191028-25-8Relevant articles and documents
Discovery of Potent and Selective PI3KγInhibitors
Drew, Samuel L.,Thomas-Tran, Rhiannon,Beatty, Joel W.,Fournier, Jeremy,Lawson, Kenneth V.,Miles, Dillon H.,Mata, Guillaume,Sharif, Ehesan U.,Yan, Xuelei,Mailyan, Artur K.,Ginn, Elaine,Chen, Jie,Wong, Kent,Soni, Divyank,Dhanota, Puja,Chen, Pei-Yu,Shaqfeh, Stefan G.,Meleza, Cesar,Pham, Amber T.,Chen, Ada,Zhao, Xiaoning,Banuelos, Jesus,Jin, Lixia,Schindler, Ulrike,Walters, Matthew J.,Young, Stephen W.,Walker, Nigel P.,Leleti, Manmohan Reddy,Powers, Jay P.,Jeffrey, Jenna L.
, p. 11235 - 11257 (2020)
The selective inhibition of the lipid signaling enzyme PI3Kγconstitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγinhibitors that attain high isoform selectivity through the divergent projection of substituents into both the selectivity and alkyl-induced pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 μM, THP-1 cells), which displays >600-fold selectivity for PI3Kγover the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an alkyl-induced pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.
N-arylation of protected and unprotected 5-bromo-2-aminobenzimidazole as organic material: Non-linear optical (nlo) properties and structural feature determination through computational approach
Ahmad, Gulraiz,Kosar, Naveen,Mumtaz, Mubeen,Rashid, Umer,Rasool, Nasir
, (2021/11/30)
The interest in the NLO response of organic compounds is growing rapidly, due to the ease of synthesis, availability, and low loss. Here, in this study, Cu(II)-catalyzed selective N-arylation of 2-aminobenzimidazoles derivatives were achieved in the presence of different bases Et3N/TMEDA, solvents DCM/MeOH/H2O, and various aryl boronic acids under open atmospheric conditions. Two different copper-catalyzed pathways were selected for N-arylation in the presence of active nucleophilic sites, providing a unique tool for the preparation of NLO materials, C-NH (aryl) derivatives of 2-aminobenzimidazoles with protection and without protection of NH2 group. In addition to NMR analysis, all synthesized derivatives (1a–1f and 2a–2f) of 5-bromo-2-aminobenzimidazole (1) were computed for their non-linear optical (NLO) properties and reactivity descriptor parameters. Frontier molecular orbital (FMO) analysis was performed to get information about the electronic properties and reactivity of synthesized compounds.
BENZIMIDAZOLE DERIVATIVES AS ANTIVIRAL AGENTS
-
, (2013/02/28)
Provided are compounds of Formulas I, II, III, IV, V, and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).
