Current Organic Chemistry - Volume 26, Issue 16, 2022

Despite its narrow therapeutic index and the toxicity issues related to renal injuries, lithium is still a first-line choice for the treatment of mania and for preventing recurrences in bipolar disorder. Nevertheless, side effects and limited efficacy in some of the cases push the search for novel tools to ameliorate these conditions, which still represent a social burden, and great efforts are being made toward the identification of alternative therapeutic options. In this context, rational drug design, drug repurposing, and computer-aided drug discovery represent time-saving and efficient strategies to pursue this goal. Inositol monophosphatase (IMPase) represents the molecular target of lithium which acts as an uncompetitive inhibitor. In this context, a screening on NIH Clinical Collection of drug-like compounds highlighted the polypharmacological drug ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) as a non-competitive, irreversible IMPase inhibitor, suggesting that this molecule could represent a valid therapeutic alternative. In this perspective article, we aim at providing a historical overview of the uses of ebselen with particular attention to its potential use as lithium-mimetic. We critically analyse this aspect by investigating in silico the molecular mechanism leading to the formation of the Se-S bond between IMPase Cys141 and ebselen. Evidence of the bond formation is supported by the crystallographic data Fenn et al. We hypothesize that the IMPase-ebselen complex promotes the association with other IMPase chains, improving the formation of the tetramer adduct, suggesting that ebselen may stabilize the human IMPase in a form that could be less active, resulting in a decreased enzymatic activity.

Leaf alcohol is a flavor and fragrance compound and has been shown to possess an intense characteristic grassy-green odor of freshly cut green grass and leaves, which is widely used as an added flavor in fragrances, food flavors and tobacco flavors to provide a fresh grassy note. However, the market has been unable to meet this surge in demand, resulting in a frequent shortage of leaf alcohol. At present, there are two processes used in industrial production: the process for the hydrogenation of 3-hexyn-1-ol and the process for the ring opening reaction of 6-methyl-3,6-dihydro-2H-pyran. The reason for the shortage is that there are certain difficulties and shortcomings in the current methods of synthesizing leaf alcohol. The disadvantages of the process for the hydrogenation of 3-hexyn-1-ol are the production security and dependability, the prime cost of catalyst and equipment. The disadvantages of the process for the ring opening reaction of 6-methyl-3,6-dihydro-2H-pyran are the product quality, production dependability, and the prime cost of the equipment. To solve this contradiction between supply and demand, many research groups are investigating chemical synthetic methods that could be applied in industrial production easily and economically. Since the discovery of leaf alcohol, much has happened in the synthesis of leaf alcohol. Many developments became market realities, so after all these years, it seemed appropriate to sum up the current trends in the synthesis of leaf alcohol. In this review, we bring a collection of various synthetic approaches leading to leaf alcohol.

Transesterification is one of the paramount chemical reactions in organic synthesis and is broadly used to synthesize the biologically and pharmacologically active heterocycles of greater medicinal importance. The transesterification reaction provides the useful synthon called β-ketoester, which bears both electrophilic and nucleophilic reactive centers, which is helpful for the construction of various complex structures with greater medicinal properties. This article discusses various methods to synthesize β-keto esters/esters via transesterification through catalysis, including nanocatalysts, and different applications of transesterification reactions in the preparation of biologically active heterocycles and production of biodiesel have also been summarized as per the available literature. The main focus of the current study is to highlight the importance of transesterification in synthesizing variety of commercial and noncommercial β - ketoesters / esters, which will be used to synthesize various biologically important heterocycles and production of biodiesel.

A green methodology was developed to obtain a large scope of Knoevenagel adducts with high yields (77-95%). The compounds were synthetized in 30 min, using aromatic aldehyde derivatives, malononitrile, water as a solvent, microwave irradiation as a heating source and in free-catalyst conditions. In a particular case, in the synthesis of the adduct derived from the α-methyl-trans-cinnamaldehyde, a [2+2] photochemical cycloaddition product was observed, a tetrasubstituted cyclobutane dimeric compound 3w’. Its complex structure was confirmed by X-ray diffraction (first time), nuclear magnetic resonance analysis and electronic structure calculations. Theoretical results suggest that the thermal decomposition of 3w’ back to 3w can occur by means of a biradical intermediate.

The increasing burden of microbial infection and emerging resistance against the available antimicrobial drugs drives the development of new agents. Two different series of indole-based compounds (VN-1 to VN-18) were synthesized and analyzed for antimicrobial activity by calculating the diameter of the inhibition zone using the broth dilution method and well diffusion method against Escherichia coli (E. coli) and environmental microbes. Most of the compounds displayed good to moderate activity against E. coli, and VN-4 and VN-9 displayed good inhibitory activity against the tested microbes. Molecular docking and binding energy calculation studies of all the synthesized compounds have been performed for targeting FabI, where most of the compounds showed significant interactions with the aromatic nicotinamide moiety of NAD+. In molecular dynamics studies, VN-9 stays inside the binding cavity for sufficient time to induce antimicrobial activity. Thus, these indole-based derivatives may lead to the development of new antimicrobial agents that may act as FabI inhibitors.

In this contribution, an operationally simple and efficient synthetic procedure for synthesizing derivatives of 4-(arylmethylene)-5-oxo-4,5-dihydroisoxazol-3-yl)acetate has been developed. This interesting synthetic protocol involves the one-pot cyclocondensation of diethyl 3-oxopentanedioate, aryl or heteroaryl aldehydes, and hydroxylamine hydrochloride catalyzed in an aqueous medium using an azolium salt as a robust organo-catalyst. In this work, for the first time, 1,3-dibenzyl-1H-benzo[d]imidazol-3-ium chloride was used as the catalyst for the synthesis of ethyl-2-(4-(arylmethylene)-5-oxo-4,5-dihydroisoxazol-3-yl)acetate derivatives from the commercially available starting materials. Notably, no by-products were observed during the multicomponent reaction. Optimization studies revealed that 5 mol% of 1,3-dibenzyl-1H-benzo[d]imidazol-3-ium chloride is sufficient to perform the experiment. Furthermore, examining the results of the temperature conditions showed that 70 ºC is the best temperature to carry out the reaction. In an optimization study, H2O was the most effective solvent to perform the three-component cyclization reaction. In this method, using H2O as the environmentally benign and inexpensive reaction medium, so from the point of view of the reaction medium, it can be said that this three-component heterocyclization obeys the principles of green chemistry. This procedure has several advantages, such as good to excellent yields, reasonable reaction times, isolation of heterocyclic products without column chromatography or other chromatographic methods, atom-economy, step-economy, and clean reaction profiles.