Synthesis of (±)‐Spongiolactone Enabling Discovery of a More Potent Derivative

An eleven‐step synthesis of (±)‐spongiolactone from 1,3‐cyclohexanedione is reported that relies on a diastereoselective, nucleophile‐catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated β‐lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure–activity studies that revealed a regio‐ and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested.     

Benign synthesis of unsymmetrical arylurea derivatives using 3-substituted dioxazolones as isocyanate surrogates

ABSTRACT

A phosgene- and metal-free synthesis of unsymmetrical arylurea derivatives utilizing 3-substituted dioxazolones and commercially available amines has been developed. The 3-substituted dioxazolones serve as the precursors of the in situ generated isocyanate intermediates in the presence of non-toxic sodium acetate as a base and methanol as a solvent under mild heating conditions. A series of unsymmetrical phenylureas including N, N’- mono-, di-, and trisubstituted derivatives are chemoselectively obtained in moderate to excellent yields from a broad scope of both 3-substituted dioxazolones and amines without a significant amount of the symmetrical byproducts. In many cases, the resulting unsymmetrical phenylureas are easily separated by filtration allowing no chromatographic purification. These investigations provide an opportunity for facile, practical, and eco-friendly synthesis of unsymmetrical diarylureas. Application of this method is demonstrated toward the gram-scale preparation of anti-cancer drugs, sorafenib and the 3-cycle continuous synthesis in conjugation with the recycle of sodium acetate and methanol process of known herbicide, daimuron.     

Semi-Synthesis of N-Aryl Amide Analogs of Piperine from Piper nigrum and Evaluation of Their Antitrypanosomal,Antimalarial, and Anti-SARS-CoV-2 Main Protease Activities

Piper nigrum, or black pepper, produces piperine, an alkaloid that has diverse pharmacological activities. In this study, N-aryl amide piperine analogs were prepared by semi-synthesis involving the saponification of piperine (1) to yield piperic acid (2) followed by esterification to obtain compounds 3, 4, and 5. The compounds were examined for their antitrypanosomal, antimalarial, and anti-SARS-CoV-2 main protease activities. The new 2,5-dimethoxy-substituted phenyl piperamide 5 exhibited the most robust biological activities with no cytotoxicity against mammalian cell lines, Vero and Vero E6, as compared to the other compounds in this series. Its half-maximal inhibitory concentration (IC₅₀) for antitrypanosomal activity against Trypanosoma brucei rhodesiense was 15.46 ± 3.09 μM, and its antimalarial activity against the 3D7 strain of Plasmodium falciparum was 24.55 ± 1.91 μM, which were fourfold and fivefold more potent, respectively, than the activities of piperine. Interestingly, compound 5 inhibited the activity of 3C-like main protease (3CL^Pro) toward anti-SARS-CoV-2 activity at the IC₅₀ of 106.9 ± 1.2 μM, which was threefold more potent than the activity of rutin. Docking and molecular dynamic simulation indicated that the potential binding of 5 in the 3CL^pro active site had the improved binding interaction and stability. Therefore, new aryl amide analogs of piperine 5 should be investigated further as a promising anti-infective agent against human African trypanosomiasis, malaria, and COVID-19.