780-05-2Relevant academic research and scientific papers
An approach to "escape from flatland": Chemo-enzymatic synthesis and biological profiling of a library of bridged bicyclic compounds
Suryanarayana Birudukota,Franke, Raimo,Hofer, Bernd
, p. 3821 - 3837 (2016/05/09)
A major reason for the low success rate in current drug development through chemical synthesis has been ascribed to the large fraction of quasi planar candidate molecules. Therefore, an "escape from flatland" strategy has been recommended for the generation of bioactive chemical entities. In a first attempt to test this recommendation, we synthesized a small collection of bridged bicyclic compounds possessing a rigid spherical core structure by combining a group of cyclic dienes with a collection of dienophiles. We started from planar biphenyl analogues and, by enzymatic dioxygenation, transformed them into hydroxylated diene structures. Using a small library of newly synthesized dienophiles, the dienes were converted into bridged bicycles via the Diels-Alder reaction. The resulting collection of 78 structures was first tested for bioactivity in a generic assay based on interference with the proliferation of mammalian cells. A more mechanism-targeted bioactivity profiling method, exploiting cellular impedance monitoring, was subsequently used to obtain suggestions for the mode of action exerted by those compounds that were the most active in the proliferation assay. Proteasome inhibition could be confirmed for 8 of a series of 9 respective candidates. Whilst 7 of these molecules showed relatively weak interference with proteasome activity, one candidate exerted a moderate but distinct inhibition. This result appears remarkable in view of the small size of the compound library, which was synthesized following a few basic considerations. It encourages the application of diverse synthetic approaches to further investigate the role of spherical shape for the success of compound libraries.
Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans
Premachandra, Ilandari Dewage Udara Anulal,Scott, Kevin A.,Shen, Chengtian,Wang, Fuqiang,Lane, Shelley,Liu, Haoping,Van Vranken, David L.
, p. 1672 - 1686 (2015/10/06)
A spiroindolinone, (1S,3R,3aR,6aS)-1-benzyl-6′-chloro-5-(4-fluorophenyl)-7′-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3′-1H-indole]-2′,4,6-trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, was found to enhance the effect of fluconazole with an EC50 value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy. Synergy from stereochemical complexity: An attempt to synthesize analogues of a known spiroindolinone led to a series of diastereomers. One spiroindolinone, termed synazo-1, was shown to exhibit potent activity (300 pM) against C. albicans in the presence of fluconazole. Synazo-1 is a true synergizer and was also highly active against some drug-resistant C. albicans strains.
DABCO-catalyzed [3+2] cycloaddition reactions of azomethine imines with N-aryl maleimides: Facile access to dinitrogen-fused heterocycles
Jia, Qianfa,Chen, Lei,Yang, Gongming,Wang, Jian,Wei, Jia,Du, Zhiyun
supporting information, p. 7150 - 7153 (2015/12/12)
DABCO-catalyzed [3+2] cycloaddition of azomethine imines with maleimides has been developed. This method could efficiently furnish dinitrogen-fused tetracyclic heterocycles in high levels of regioselectivity and with good yields.
A rapid and simple amine-catalyzed microwave-assisted isomerization of maleamides into fumaramides
Majce, Vita,Ko?evar, Marijan,Polanc, Slovenko
supporting information; experimental part, p. 3287 - 3290 (2011/06/28)
An improved, efficient, and simple method for the synthesis of nonsymmetrical diamides of fumaric acid is reported. Starting from commercially available substrates, maleic diamides are formed in two steps, and then isomerized in a focused microwave reactor in acetonitrile as the solvent in the presence of a catalytic amount of piperidine, giving the corresponding fumaramides in high yields and purity.
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.
Synthesis and in vitro evaluation of N-substituted maleimide derivatives as selective monoglyceride lipase inhibitors
Matuszak, Nicolas,Muccioli, Giulio G.,Labar, Geoffray,Lambert, Didier M.
experimental part, p. 7410 - 7420 (2010/04/30)
The endocannabinoid 2-arachidonoylglycerol (2-AG) plays a major role in many physiological processes, and its action is quickly terminated via enzymatic hydrolysis catalyzed by monoglyceride lipase (MGL). Regulating its endogenous level could offer therapeutic opportunities; however, few selective MGL inhibitors have been described so far. Here, we describe the synthesis of N-substituted maleimides and their pharmacological evaluation on the recombinant human fatty acid amide hydrolase (FAAH) and on the purified human MGL. A few N-arylmaleimides were previously described (Saario, S. M.; Salo, O. M.; Nevalainen, T.; Poso, A.; Laitinen, J. T.; Jarvinen, T.; Niemi, R. Characterization of the Sulfhydryl-Sensitive Site in the Enzyme Responsible for Hydrolysis of 2-Arachidonoylglycerol in Rat Cerebellar Membranes. Chem. Biol. 2005, 12, 649-656) as MGL inhibitors, and along these lines, we present a new set of maleimide derivatives that showed low micromolar IC50 and high selectivity toward MGL vs FAAH. Then, structure-activity relationships have been investigated and, for instance, 1-biphenyl-4-ylmethylmaleimide inhibits MGL with an IC50 value of 790 nM. Furthermore, rapid dilution experiments reveal that these compounds act as irreversible inhibitors. In conclusion, N-substituted maleimides constitute a promising class of potent and selective MGL inhibitors.
Substituent chemical shifts of N-arylsuccinanilic acids, N-arylsuccinimides, N-arylmaleanilic acids, and N-arylmaleimides
Lee, Hye Sun,Yu, Ji Sook,Lee, Chang Kiu
scheme or table, p. 711 - 715 (2010/07/05)
NMR spectra of a series of N-arylsuccinanilic acids, N-arylsuccinimides, N-arylmaleanilic acids, and N-arylmaleimides were examined to estimate the electronic effect of the amide and imide groups on the chemical shifts of the hydrogen and carbon nuclei of the benzene ring.
First triphenylphosphine promoted reduction of maleimides to succinimides
Pal, Bikash,Pradhan, Prasun K.,Jaisankar, Parasuraman,Giri, Venkatachalam S.
, p. 1549 - 1552 (2007/10/03)
Triphenylphosphine (TPP) in refluxing methanol effectively reduces maleimides 1a-g to the corresponding succinimides 2a-g in good yields. It was observed that some maleimides obtained from aromatic halogen compounds 1h-j were transformed into the corresponding succinamic acid methyl esters 3a-c by this reaction.
INFLUENCE OF MEDIUM AND SUBSTITUENTS ON ACYLATION OF AROMATIC AMINES AND THEIR POLYMERIC ANALOGS WITH MALEIC ANHYDRIDE
Donya, A. P.,Pakter, M. K.,Sokhina, S. I.
, p. 2093 - 2097 (2007/10/02)
Correlation relationships describing the influence of substituents and solvents on the rate of acylation of aromatic amines and their polymeric analogs with maleic anhydride have been derived.
