Current Organic Chemistry - Online First

The escalating issue of malaria, including the parasite's resistance to the most effective antimalarial drugs, underscores the significance of discovering a novel antimalarial agent. Extensive research has been conducted on the phytochemicals, including triterpenoids, due to their efficacy in combating malaria. Therefore, in this study, we describe the semisynthesis and characterization of triterpenoids of lupane derivatives by simple modification at the C-3 position, including the evaluation of their efficacy, both in vitro against the Plasmodium falciparum FCR-3 strain and in silico molecular docking simulations targeting the PfATP6 protein. As a result, the structural modification at the C-3 position with 2-furoyl moiety (2b) shows a moderate activity with IC50 = 20.8 ± 0.7 μM, compared to its precursor lupeol (2), which shows a weak activity with IC50 = 122.1 ± 0.3 μM (positive control chloroquine; IC50 = 15.0 ± 0.1 μM). Molecular docking demonstrated a good interaction between 2b and the active site of PfATP6 protein, with a binding energy of - 8.0 ± 0.0 kcal mol^-1. The 2-furoyl ring in 2b shows the binding interaction with the Asn1039 residue via hydrogen bonds. Therefore, compound 2b is identified as a promising candidate as a lead compound for further antiplasmodial studies.

The Boyland-Sims peroxydisulfate oxidation is a highly effective method for the introduction of a hydroxyl function into aromatic amines. The simplicity of the process, as well as the absence of the need to protect sensitive functional groups, are the reaction's defining characteristics. Nevertheless, the low yield of the target products restricts the practical application of the reaction. The present study investigates the peroxydisulfate oxidation of aniline under modified conditions of the Boyland-Sims reaction. The yield and ratio of ortho- and para-aminophenols formed in the oxidation of aniline were found to depend on the reaction conditions. Previous studies on this reaction have been conducted at ambient temperature. It was determined that these temperature conditions are inadequate for the complete oxidation of aniline. It was found that increasing the temperature to 45°C resulted in a twofold increase (up to 35%) in the yield of reaction products, which, however, remains inadequate for the practical application of the reaction. Consequently, modifications to the Boyland-Sims reaction conditions were proposed. These comprised the use of metallophthalocyanine catalysts or a second oxidizing agent, hydrogen peroxide. Both modifications enabled a substantial augmentation in the yield of reaction products, ortho- and para-aminophenols. In the presence of metallophthalocyanines, the yield of intermediate 2(4)-aminophenylsulfates increased to 54-85%. Among the studied catalysts, cobalt phthalocyanine proved to be the most active. Its addition allowed increasing the yield of 2(4)-aminophenylsulfates up to 85%, while the ratio of ortho- and para-aminophenols in the mixture was shifted towards the para-isomer, with a ratio of 1:7. However, the utilization of a combination of two oxidizing agents, ammonium persulfate and hydrogen peroxide, led to the unexpected formation of para-aminophenol as the predominant reaction product, accompanied by the presence of trace amounts of the ortho-isomer.

Alarming data on the neglected tropical disease leishmaniasis, especially for global visceral cases, have motivated the development of novel drugs to overcome the emergence of resistance. In this context, quinoline derivatives, especially quinoline-4-carboxylic acids, have shown promising antileishmanial activity. More recently, acetanilide linked quinoline derivatives revealed selective antileishmanial activity. Now, we are motivated to investigate the influence of the substituent group on antileishmanial and toxicity properties of sixteen 2-acetanilide 2-arylquinoline-4-carboxylates. To this end, the precursors, 2-arylquinoline-4-carboxylic acids, prepared from isatin through the Pfitzinger reaction, and 2-chloroacetanilides were used in an alkylation reaction to obtain the final products (5e-t) in yields of 40-88%. Next, 2-acetanilide 2-arylquinoline-4-carboxylates (5e-t) had their in silico/vitro activity evaluated against Leishmania infantum promastigotes. From the MolPredictX program, all compounds were predicted to be active, and only four halogenated compounds (5k, 5n, 5o, 5r) were active by in vitro assays, with the best result for the compound 5n (R/R’ = Br/Cl), IC50 = 17.08 ± 1.09 µM. From the pkCSM program, these compounds were predicted as non-mutagenic, hepatotoxic, and highly cytotoxic on Flathead Minnows. On the other hand, compounds showed moderate ecotoxicity on Artemia salina, with IC50 = 256-297 µg.mL^-1. Finally, in contrast of Amphotericin B which caused relevant erythrocyte lysis starting from 50 μM, none of the compounds showed hemolytic activity. Furthermore, compounds were more selective against L. infantum promastigotes than against human erythrocytes, with a selectivity index (HC50/IC50) > 15.63, which demonstrates a promising therapeutic window for 2-acetanilide 2-arylquinoline-4-carboxylates.

