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.

A sustainable two-step protocol was developed for the synthesis of the antihistamine drug Thenfadil by combining a reductive amination process with a Cu-catalyzed Ullmann-type C− N coupling reaction run in environmentally responsible deep eutectic solvents (DESs), constructed from biobased compounds. Under optimized conditions, both reactions proceed smoothly under aerobic conditions and in the absence of any additional ligand, with the desired active pharmaceutical ingredient isolated in an overall reaction yield of 39% with an effective suppression of the side products arising from competitive Cu-catalyzed C−O coupling reactions. A novel and simplified workup procedure has also been set up, which avoids the need for chromatographic purification, while allowing the recovery and the recycling of the unreacted intermediate secondary amine. The potential application and the robustness of the proposed methodology has been demonstrated (a) in scale-up studies up to 50 g of substrate in 0.5 kg of DES, taking place with no decrease in the reaction yield, and (b) in the synthesis of three other ethylenediamine derivatives (Thenfadil's analogs) like tripelennamine, methaphenilene, and thonzylamine in 39%−44% overall yield. Typical metrics applied at First and Second Pass, according to the CHEM21 Metrics Toolkit, have been calculated as well for the whole synthetic procedure of Thenfadil and results compared with those of the classical procedure.

Primary amines are activated by copper(I)-based Lewis acid promoters in an A3-coupling one-pot solventless reaction with aldehydes and phenylacetylene for the synthesis of secondary propargylamines. The reaction is promoted by a CuSO4/NaI system, a practical precursor of the in situ generated effective CuI/I2 system, that worked well, but only in a restricted number of examples. Substitution of I2 with CeCl3·7H2O in a one-pot two-step reaction provided good yields and a wider applicability, with the added value given by a safer procedure.

A catalyst-free heterocyclization reaction of α-chloroglycinates with thiobenzamides or thioureas leading to 2,4-disubstituted-5-acylamino-1,3-thiazoles has been developed. The methodology provides straightforward access to valuable building blocks for pharmaceutically relevant compounds.