Imidazoacridinone Derivatives as Efficient Sensitizers in Photoantimicrobial Chemotherapy

Abstract

The objective of this study was to investigate a new potential photosensitizer (PS) in the photodynamic inactivation (PDI) of microorganisms in vitro (11 reference strains and 13 clinical isolates, representing common Gram-positive and Gram-negative human pathogens), with special emphasis on Candida albicans. We studied the light-induced cytotoxicity of the imidazoacridinone derivative C1330 toward fungal cells grown in planktonic form. We examined the influence of various parameters (time of incubation, PDI quencher effect, and C1330 accumulation in C. albicans cells) on the efficacy of light-dependent cytotoxicity. Additionally, we checked for the potential cyto-and phototoxic activity of C1330 against human dermal keratinocytes. In our research, we used a broadband incoherent blue light source (380 to 470 nm) with an output power of 100 mW/cm 2 . In vitro studies showed that the C1330 action against C. albicans was a light-dependent process. C1330 was an efficient photosensitizer in the photodynamic inactivation of C. albicans, which reduced the growth of planktonic cells by 6.1 log 10 units. Efficient accumulation of PS in the nucleus and vacuoles was observed after 30 min of incubation, which correlated with the highest photokilling efficacy. Significant changes in intracellular structure were observed upon illumination of C1330-incubated C. albicans cells. In the case of the human HaCaT cell line, approximately 40% of cells survived the treatment, which indicates the potential benefit of further study of the application of C1330 in photoantimicrobial chemotherapy. These data suggest that PDI may be a viable approach for the treatment of localized C. albicans infections.

‘Acridines’ as New Horizons in Antifungal Treatment

“…Acridine and acridone derivatives are molecules with fluorescence properties that have also been demonstrated to possess photosensitizing properties [26][27][28]. Studies performed by Taraszkiewicz et al showed that imidazoacridinones ( Figure 3) were efficient photosensitizers in the PDI of C. albicans and significantly inhibited the growth of planktonic cells [27]. The highest photokilling efficacy was observed for C-1330, which correlated with an efficient accumulation in the nucleus and vacuoles.…”

“…As described for imidazoacridinone C-1311 ( Figure 4) and its nine derivatives, only three of those that entered in fungal cells (C-1330, C-1415 and C-1558) showed phototoxic antifungal activity ( Figure 3). Despite the high efficiency of C-1311 as an anticancer compound that intercalates into DNA and inhibits human topoisomerase II [29] (was in phase II clinical trials for the treatment of breast cancer [30]), it was unable to accumulate in C. albicans cells and no antifungal activity was observed [27]. Results of experimental investigations demonstrated that the fungicidal activity, which is lightinduced, might depend on the production of superoxide anions [28].…”

“…Amsacrine (m-AMSA) (Figure 1), obtained by Denny's group [33,34], was the first synthetic drug approved for clinical usage that was shown to act as a topoisomerase inhibitor. There has been substantial work showing that the mode of action of m-AMSA as DNA intercalation Despite the high efficiency of C-1311 as an anticancer compound that intercalates into DNA and inhibits human topoisomerase II [29] (was in phase II clinical trials for the treatment of breast cancer [30]), it was unable to accumulate in C. albicans cells and no antifungal activity was observed [27]. Results of experimental investigations demonstrated that the fungicidal activity, which is light-induced, might depend on the production of superoxide anions [28].…”

“…- [17] 1,8-dioxoacridine derivatives - [27,28] Acridine conjugates with branched lysine peptides C. albicans A. niger…”

“…Efficient photosensitizers in photodynamic inactivation (PDI) of C. albicans[27]. Et, -CH 2 CH 3 ; Me, -CH 3 ; OMe, -OCH 3 ; t-butyl, -C(CH 3 ) 3.Molecules 2020, 25, x FOR PEER REVIEW 5 of 13…”