19503-64-1Relevant articles and documents
Design, synthesis, and biological activities of closantel analogues: Structural promiscuity and its impact on onchocerca volvulus
Garner, Amanda L.,Gloeckner, Christian,Tricoche, Nancy,Zakhari, Joseph S.,Samje, Moses,Cho-Ngwa, Fidelis,Lustigman, Sara,Janda, Kim D.
, p. 3963 - 3972 (2011/08/05)
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 L3moltingwas 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.
Design, synthesis, and multivariate quantitative structure-activity relationship of salicylanilides-potent inhibitors of type III secretion in Yersinia
Dahlgren, Markus K.,Kauppi, Anna M.,Olsson, Ing-Marie,Linusson, Anna,Elofsson, Mikael
, p. 6177 - 6188 (2008/09/16)
Analogues to the salicylanilide N-(4-Chlorophenyl)-2-acetoxy-3,5- diiodobenzamide, 1a, an inhibitor of type III secretion (T3S) in Yersinia, were selected, synthesized, and biologically evaluated in three cycles. First, a set of analogues with variations in the salicylic acid ring moiety was synthesized to probe possible structural variation. A basic structure-activity relationship was established and then used to cherry-pick compounds from a principal component analysis score plot of salicylanilides to generate a second set. A third set with increased likelihood of biological activity was designed using D-optimal onion design. A quantitative structure-activity relationship model using hierarchical partial least-square regression to latent structures (Hi-PLS) was computed using PLS score vectors of building blocks correlated to the % inhibition of T3S as a response. A PLS discriminant analysis (PLS-DA) model was derived using the same descriptor set as that for the Hi-PLS model. Both models were validated with an external test set.
