Green Solvents for Eco-Friendly Synthesis of Dimethindene: A Forward-Looking Approach.

Dimethindene is a selective histamine H1 antagonist and is commercially available as a racemate. Upon analyzing the synthetic pathways currently available for the industrial preparation of dimethindene, we set up a sustainable approach for the synthesis of this drug, switching from petroleum-based volatile organic compounds (VOCs) to eco-friendly solvents, such as 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether (CPME) belonging to classes 3 and 2, respectively. Beyond decreasing the environmental impact of the synthesis (E-factor: 24.1-54.9 with VOCs; 12.2-22.1 with 2-MeTHF or CPME), this switch also improved the overall yield of the process (from 10% with VOCs to 21-22% with 2-MeTHF or CPME) and remarkably simplified the manual operations, working under milder conditions. Typical metrics applied at the first and second pass, according to the CHEM21 metrics toolkit, were also calculated for the whole synthetic procedure of dimethindene, and the results were compared with those of the classical procedure.

Metal-Promoted Heterocyclization: A Heterosynthetic Approach to Face a Pandemic Crisis.

The outbreak of SARS-CoV-2 has drastically changed our everyday life and the life of scientists from all over the world. In the last year, the scientific community has faced this worldwide threat using any tool available in order to find an effective response. The recent formulation, production, and ongoing administration of vaccines represent a starting point in the battle against SARS-CoV-2, but they cannot be the only aid available. In this regard, the use of drugs capable to mitigate and fight the virus is a crucial aspect of the pharmacological strategy. Among the plethora of approved drugs, a consistent element is a heterocyclic framework inside its skeleton. Heterocycles have played a pivotal role for decades in the pharmaceutical industry due to their high bioactivity derived from anticancer, antiviral, and anti-inflammatory capabilities. In this context, the development of new performing and sustainable synthetic strategies to obtain heterocyclic molecules has become a key focus of scientists. In this review, we present the recent trends in metal-promoted heterocyclization, and we focus our attention on the construction of heterocycles associated with the skeleton of drugs targeting SARS-CoV-2 coronavirus.

Bioactivity and Structural Properties of Novel Synthetic Analogues of the Protozoan Toxin Climacostol.

Climacostol (5-[(2Z)-non-2-en-1-yl]benzene-1,3-diol) is a resorcinol produced by the protozoan Climacostomum virens for defence against predators. It exerts a potent antimicrobial activity against bacterial and fungal pathogens, inhibits the growth of several human and rodent tumour cells, and is now available by chemical synthesis. In this study, we chemically synthesized two novel analogues of climacostol, namely, 2-methyl-5 [(2Z)-non-2-en-1-yl]benzene-1,3-diol (AN1) and 5-[(2Z)-non-2-en-1-yl]benzene-1,2,3-triol (AN2), with the aim to increase the activity of the native toxin, evaluating their effects on prokaryotic and free-living protists and on mammalian tumour cells. The results demonstrated that the analogue bearing a methyl group (AN1) in the aromatic ring exhibited appreciably higher toxicity against pathogen microbes and protists than climacostol. On the other hand, the analogue bearing an additional hydroxyl group (AN2) in the aromatic ring revealed its ability to induce programmed cell death in protistan cells. Overall, the data collected demonstrate that the introduction of a methyl or a hydroxyl moiety to the aromatic ring of climacostol can effectively modulate its potency and its mechanism of action.