Synthesis and evaluation of nitrostyrene derivative compounds, new snake venom phospholipase A 2 inhibitors

Abstract

Several nitrostyrene derivatives were synthesized and their inhibitive activities on phospholipase A 2 (PLA 2) from Bothrops jararacussu venom were evaluated. Some compounds were very efficient as inhibition agents against edema-inducing, enzymatic and myotoxic activities. Data revealed that the size of the substitute and substitution position in the nitrostyrene moiety had important influence on the inhibition capacities. The enzymatic kinetic studies show that the nitrostyrene derivatives compounds inhibit PLA 2 in a non-competitive manner. The electronic, molecular and topologic parameters were calculated using ab initio quantum calculations (density functional theory—DFT) and analyzed by chemometric methods (principal component analysis (PCA) and hierarchical cluster analysis (HCA)) in order to build models able to establish relationships between the electronic features and the structure–activity presented by the target compound. Compounds with the nitro group in the ortho, meta and para position (compounds 2–4) on the aromatic ring were more efficient in the inhibition of PLA 2 activity in all tests. These results indicate that the influence of the nitro group in the aromatic ring is, in fact, important. In addition, quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA 2 present lower values of highest occupied molecular orbital (HOMO) energy and polarizability, suggesting the formation of a charge-transferring complex between the nitrostyrene compounds and PLA 2.