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

Abstract

<i>Piper nigrum</i>, or black pepper, produces piperine, an alkaloid that has diverse pharmacological activities. In this study, <i>N</i>-aryl amide piperine analogs were prepared by semi-synthesis involving the saponification of piperine (<b>1</b>) to yield piperic acid (<b>2</b>) followed by esterification to obtain compounds <b>3</b>, <b>4</b>, and <b>5</b>. The compounds were examined for their antitrypanosomal, antimalarial, and anti-SARS-CoV-2 main protease activities. The new 2,5-dimethoxy-substituted phenyl piperamide <b>5</b> 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 <i>Trypanosoma brucei rhodesiense</i> was 15.46 ± 3.09 μM, and its antimalarial activity against the 3D7 strain of <i>Plasmodium falciparum</i> was 24.55 ± 1.91 μM, which were fourfold and fivefold more potent, respectively, than the activities of piperine. Interestingly, compound <b>5</b> 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 <b>5</b> in the 3CL^pro active site had the improved binding interaction and stability. Therefore, new aryl amide analogs of piperine <b>5</b> should be investigated further as a promising anti-infective agent against human African trypanosomiasis, malaria, and COVID-19.