Editorial

Editorial Commentary

Editorial     

Anodic bromination of aromatic compounds in acetonitrile

The electrochemical bromination of benzene, toluene and p-xylene has been investigated in acetonitrile; even if the mechanism was found to be somewhat similar to that postulated in a previous paper for acetic acid as the solvent, the yields of the brominated products in this case are near to 100% because the solvent is not brominated in these conditions.     

Studies on the synthesis of heterocyclic compounds. Part II. Action of phosphorus oxychloride on N-Methyl-N-1-phenyl-3-methylpyrazol-5-yl)-2-acetamidobenzamide

During attempts to prepare the tricyclic ring system of type III by cyclization of N-methyl-N-(1-phenyl-3-methylpyrazol-5-yl)-2-acetamido benzamide (Ib) under Bischler-Napieralski reaction conditions, the formation of the macro-heterocycle IV was observed, whose structure was determined on the basis of analytical and spectroscopic data as well as on some transformation products.     

Studies on the synthesis of heterocyclic compounds. III. Preparation of some pyrazolo[3,4-C] [1,5]benzodiazocin-10(11H)one derivatives

Starting from the readly available N-melhyl-N-(1-phenyl-3-R-pyrazol-5-yl)-2-nitrobenzamides (1a,b), the pyrazoles, 4-aeetyl substituted 2a,b, were prepared in high yield. Reduction of 2a gave the amino derivative 4a, which was eyclized to the desired pyrazolo[3,4-c][1,5]benzodiazo-cin-10(11H)one (5a). Compound 2b afforded 5b directly. Compound 5b was also prepared by the action of phosphorus oxychloride on N-methyl-N-(1,3-diphenylpyrazol-5-yl)-2-acetamido-benzamide (6b).     

Allosteric Control of Naphthalene Diimide Encapsulation and Electron Transfer in Porphyrin Containers: Photophysical Studies and Molecular Dynamics Simulation

The complexation processes of N,N’-dibutyl-1,4,5,8-naphthalene diimide ( NDI ) into two types of π-electron-rich molecular containers consisting of two Zn(II)-porphyrins connected by four flexible linkers of two different lengths, were characterized by means of absorption and emission spectroscopies and molecular dynamics simulation. Notably, the addition of NDI leads to a strong quenching of the fluorescence of both cages only when they are in an open conformation suitable for guest encapsulation, a situation triggered by silver(I) ions binding to the lateral triazoles. Molecular dynamics simulations confirm the fast binding of NDI , likely assisted by NDI -silver(I) interactions. Upon NDI complexation, the two porphyrin macrocycles get closer, with an optimized face to face orientation, suggesting an induced-fit mechanism through π–π interactions with the NDI aromatic cycle. Ultrafast transient absorption experiments allowed to identify the process of quenching of the Zn-porphyrin fluorescence as an efficient photoinduced electron transfer reaction between the cage porphyrin and the included NDI guest. The process occurs on fast and ultrafast time scales in the two complexes (1.5 ps and ≤300 fs) leading to a short-lived charge separated state (charge recombination lifetimes in the order of 30–40 ps). The combined computational and experimental approach used here is able to furnish a reliable model of the NDI -cage complexation mechanism and of the corresponding electron transfer reaction, attesting the allosteric control of both processes by the silver(I) ions.     

Structure and solvation properties of aqueous sulfobetaine micelles in the presence of organic spin probes: a Molecular Dynamics simulation study

Structural and mechanical-dynamical information on a micelle formed by 72 monomers of N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (SB 3–12) in water solution have been obtained through Molecular Dynamics simulations. Additional simulations have been carried out to evaluate whether and to what extent the structural features of the micelle are affected by the presence of a spin probe, typically utilized for the experimental characterization of these, rather complex, systems. Results indicate that the micelle shows a spherical shape not heavily influenced by the presence of the probe which only produces a slight volume increase. Further analysis also indicates that the probe, although inducing scarce alterations at the micelle-solvent interface, heavily influences the micelle core which appears less stable (more fluctuating) and less hydrated. Finally, analysis of residence times of water indicate—in line with many previous studies—the presence of a dual population characterized by different interactions with micelle interior.     

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

The main protease (M^pro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M^pro, a cysteine protease, have been determined, facilitating structure-based drug design. M^pro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41–Cys145, M^pro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nucleophile Cys145 have been debated in previous studies of SARS-CoV M^pro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 M^pro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of M^pro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored N_δ (HD) and N_ϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 M^pro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.

The main protease (M^pro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics.     

Studies on the synthesis of heterocyclic compounds. Part V. A novel synthesis of some pyridazin-4-(1H)one derivatives and their reaction with hydrazine

Some phenylazo derivatives of β-dicarbonyl compounds 1a,b,c,d reacted with dimethylformamide dimethylacetal to yield new 1-phenyl-3-R-4-(1H)pyridazinones 3a,e and 4. When compounds 3a and 3e were treated with hydrazine hydrate, they gave rise to pyrazolo[4,3-c]pyridazines 5 and 7 , respectively. By the action of hydrazine hydrate on compound 4 , the 1-phenyl-3-(1H-pyrazol-3-yl)-4-(1H)pyridazinone 8 was obtained. The structures of all the new compounds were assigned on the basis of satisfactory analytical and spectroscopic data.