Martin Kratky
PC17 – Martin Kratky
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
martin.kratky@faf.cuni.cz
| 3,5-Diiodosalicylaldehyde: A Valuable Building Block for Novel Antifungal Agents |
| Krátký Martin1, Vávrová Pavlína1, and Konečná Klára2 1 Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic |
| Abstract The increasing global burden of fungal infections, combined with emerging resistance and toxicity of used drugs, highlights the urgent need for new antifungal agents. Current pipeline remains insufficient to adequately address priority fungal pathogens. Therefore, the synthesis of new molecules is essential for identification of novel chemotypes for safer and more effective antifungals [1]. Iodinated aromatics [2] and salicylic scaffolds [3] represent attractive motifs in antifungal design, demonstrating potency against various species, including resistant isolates. That is why we investigated iodinated salicylic-based compounds as promising antifungal agents. We identified a condensate of 3,5-diiodosalicylaldehyde with D-cycloserine with potent activity, with MIC values ³3.9 µM for yeasts and ³15.62 µM for moulds, accompanied by mild inhibition of Gram-positive bacteria and mycobacteria (MIC ≥62.5 µM). This finding inspired an extensive structure–activity relationship study, focused on the positional isomer of 3,5-diiodosalicyl-aldehyde, modification of the phenolic group, the linker between the aldehyde and the second part of the molecule (imine, hydrazone, hydrazide–hydrazone), and substituent R (Figure 1). The results highlight the importance of the 3,5-diiodosalicylidene moiety. Among the linkers studied, the hydrazide–hydrazone group, followed by the imine moiety, contributed most to enhanced activity. Activity was also favored by an (hetero)aromatic substituent R, although hydrazones bearing (cyclo)alkyls also exhibited some activity. The most active analogues showed MIC values as low as 0.49 µM, selective antifungal activity and no cytotoxicity. Evaluation against clinical isolates and detailed characterization of antifungal activity are ongoing.  |
| References [1] World Health Organization. Antifungal agents in clinical and preclinical development: overview and analysis; WHO: Geneva, Switzerland, 2025. pp. 1–73. [2] Ihssen, J.; Reiss, R.; Luchsinger, R.; Thöny-Meyer, L.; Richter, M. Laccase-Catalyzed Synthesis of Iodinated Phenolic Compounds with Antifungal Activity. PLoS ONE 2014, 9, e89924. DOI: 10.1371/journal.pone.0089924. [3] Biersack, B. The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides. Int. J. Mol. Sci. 2024, 25, 5977. DOI: 10.3390/ijms25115977. This work was supported by Ministry of Health of the Czech Republic, grant nr. NW24-05-00539. |