title: New chemotypes for wALADin1-like inhibitors of delta-aminolevulinic acid dehydratase from Wolbachia endobacteria.
abstract: Substituted benzimidazoles of the wALADin1-family have recently been identified as a new class of species-selective inhibitors of delta-aminolevulinic acid dehydratase (ALAD) from Wolbachia endobacteria of parasitic filarial worms. Due to its Wolbachia-dependent antifilarial activity, wALADin1 is a starting point for the development of new drugs against filarial nematodes. We now present several other chemotypes of ALAD inhibitors that have been identified based upon their molecular similarity to wALADin1. A tricyclic quinoline derivative (wALADin2) with a different inhibitory mechanism and improved inhibitory potency and selectivity may represent an improved drug lead candidate.
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Sigmund-Freud Str. 25, 53127 Bonn, Germany; LIMES Institute, Chemical Biology & Medicinal Chemistry Unit, Universität Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Lentz
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stumpfe
authors.forename: Juergen
authors.initials: J
authors.lastname: Bajorath
authors.forename: Michael
authors.initials: M
authors.lastname: Famulok
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Pfarr
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017178:Brugia malayi / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005369:Filaricides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D011804:Quinolines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020577:Wolbachia / Q000201:enzymology*
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D005369:Filaricides; D011804:Quinolines; D013876:Thiophenes; C583087:wALADin1 compound; C037219:quinoline; D000623:Porphobilinogen Synthase
keywords: Brugia malayi; Delta-aminolevulinic acid dehydratase; Heme biosynthesis; Wolbachia; wALADin