Background: Pyrrolo[1,2-α][1,4]benzodiazepines (PBDs) have been described as a novel class of antifungal compounds with activity against dermatophytes and Aspergillus fumigatus. The initial structure-activity relationship showed that compounds with a chlorine substitution at position 7 have a higher activity compared with regioisomers or other substituents.
Methods: The present study evaluated more analogues with a 7-chlorine-substitution in vitro against a broad panel of clinically relevant fungal species. The Microsporum canis model in guinea pigs was used to assess the in vivo efficacy after oral and topical administration.
Results: IC50 values in the low micromolar range (IC50 0.6-8.0 μM for dihydro-PBDs; 0.1-0.7 μM for oxidized PBDs) confirmed the potent and selective in vitro activity of PBDs against dermatophytes, while the activity against A. fumigatus and Candida parapsilosis was slightly lower. For dihydro-PBDs, para-substitution showed superior activity, while oxidized compounds with a meta-substitution performed best. Oxidized Compound O with meta-CF2CH3-substitution showed excellent IC50 values of 0.6 μM against M. canis, 2.0 μM against Trichophyton mentagrophytes and 0.7 μM against Trichophyton rubrum, matching or outperforming the activity of itraconazole (IC50 values of 2.0, 0.4 and 0.6 μM, respectively). In vivo, topical application of a 0.25% formulation of Compound O gave a lesion reduction of >90% compared with placebo-treated animals. Oral administration of this compound at 20 mg/kg showed superior therapeutic efficacy compared with the reference drug itraconazole.
Conclusions: In conclusion, PBDs with a chlorine atom at position 7 are very promising antifungal candidates with convincing in vitro and in vivo activity particularly against dermatophytes and should be studied in greater detail to explore their full potential in the treatment of dermatophytoses.
Keywords: antifungal profiling; dermatophytes; lead discovery.
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