title: Pyrrolo[1,2-α][1,4]benzodiazepines show potent in vitro antifungal activity and significant in vivo efficacy in a Microsporum canis dermatitis model in guinea pigs.
abstract: 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.
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Paulussen
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: de Wit
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Boulet
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.affiliation: Janssen, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Meerpoel
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium louis.maes@ua.ac.be.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D003881:Dermatomycoses / Q000188:drug therapy / Q000382:microbiology*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008864:Microsporum / Q000187:drug effects*; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D001381:Azepines; D011758:Pyrroles; C506245:Pyrrolo(1,2-a)(1,4)benzodiazepine
keywords: antifungal profiling; dermatophytes; lead discovery