New heteroaryl carbamates: synthesis and biological screening in vitro and in mammalian cells of wild-type and mutant HIV-protease inhibitors

New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6 nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results. The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors

Engineering memory with an extrinsically disordered kinase

Synaptic plasticity plays a crucial role in memory formation by regulating the communication between neurons. Although actin polymerization has been linked to synaptic plasticity and dendritic spine stability, the causal link between actin polymerization and memory encoding has not been identified yet. It is not clear whether actin polymerization and structural changes in dendritic spines are a driver or a consequence of learning and memory. Using an extrinsically disordered form of the protein kinase LIMK1, which rapidly and precisely acts on ADF/cofilin, a direct modifier of actin, we induced long-term enlargement of dendritic spines and enhancement of synaptic transmission in the hippocampus on command. The activation of extrinsically disordered LIMK1 in vivo improved memory encoding and slowed cognitive decline in aged mice exhibiting reduced cofilin phosphorylation. The engineered memory by an extrinsically disordered LIMK1 supports a direct causal link between actin-mediated synaptic transmission and memory

Stereoselective Intramolecular Cyclization to 4-(Hydroxymethyl)-3-(1H-indolyl)oxazolidin-2-ones

A simple high-yield three-steps route to optically active 4-hydroxymethyl-3-(1Hindolyl) oxazolidin-2-ones from (S)-glycidol is described. The key intermediates (R)-oxiran-2- ylmethyl 1H-indol-4/-5-ylcarbamates are obtained in high yields from (S)-glycidol. These are readily transformed to oxazolidin-2-ones, very interesting building blocks in drug synthesis

Nickel-Catalyzed C-Br/C-H Bis-phenylation of Methyl 4-Bromocrotonate: A Stereoselective Entry to Methyl (E)-3,4-Diphenylbut-2-enoate

A method for C-Br/C-H bis-phenylation of methyl 4-bromocrotonate via nickel-catalyzed cross-coupling reaction has been developed. This protocol involves commercially available catalyst components and furnishes a suitable doubly phenylated building block

Ligand Free Suzuki Coupling of Arylboronic Acids with Methyl (E)-4-Bromobut-2-enoate: Synthesis of Unconventional Cores of HIV-1 Protease Inhibitors

An effective ligand free Suzuki coupling protocol to unite methyl (E)-4-bromobut-2-enoate with several arylboronic acids has been accomplished. Thus a number of variously functionalized methyl 4-arylcrotonates have been achieved in high to excellent yields under mild conditions. This method enables the preparation of diverse aryl-substituted cores of HIV-1 protease inhibitors