64198-95-4Relevant articles and documents
Antifungal, cytotoxic and SAR studies of a series of N-alkyl, N-aryl and N-alkylphenyl-1,4-pyrrolediones and related compounds
Sortino,Garibotto,Cechinel Filho,Gupta,Enriz,Zacchino
experimental part, p. 2823 - 2834 (2011/06/21)
The synthesis, in vitro evaluation and SAR studies of 67 maleimides and derivatives acting as antifungal agents are reported. A detailed SAR study supported by theoretical calculations led us to determine that: an intact maleimido ring appears to be necessary for a strong antifungal activity, dissimilarly affected by the substituents in positions 2 and 3. The best activities were shown by 2,3-nonsubstituted followed by 2,3 dichloro- and 2-methyl-substituted maleimides. They all were fungicide rather than fungistatic enhancing the importance of their antifungal activity. 2,3-Dimethyl and 2,3-diphenyl-maleimides possessed marginal or null activity. The presence of a flexible connecting chain in N-phenylalkyl maleimides appears not to be essential for antifungal activity, although its length shows a correlation with the antifungal behavior, displaying maleimides with alkyl chains of n = 3 and n = 4 the best antifungal activities in most fungi. Different substituents on the benzene ring did not have a clear influence on the activity. Values of chemical potential properties as well as of energy do not sufficiently discriminate between active and inactive compounds. Nevertheless, it was found that, although log P alone is not strong enough to properly predict the antifungal activity, the comparison of its values for compounds within the same sub-type, showed an enhancement of antifungal activity along with an increment of lipophilicity. In addition, the LUMO's electronic clouds of the highly active compounds showed to be concentrated on the imido ring, indicating that their carbon atoms are potential sites for nucleophilic attack. Same results were obtained from MEPs. Most of the active compounds did not show cytotoxic activity against human cancer cell lines and no one possessed hemolytic activity, indicating that their activity is selective to pathogenic fungi and that they are not toxic at MIC concentrations.
N-Phenyl and N-phenylalkyl-maleimides acting against Candida spp.: Time-to-kill, stability, interaction with maleamic acids
Sortino, Maximiliano,Cechinel Filho, Valdir,Correa, Rogerio,Zacchino, Susana
, p. 560 - 568 (2008/09/18)
N-Phenyl and N-phenylalkyl maleimides (alkyl chain = (CH2)n; n = 0-4) and their respective open derivatives (maleamic acids) were evaluated against Candida spp. with the microbroth dilution method following the guidelines of CLSI (formely NCCLS). MIC values of maleimides without pre-incubation and submitted to different pre-incubation times into the growth media, time-to-kill studies as well as a time-dependent UV-spectroscopy study of the maleimides in water, led to determine that maleimides display antifungal activities with their intact maleimide ring, being in addition their activities not dependent on the length of the alkyl chain. They are not only fungistatic but fungicidal with very low MICs and MFCs, displaying strong fungicide activities not only against standardized but also clinical isolates of Candida albicans and non-albicans Candida spp.
