Potential Original Drug for Aspergillosis: In Vitro and In Vivo Effects of 1-N,N-Dimethylamino-5-Isocyanonaphthalene (DIMICAN) on Aspergillus fumigatus

Abstract

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.

Preparation and Optical Study of 1-Formamido-5-Isocyanonaphthalene, the Hydrolysis Product of the Potent Antifungal 1,5-Diisocyanonaphthalene

“…The resulting intramolecular charge transfer (ICT) gives rise to excellent solvatochromic properties, as we previously demonstrated through 1-amino-5-isocyanonaphthalene (ICAN) [11]. The spectrophysical properties are easily controlled by the relative positions of the -NH2 and -NC groups [12], as well as the substituents (reactive [14,16] or inert [13,18,22]) on the -NH2 group or by exchanging the aromatic core [19][20][21]. The synthesis of ICAN derivatives is cheap and straightforward since the respective aromatic diamine is reacted smoothly with in situgenerated dichlorocarbene (:CCl2) in basic solution [11].…”

“…Utilizing the strong electron withdrawing (EW) nature of the isonitrile group, Nagy et al recently developed a novel class of push-pull fluorophores, where the isocyanide group is connected to an aromatic amine [11][12][13][14][15][16][17][18][19][20][21][22]. The resulting intramolecular charge transfer (ICT) gives rise to excellent solvatochromic properties, as we previously demonstrated through 1-amino-5-isocyanonaphthalene (ICAN) [11].…”

“…However, recently, we demonstrated that 1,5-diisocyanonaphthalene (DIN) could be very effective in the treatment of multidrug-resistant Aspergillus and Candida strains [18,22]. Since Aspergillus fumigatus is one of the most lethal fungal infections, especially for COVID-19 patients [23], the understanding of the solution state properties of DIN is of paramount importance.…”

Excited state iminium form can explain the unexpected solvatochromic behavior of symmetric 1,5- and 1,8-diaminonaphthalenes

“…Very recently we demonstrated that 1,5-DAN is the precursor of a promising family of smart solvatochromic dyes, namely 1-amino-5-isocyanonaphthalenes (ICANs), 1 whose properties are similar to that of PRODAN, 2 however much cheaper and easier to prepare. In addition, ICANs turned out to be promising antifungals 3 against multidrug-resistant Candida and Aspergillus strains, which have high mortality rates in immunosuppressed (for example COVID) patients. During our quest to prepare new ICAN derivatives the most obvious starting molecule was 1,8-DAN.…”

“…This is not the case for 1,8-DAN and 2,3-DAN, where the originally symmetric structure at S 0 distorted under excitation and both the bond lengths and the bond angles alter for the NH 2 groups at the S 1 state. One of the amino groups moves closer to the aromatic core, forming an sp 2 [d(C-N) = 1.35 Å, y = 3601],13 while the other moves further and transforming to sp3 character [d(C-N) = 1.48 Å, y = 3281]. 13 Surprisingly, NH 2 (1, a) becomes clearly sp 3 [d(C-N) = 1.45 Å, y = 3281] and NH 2 (8, b) sp 2 [d(C-N) = 1.367 Å, y = 3601] (Fig.…”