Vol. 23 No. 1 (2025)

The fundamental physicochemical features of drugs acting on the central nervous system (CNS) determine their ability to penetrate the blood-brain barrier (BBB) and be active against the CNS activities. In this paper, we study two well-known groups of drugs used or prescribed by physicists to treat CNS disorders. One group of drugs belongs to pain killers (the Molecules of Mercy), and the other group belongs to the mind-changers (the Molecules of Mysticism). These two groups of CNS drugs differ in a number of physicochemical parameters: molecular weight, lipophilicity, hydrogen bound acceptor count, hydrogen bond donor count, polar surface area, polarizability, flexibility, bioavailability, and their behavior (agreement or disagreement) related to specific structural conditions, in particular the Lipinski’s rule, Ghose filter, Veber’s rule, Multi-Drug Data Report (MDDR) criteria. In the study of 41 well-known drugs that affect the CNS (both approved or illegal), it has been found that painkillers that do not cause addiction have a physicochemical profile other than those of mind-changer drugs that are very often addictive. 

The features of physicochemical parameters associated with the profiles of “pain killer” and “mind-changer” drugs are discussed.

The efficient and scalable synthesis of homoallylic amines is a subject of significant interest due to the potential applications of these compounds in medicinal and synthetic chemistry. The three-component Petasis reaction is an excellent approach for obtaining these compounds. Based on previous studies, this work explores the α-aminoallylation of ketones and aldehydes using allylboronic acid pinacol ester. Compared to classical methods, the protocol developed reduces the excess of reagents, increasing the environmental friendliness of the process, while maintaining high yields. A wide range of substrates, including various aliphatic, cyclic, and heterocyclic ketones, was studied to identify factors affecting the reactivity. The method was also successfully applied to aldehydes, producing amine-containing building blocks on a large scale. Various work-up procedures were optimized for efficient isolation of the homoallylamines synthesized without the need for chromatographic purification.

The Diels-Alder reaction remains one of the most versatile and widely employed cycloaddition strategies in synthetic organic chemistry. The development of functionalized dienes, particularly Danishefsky’s diene (DD) and Rawal’s diene (RD), has significantly expanded the synthetic potential of this reaction. A comparative analysis of these two dienes has been performed in this study; in particular their reactivity with aldehyde dienophiles, leading to pyran derivatives – key intermediates in the pharmaceutical synthesis, has been analyzed. The reactivity, scope, and reaction conditions for both dienes have been assessed. Although DD is well studied and widely used in synthetic protocols, RD exhibits higher reactivity, especially under mild thermal conditions, eliminating the need for the Lewis acid catalysis. Experimental results for eight aldehyde substrates have revealed key differences in their efficiency and scalability. The data obtained emphasize the complementary nature of DD and RD in synthetic applications, providing valuable recommendations for optimizing diene selection in complex organic transformations.

A ring-closing metathesis (RCM) strategy was employed for the synthesis of spirooxetane compounds with a tetrahydrofuran (THF) core. The approach proposed relied on the preparation of an unsaturated spirooxetane from vinyl oxetanol. The reaction sequence involved the NaH-mediated О-alkylation with methyl 2-(bromomethyl)acrylate in the presence of TBAI. The subsequent RCM reaction using the Grubbs’ II catalyst gave the dihydrofuran carboxylate with a yield of 70 %. The hydrogenation under high-pressure conditions using a Pearlman’s catalyst made it possible to obtain the saturated THF-derived carboxylate, which was then subjected to alkaline hydrolysis to give a stable lithium carboxylate. The corresponding alcohol obtained via LiAlH₄-mediated reduction of the ester was oxidized to the corresponding aldehyde using DMP. The alcohol was further converted into a mesylate serving as a precursor for the corresponding amine and bromide. The set of dioxane analogs proposed can serve as promising building blocks readily available on a multigram scale for the scientific community.

Monosubstituted gem-difluorocyclopropenes undergo hydrolysis yielding cyclopropenones and acrylic acid derivatives. Herein, we investigate the reaction routes of hydrolysis for both aromatic and alkyl derivatives. The study supports the idea that the formation of a cyclopropenyl cation controls the reactivity of gem-difluorocyclopropenes, and aromatic substituents accelerate the hydrolysis via the resonance stabilization. Reaction conditions, including the solvent composition and temperature, significantly affect the conversion and the product selectivity. This information facilitates the preparative synthesis and improves understanding of the fluorinated cyclopropene reactivity.

A practical and convenient method for the synthesis of pyridine-3-thiols using substituted 3-iodopyridines as starting compounds has been developed. Based on the use of thiobenzoic acid as a sulfur donor in a two-step procedure, this approach made it possible to synthesize a number of pyridine-3-thiols with F, Cl, Br, CH₃, OCH₃ substituents at various positions of the pyridine ring. The procedure presented gives high yields of the target products with a purity of 95% and is suitable for synthesis in tens of grams.

Pyrazolines are an important class of heterocyclic compounds known for their biological activities, making them attractive objects for medicinal chemistry. This study investigated the regioselective [3+2]-cycloaddition of diazomethane with para-substituted styrenes featuring electron-withdrawing (EWG) and electron-donating (EDG) groups. Experimental results have demonstrated that the electronic properties of substituents significantly affect the reaction efficiency and regioselectivity, as well as the product stability. At the same time, EWG provided lower activation barriers and higher reaction yields. Calculations performed by the density functional theory (DFT) method confirmed the experimental data allowing us to understand in detail the reaction mechanism, activation energy values, and thermodynamic parameters. This integrated experimental and theoretical approach improves understanding of the effects of substituents, contributing to the rational design of substituted pyrazolines.