAIM, ¹H NMR conformational studies and QSAR modeling of thirty-two anti-Leishmania amazonensis Morita-Baylis-Hillman Adducts

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• 作者：Edilson B.A. Filho ; Ingrid A. Moraes ; Karen C. Weber ; Gerd B. Rocha ; M¨¢rio L.A.A. Vasconcellos
• 关键词：Morita&ndash ; Baylis&ndash ; Hillman Adducts ; Leishmania amazonensis ; DFT/PCM ; QTAIM ; QSAR
• 刊名：Journal of Molecular Structure
• 出版年：2012
• 出版时间：29 August, 2012
• 年：2012
• 卷：1022
• 期：Complete
• 页码：72-80
• 全文大小：1495 K

文摘

Morita-Baylis-Hillman Adducts (MBHA) has been recently synthesized and bio-evaluated by our research group against Leishmania amazonensis, parasite that causes cutaneous and mucocutaneous leishmaniasis. We present here a theoretical conformational study of thirty-two leismanicidal MBHA by B3LYP/6-31+g(d) calculations with Polarized Continuum Model (PCM) to simulate water influence. Intramolecular Hydrogen Bonds (IHBs) indicated to control the most conformational preferences of MBHA. Quantum Theory Atoms in Molecules (QTAIM) calculations were able to characterize these interactions at Bond Critical Point level. Compounds presenting an unusual seven member IHB between NO₂ group and hydroxyl moiety, supported by experimental spectroscopic data, showed a considerable improvement of biological activity (lower IC₅₀ values). These results are in accordance to redox NO₂ mechanism of action. Based on structural observations, some molecular descriptors were calculated and submitted to Quantitative Structure-Activity Relationship (QSAR) studies through the PLS Regression Method. These studies provided a model with good validation parameters values (R² = 0.71, Q² = 0.61 and  = 0.92).