4214-48-6Relevant academic research and scientific papers
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.
Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)
Steffen, Jamin D.,Coyle, Donna L.,Damodaran, Komath,Beroza, Paul,Jacobson, Myron K.
, p. 5403 - 5413 (2011/10/02)
The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.
Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria
Macielag, Mark J.,Demers, James P.,Fraga-Spano, Stephanie A.,Hlasta, Dennis J.,Johnson, Sigmond G.,Kanojia, Ramesh M.,Russell, Ronald K.,Sui, Zhihua,Weidner-Wells, Michele A.,Werblood, Harvey,Foleno, Barbara D.,Goldschmidt, Raul M.,Loeloff, Michael J.,Webb, Glenda C.,Barrett, John F.
, p. 2939 - 2945 (2007/10/03)
A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron- attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2,3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6.3 μM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
Relationships between the chemical structure of antimycobacterial substances and their activity against atypical strains. Part 14: 3-Aryl-6,8-dihalogeno-2H-1,3-benzoxazine-2,4(3H)-diones)
Waisser, Karel,Hladuvkova, Jana,Gregor, Jiri,Rada, Tomas,Kubicova, Lenka,Klimesova, Vera,Kaustova, Jarmila
, p. 3 - 6 (2007/10/03)
A set of eight derivatives of 6,8-dichloro-3-phenyl-2H-benzoxazine-2,4(3H)-dione and nine derivatives of 6,8-dibromo-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dione, substituted on the phenyl ring, was prepared by the reaction of the corresponding salicylanilides with ethyl chloroformate. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. Their activity increases with increasing hydrophobicity and electron-withdrawing ability of the substituents on the phenyl ring.
