O,S,Se-containing Biginelli products based on cyclic ß-ketosulfone and their postfunctionalization.

A one-pot three-component Biginelli synthesis of dihydropyrimidinones/thiones/selenones via acetic acid or solvent-free Yb(OTf)3-catalyzed tandem reaction of ß-ketosulfone (dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide), an appropriate urea, and arylaldehyde has been developed. The reaction proceeds with high chemo- and regioselectivity to give diverse DHPMs in reasonable yields up to 95%. Moreover, an SO2-containing analogue of anticancer drug-candidate enastron (SO2 vs C=O) was obtained by using the here reported method in gram scale. We also demonstrate the reactivity of the Biginelli product in various directions - synthesis of condensed thiazoles and tetrazoles. In silico assessment of ADMET parameters shows that most compounds meet the lead-likeness requirements. The biological profiles of new compounds demonstrate high probability levels of activity against the following pathogens/diseases: Candida albicans, Alphis gossypii, Tripomastigote Chagas, Tcruzi amastigota, Tcruzi epimastigota, Leishmania amazonensis, and Dengue larvicida.

Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-induced Neurodegeneration.

Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage- gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.

Targeting a Cryptic Pocket in a Protein-Protein Contact by Disulfide-Induced Rupture of a Homodimeric Interface.

Interference with protein-protein interfaces represents an attractive as well as challenging option for therapeutic intervention and drug design. The enzyme tRNA-guanine transglycosylase, a target to fight Shigellosis, is only functional as a homodimer. Although we previously produced monomeric variants by site-directed mutagenesis, we only crystallized the functional dimer, simply because upon crystallization the local protein concentration increases and favors formation of the dimer interface, which represents an optimal and highly stable packing of the protein in the solid state. Unfortunately, this prevents access to structural information about the interface geometry in its monomeric state and complicates the development of modulators that can interfere with and prevent dimer formation. Here, we report on a cysteine-containing protein variant in which, under oxidizing conditions, a disulfide linkage is formed. This reinforces a novel packing geometry of the enzyme. In this captured quasi-monomeric state, the monomer units arrange in a completely different way and, thus, expose a loop-helix motif, originally embedded into the old interface, now to the surface. The motif adopts a geometry incompatible with the original dimer formation. Via the soaking of fragments into the crystals, we identified several hits accommodating a cryptic binding site next to the loop-helix motif and modulated its structural features. Our study demonstrates the druggability of the interface by breaking up the homodimeric protein using an introduced disulfide cross-link. By rational concepts, we increased the potency of these fragments to a level where we confirmed their binding by NMR to a nondisulfide-linked TGT variant. The idea of intermediately introducing a disulfide linkage may serve as a general concept of how to transform a homodimer interface into a quasi-monomeric state and give access to essential structural and design information.

Open and rearranged norbornane derived polycyclic cage molecules as potential neuroprotective agents through attenuation of MPP+- and calcium overload-induced excitotoxicity in neuroblastoma SH-SY5Y cells.

The neuroprotective effects of closed polycyclic cage molecules such as NGP1-01, memantine and amantadine have been extensively explored. These effects are mostly linked to the antagonism of the N-methyl-d-aspartate (NMDA) receptor- and the blockage of voltage gated calcium channels (VGCC). The synthesis of structurally related open and rearranged cage derivatives has been studied in depth. However, very little is known on their neuroprotective effects. In this study, a series of open and rearranged polycyclic cage molecules containing a norbornane derived scaffold were synthesised and evaluated for cytotoxicity, neuroprotection and calcium blocking effects via the NMDA receptor and VGCC on neuroblastoma cells at a 10 µM concentration. All compounds showed negligible cytotoxicity and were able to significantly attenuate MPP+-induced neurotoxicity between 26.07 ± 12.50% to 48.42 ± 0.76%, with compound 14 showing the best neuroprotective effect. In comparison to known NMDA receptor antagonists, all compounds demonstrated moderate to excellent calcium blocking effects of 26.50 ± 2.28 to 72.95 ± 3.38%. Docking studies suggest that these compounds are able to show significant NMDA receptor channel blocking ability since they bind in a comparable manner to the crystallographic pose of MK-801 inside the NMDAR ion channel. Some compounds were also able to attenuate calcium influx through VGCC channels between 21.28 ± 3.69% to 50.34 ± 7.67%. Compound 4 and 15 showed the highest inhibition of calcium influx at the VGCC and NMDA receptor, respectively. The compounds exhibiting good cytotoxicity-, neuroprotective- and calcium blocking profiles could potentially act as neuroprotective agents to clinically benefit people suffering from neurodegenerative disorders.

The formation of the salt and neutral molecule cocrystal from equimolar solution of heliamine and bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid.

The possible interaction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (heliamine) with bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid anhydride has been studied. Instead of the reaction with heliamine, the acid anhydride was hydrolyzed into the appropriate dicarboxylic acid. An equimolar mixture of unreacted heliamine and in-situ-generated dicarboxylic acid crystallized in space group P21/c. The comprehensive study of the obtained crystals shows that the peculiarities of the crystallization process lead to the formation of the salt-cocrystal structure where the dianion interacts simultaneously with two cations forming a chain as the primary structural motif. The neutral molecules of dicarboxylic acid link the dianions of the neighbouring chains, forming a layer as the secondary structural motif. As a result, the stronger hydrogen bonds formed by the neutral molecules play a secondary role in the crystal structure formation.