Search Results (4)

Aromatic isocyanides have gained a lot of attention lately as promising antifungal and anticancer drugs, as well as high-performance fluorescent analytical probes for the detection of toxic metals, such as mercury, even in vivo. Since this topic is relatively new and aromatic isocyanides possess unique photophysical properties, the understanding of structure–behavior relationships and the preparation of novel potentially biologically active derivatives are of paramount importance. Here, we report the photophysical characterization of 1,5-diisocyanonaphthalene (DIN) backed by quantum chemical calculations. It was discovered that DIN undergoes hydrolysis in certain solvents in the presence of oxonium ions. By the careful control of the reaction conditions for the first time, the nonsymmetric product 1-formamido-5-isocyanonaphthalene (ICNF) could be prepared. Contrary to expectations, the monoformamido derivative showed a significant solvatochromic behavior with a ~50 nm range from hexane to water. This behavior was explained by the enhanced H-bond-forming ability of the formamide group. The significance of the hydrolysis reaction is that the isocyano group is converted to formamide in living organisms. Therefore, ICNF could be a potential drug (for example, antifungal) and the reaction can be used as a model for the preparation of other nonsymmetric formamido–isocyanoarenes. In contrast to its relative 1-amino-5-iscyanonaphthalene (ICAN), ICNF is highly fluorescent in water, enabling the development of a fluorescent turnoff probe. Full article

As the recent outbreak of coronavirus disease 2019 (COVID-19) has shown, viral infections are prone to secondary complications like invasive aspergillosis with a high mortality rate, and therefore the development of novel, effective antifungals is of paramount importance. We have previously demonstrated that 1-amino-5-isocyanonaphthalene (ICAN) derivatives are promising original drug candidates against Candida strains (Patent pending), even against fluconazole resistant C. albicans. Consequently, in this study ICANs were tested on Aspergillus fumigatus, an opportunistic pathogen, which is the leading cause of invasive and systematic pulmonary aspergillosis in immunosuppressed, transplanted and cancer- or COVID-19 treated patients. We have tested several N-alkylated ICANs, a well as 1,5-naphthalene-diisocyanide (DIN) with the microdilution method against Aspergillus fumigatus strains. The results revealed that the diisocyanide (DIN) was the most effective with a minimum inhibitory concentration (MIC) value as low as 0.6 µg mL⁻¹ (3.4 µM); however, its practical applicability is limited by its poor water solubility, which needs to be overcome by proper formulation. The other alkylated derivatives also have in vitro and in vivo anti-Aspergillus fumigatus effects. For animal experiments the second most effective derivative 1-N, N-dimethylamino-5-isocyanonaphthalene (DIMICAN, MIC: 7–8 µg mL⁻¹, 36–41 µM) was selected, toxicity tests were made with mice, and then the antifungal effect of DIMICAN was tested in a neutropenic aspergillosis murine model. Compared to amphotericin B (AMB), a well-known antifungal, the antifungal effect of DIMICAN in vivo turned out to be much better (40% vs. 90% survival after eight days), indicating its potential as a clinical drug candidate. Full article

Aromatic isocyanides including isocyanonaphthalene derivatives have been proven to be very effective fluorescent sensors for the quantification of Hg(II) ions in water. Thus, the reaction of 1,5-isocyanoaminonaphthalene (1,5-ICAN), which is one of the most important members of this family, with water and HgCl₂ as the oxidation agents, was studied by fluorescence spectroscopy and mass spectrometry in order to get deeper insight into the kinetics and mechanistic details of this complex reaction. The reactions of 1,5-ICAN with water and HgCl₂ were performed in various water/co-solvent mixtures of different compositions. The co-solvents used in this study were both aprotic solvents including tetrahydrofuran, acetonitrile and N,N-dimethylformamide and protic solvents, such as ethanol and 2-propanol. It was found that in aprotic solvents the conversion of the isocyano group to amino moiety takes place, while in protic solvents the corresponding carbamate (urethane) group is formed in addition to the amino moiety. The variation of the resulting fluorescence intensities versus time curves were described using an irreversible, consecutive reaction model, in which the formation of isocyanate and carbamic acid intermediates, as well as diamino and carbamate (in the case of protic solvents) products were assumed. The formation of these intermediates and products was unambiguously confirmed by mass spectrometric measurements. Furthermore, by fitting the model to the experimental fluorescence versus time curves, the corresponding rate coefficients were determined. It was observed that the overall rate of transformation of the isocyano group to amino moiety increased with the water concentration and the polarity of the co-solvent. It was also supported that formation of diamino and carbamate derivatives in protic solvents takes place simultaneously and that the ratio of the amino to the carbamate function increased with the increasing water concentration. In addition, with an extension, the model presented herein proved to be capable of describing the kinetics of the transformation of 1,5-diisocyanonaphthalene (1,5-DIN) into 1,5-diaminonaphthalene (1,5-DAN) in the mixtures of water/aprotic solvents. Full article

Multiple drug resistant fungi pose a serious threat to human health, therefore the development of completely new antimycotics is of paramount importance. The in vitro antifungal activity of the original, 1-amino-5-isocyanonaphthalenes (ICANs) was evaluated against reference strains of clinically important Candida species. Structure-activity studies revealed that the naphthalene core and the isocyano- together with the amino moieties are all necessary to exert antifungal activity. 1,1-N-dimethylamino-5-isocyanonaphthalene (DIMICAN), the most promising candidate, was tested further in vitro against clinical isolates of Candida species, yielding a minimum inhibitory concentration (MIC) of 0.04–1.25 µg/mL. DIMICAN was found to be effective against intrinsically fluconazole resistant Candida krusei isolates, too. In vivo experiments were performed in a severly neutropenic murine model inoculated with a clinical strain of Candida albicans. Daily administration of 5 mg/kg DIMICAN intraperitoneally resulted in 80% survival even at day 13, whereas 100% of the control group died within six days. Based on these results, ICANs may become an effective clinical lead compound family against fungal pathogens. Full article