The use of micelles enables the resolution of a number of problems associated with the aggregation and reduction in photocatalytic activity of porphyrins. The formation of transport systems is impossible without information on the localization of porphyrins containing hydrophilic and hydrophobic parts in highly organized systems, such as liposomes or model systems–micelles. To solve the above issues, 5,10,15,20-tetra(3ʹ,4ʹ-dihydroxyphenyl)porphin (Por(OH)8), 5-(3ʹ,4ʹ-dihydroxyphenyl)-10,15,20-triphenylporphin (Por(OH)2), and 5-(3ʹ,4ʹ-dihydroxyphenyl)-10,15,20-tri(pyridinium-3ʹ-yl)porphine (PorN (OH)2) were synthesized, and their state was studied in aqueous media in the presence of an anionic surfactant in the premicellar region. It was found that the porphyrins are sedimentation-stable in the premicellar region, while in the micellar region, Por(OH)2 and PorN(OH)2 are localized inside SDS micelles. However, the peripheral substituents of PorN(OH)2 are oriented toward the “head” of the surfactant. Por(OH)8 is the worst isolated from water molecules of all the studied porphyrins, and can be located both on the surface and inside the micelle, orienting the OH groups toward the surface of the micelle, or the channels inside it. The results obtained can be used to design transport systems for the delivery of hydroxy-substituted porphyrin photosensitizers.

Heterocyclic compounds, which contain at least one heteroatom (e.g., nitrogen, oxygen, sulfur) within their ring structures, are crucial in pharmaceuticals and agrochemicals due to their bioactive properties. They serve as the core components of numerous drugs, including antibiotics, anticancer agents, and agrochemicals like pesticides. Given the increasing demand for these compounds, the need for efficient and sustainable synthetic methods has become paramount. Multicomponent reactions (MCRs) have emerged as a powerful tool for the rapid and efficient synthesis of heterocyclic frameworks. By combining three or more reactants in a single step, MCRs offer high atom economy, reduced waste, and simplified reaction protocols. Solid base catalysts have been extensively utilized to improve the sustainability of these reactions further. These catalysts, including metal oxides and supported alkali metals, provide several advantages: enhanced selectivity, ease of recovery and reuse, and minimal environmental impact. This review explores the diverse MCR strategies for heterocyclic synthesis using solid base catalysts. It highlights their role in promoting green chemistry by enabling scalable and environmentally benign processes. Key examples, such as the synthesis of imidazoles, pyridines, pyrans, pyrimidine, etc, are discussed, demonstrating these methods' efficiency and industrial relevance. Solid base catalysis ensures operational simplicity and aligns with sustainable chemistry goals, making it a cornerstone in modern heterocyclic synthesis.

Establishing the fundamental possibility of the existence of the heteroligand macrotetracyclic complexes of vanadium, chromium, manganese, and iron-containing in the inner coordination sphere phthalocyanine, oxygen (O^2-) and fluorine (F^-) ions and having general [MPc(O)F] formula (M= V, Cr, Mn, Fe), by using of quantum-chemical calculation of parameters of their molecular/electronic structures and thermodynamical characteristics. The molecular and electronic structures of the above-mentioned heteroligand macrotetracyclic chelates of 3d elements (M) of the type [MPc(O)F] (M= V, Cr, Mn, Fe) which are unknown at present, were theoretically investigated. Standard thermodynamic parameters of formation (standard enthalpy DH⁰f, 298, entropy S⁰f, 298, and Gibbs’s energy DG⁰f, 298) for these macrocyclic compounds were calculated, too. Identifying details of molecular and electronic structures of compounds indicated above. Density functional theory (DFT) model chemistries (B3PW91/TZVP and OPBE/TZVP) with a combination of the D3 version of Grimme’s dispersion. The data on the geometric parameters of the molecular structure of these complexes are presented; it was shown that MN4 chelate nodes, all metal-chelate and 6-membered non-chelate rings in each of these macrocyclic coordination compounds, are practically planar with a small deviation from coplanarity (not more 3^o); nonetheless, N4 grouping from donor nitrogen atoms and 5-membered non-chelate rings are strictly planar. Wherein, the bond angles between two donor nitrogen atoms and M atom are not equal to 90^o; a similar situation occurs for the bond angles between donor atoms N, M, and O or F (notwithstanding the bond angles formed by M, O, and F atoms are exactly 180°). Also, NBO analysis data and the values of the standard enthalpy, entropy, and Gibbs energy of the formation of these compounds were presented. Specific features of DFT calculated molecular and electronic structures of the heteroligand metal macrocyclic compounds have been discussed. It has been shown that good agreement between the parameters of molecular structures obtained by two various DFT model chemistries takes place. Also, it has been noted that predicting the possibility of the existence of exotic coordination compounds and modeling their molecular/electronic structures using modern quantum chemical calculations (and, in particular, using DFT of various levels) is a very useful tool for solving problems associated with such synthesis.