139336-31-5Relevant articles and documents
N-alkylated thiazolidine-2,4-dione analogs as PTP1B inhibitors: synthesis, biological activity, and docking studies
Mahapatra, Manoj K.,Kumar, Rajnish,Kumar, Manoj
, p. 1176 - 1183 (2017)
Protein tyrosine phosphatase 1B enzyme has been found to be a negative regulator of insulin and leptin signaling pathway. It has gained considerable attention to medicinal chemists as a new therapeutic target for intervention in the treatment of type2 diabetes. A series of N-substituted-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione derivatives were synthesized and screened in vitro for protein tyrosine phosphatase 1B inhibitory activity and in vivo for anti-hyperglycaemic activity. The introduction of alkyl/halo alkyl moiety onto the amidic nitrogen of thiazolidine-2,4-dione ring was intended to enhance the inhibitor-enzyme affinity and hence, good protein tyrosine phosphatase 1B inhibition. The nature of interactions which governs the binding mode of ligands inside the active site of protein tyrosine phosphatase 1B was further studied by molecular docking simulation. Compound 7 was found to be a potent protein tyrosine phosphatase 1B inhibitor with IC50 9.96 μM. The synthesized compounds have also shown significant lowering of blood glucose level.
Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3β and Tau-Aggregation Inhibitors
Gandini, Annachiara,Bartolini, Manuela,Tedesco, Daniele,Martinez-Gonzalez, Loreto,Roca, Carlos,Campillo, Nuria E.,Zaldivar-Diez, Josefa,Perez, Concepción,Zuccheri, Giampaolo,Miti, Andrea,Feoli, Alessandra,Castellano, Sabrina,Petralla, Sabrina,Monti, Barbara,Rossi, Martina,Moda, Fabio,Legname, Giuseppe,Martinez, Ana,Bolognesi, Maria Laura
, p. 7640 - 7656 (2018/09/06)
Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3β and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC50 values toward GSK-3β, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 μM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.
Privileged scaffolds or promiscuous binders: A comparative study on rhodanines and related heterocycles in medicinal chemistry
Mendgen, Thomas,Steuer, Christian,Klein, Christian D.
supporting information; experimental part, p. 743 - 753 (2012/03/11)
Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compounds that appear as "frequent hitters" in screening campaigns and therefore have little value in drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines and related compounds in screening campaigns, we decided to perform a systematic study on their promiscuity. An amount of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compounds were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compounds in published X-ray cocrystal structures were analyzed. The results indicate that the exocyclic, double bonded sulfur atom in rhodanines and thiohydantoins, in addition to other structural features, offers a particularly high density of interaction sites for polar interactions and hydrogen bonds. This causes a promiscuous behavior at concentrations in the "screening range" but should not be regarded as a general knockout criterion that excludes such screening hits from further development. It is suggested that special criteria for target affinity and selectivity are applied to these classes of compounds and that their exceptional and potentially valuable biomolecular binding properties are consequently exploited in a useful way.
