290333-07-2Relevant academic research and scientific papers
Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation in Vivo
Halkina, Tamara,Henderson, Jaclyn L.,Lin, Edward Y.,Himmelbauer, Martin K.,Jones, J. Howard,Nevalainen, Marta,Feng, Jun,King, Kristopher,Rooney, Michael,Johnson, Joshua L.,Marcotte, Douglas J.,Chodaparambil, Jayanth V.,Kumar, P. Rajesh,Patterson, Thomas A.,Murugan, Paramasivam,Schuman, Eli,Wong, Laiyee,Hesson, Thomas,Lamore, Sarah,Bao, Channa,Calhoun, Michael,Certo, Hannah,Amaral, Brenda,Dillon, Gregory M.,Gilfillan, Rab,De Turiso, Felix Gonzalez-Lopez
, p. 6358 - 6380 (2021)
Structural analysis of the known NIK inhibitor 3 bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by 8 (cell IC50: 571 nM). Systematic optimization of this series of analogs l
Second-Generation Meridianin Analogues Inhibit the Formation of Mycobacterium smegmatis Biofilms and Sensitize Polymyxin-Resistant Gram-Negative Bacteria to Colistin
Melander, Christian,Melander, Roberta J.,Zeiler, Michael J.
supporting information, p. 1672 - 1679 (2020/08/05)
Drug-resistant bacteria are rapidly becoming a significant problem across the globe. One element that factors into this crisis is the role played by bacterial biofilms in the recalcitrance of some infections to the effects of conventional antibiotics. Bacteria within a biofilm are highly tolerant of both antibiotic treatment and host immune responses. Biofilms are implicated in many chronic infections, including tuberculosis, in which they can act as bacterial reservoirs, requiring an arduous antibiotic regimen to eradicate the infection. A separate, compounding problem is that antibiotics once seen as last-resort drugs, such as the polymyxin colistin, are now seeing more frequent usage as resistance to front-line drugs in Gram-negative bacteria becomes more prevalent. The increased use of such antibiotics inevitably leads to an increased frequency of resistance. Drugs that inhibit biofilms and/or act as adjuvants to overcome resistance to existing antibiotics will potentially be an important component of future approaches to antibacterial treatment. We have previously demonstrated that analogues of the meridianin natural product family possess adjuvant and antibiofilm activities. In this study, we explore structural variation of the lead molecule from previous studies, and identify compounds showing both improved biofilm inhibition potency and synergy with colistin.
Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents
Yadav, Rammohan R.,Sharma, Sadhana,Joshi, Prashant,Wani, Abubakar,Vishwakarma, Ram A.,Kumar, Ajay,Bharate, Sandip B.
, p. 2948 - 2952 (2015/06/22)
Meridianins are a group of marine-derived indole alkaloids which are reported to possess kinase inhibitory activities. In the present Letter, we report synthesis of N1-substituted and C-ring modified meridianin derivatives and their evaluation as Dyrk1A inhibitors and neuroprotective agents. Among the library of 52 compounds screened, morpholinoyl linked derivative 26b and 2-nitro-4-trifluoromethyl phenyl sulfonyl derivative 29v displayed potent inhibition of Dyrk1A with IC50 values of 0.5 and 0.53 μM, respectively. The derivative 26b also inhibited Dyrk2 and Dyrk3 with IC50 values of 1.4 and 2.2 μM, respectively showing 2.2 and 4.4 fold selectivity for Dyrk1A with respect to Dyrk2 and Dyrk3. The compound 26b was not cytotoxic to human neuroblastoma SH-SY5Y cells (IC50 >100 μM) and it displayed significant neuroprotection against glutamate-induced neurotoxicity in these cells at 10 μM. Molecular modelling studies of compound 26b led to identification of key interactions in the binding site of Dyrk1A and the possible reasons for observed Dyrk1A selectivity over Dyrk2.
3,5-bis(aminopyrimidinyl)indole derivatives: Synthesis and evaluation of pim kinase inhibitory activities
Lee, Jinho,More, Kunal N.,Yang, Seun-Ah,Hong, Victor S
, p. 2123 - 2129 (2014/09/16)
Pim kinases are promising targets in the treatment of hematopoietic and solid cancers. Meridianin C was chosen as a starting point to discover novel pim kinase inhibitors. Using known pim kinase's structural information, aminopyrimidine was introduced to
Synthesis, protein kinase inhibitory potencies, and in vitro antiproliferative activities of meridianin derivatives
Giraud, Francis,Alves, Georges,Debiton, Eric,Nauton, Lionel,Théry, Vincent,Durieu, Emilie,Ferandin, Yoan,Lozach, Olivier,Meijer, Laurent,Anizon, Fabrice,Pereira, Elisabeth,Moreau, Pascale
, p. 4474 - 4489 (2011/09/14)
The synthesis of new meridianin derivatives is described. The indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or by nitro or amino groups. Additionally, an iodine atom or various aryl groups were introduced at the C-5 position of the 2-aminopyrimidine ring. These compounds as well as some of their synthetic intermediates were tested for their kinase inhibitory potencies and for their in vitro antiproliferative activities. We found that this series of compounds is particularly interesting in the development of new inhibitors of DYRK1A and CLK1 kinases. The most effective compounds toward these two kinase families are the 6- and 7-bromo derivatives 30, 33, and 34 that showed more than 45-fold selectivity toward DYRK1A/CLK1 kinases over the other kinases tested. Meridianin derivatives could thus be developed toward potent and selective inhibitors of key RNA splicing regulators and potential therapeutic agents.
