title: Design, synthesis, and biological activities of closantel analogues: structural promiscuity and its impact on Onchocerca volvulus.
abstract: Onchocerciasis, or river blindness, is a neglected tropical disease that affects more than 37 million people worldwide, primarily in Africa and Central and South America. We have disclosed evidence that the larval-stage-specific chitinase, OvCHT1, may be a potential biological target for affecting nematode development. On the basis of screening efforts, closantel, a known anthelmintic drug, was discovered as a potent and highly specific OvCHT1 inhibitor. Originally, closantel's anthelmintic mode of action was believed to rely solely on its role as a proton ionophore; thus, the impact of each of its biological activities on O. volvulus L3 molting was investigated. Structure-activity relationship studies on an active closantel fragment are detailed, and remarkably, by use of a simple salicylanilide scaffold, compounds acting only as protonophores or chitinase inhibitors were identified. From these data, unexpected synergistic protonophore and chitinase inhibition activities have also been found to be critical for molting in O. volvulus L3 larvae.
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, La Jolla, CA 92037, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Garner
authors.forename: Christian
authors.initials: C
authors.lastname: Gloeckner
authors.forename: Nancy
authors.initials: N
authors.lastname: Tricoche
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Zakhari
authors.forename: Moses
authors.initials: M
authors.lastname: Samje
authors.forename: Fidelis
authors.initials: F
authors.lastname: Cho-Ngwa
authors.forename: Sara
authors.initials: S
authors.lastname: Lustigman
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004847:Epithelial Cells; D005369:Filaricides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D000882:Haplorhini; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007814:Larva / Q000187:drug effects; D015394:Molecular Structure; D018978:Molting / Q000187:drug effects; D017181:Onchocerca volvulus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D009855:Onchocerciasis / Q000188:drug therapy / Q000469:parasitology; D015827:Onchocerciasis, Ocular / Q000188:drug therapy / Q000469:parasitology; D011522:Protons; D012458:Salicylanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005369:Filaricides; D007476:Ionophores; D011522:Protons; D012458:Salicylanilides; D002688:Chitinases; C023342:closantel