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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-04, Vol.27 (9), p.2841
• Main Authors: Wansri, Rattanaporn, Lin, Aye Chan Khine, Pengon, Jutharat, Kamchonwongpaisan, Sumalee, Srimongkolpithak, Nitipol, Rattanajak, Roonglawan, Wilasluck, Patcharin, Deetanya, Peerapon, Wangkanont, Kittikhun, Hengphasatporn, Kowit, Shigeta, Yasuteru, Liangsakul, Jatupol, Suroengrit, Aphinya, Boonyasuppayakorn, Siwaporn, Chuanasa, Taksina, De-Eknamkul, Wanchai, Hannongbua, Supot, Rungrotmongkol, Thanyada, Chamni, Supakarn
• Format: Article
• Language: English
• Subjects: Acids; African trypanosomiasis; Alkaloids - chemistry; Alkaloids - pharmacology; Analogs; Animals; anti-SARS-CoV-2 main protease; Antiinfectives and antibacterials; antimalaria; Antimalarial activity; Antimalarial agents; Antimalarials - pharmacology; antitrypanosoma; Aromatic compounds; Benzodioxoles; Binding; Bioavailability; black pepper; Cell lines; Coronaviruses; COVID-19; Cytotoxicity; Disease transmission; Esterification; Humans; Infectious diseases; Malaria; Mammals; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Parasites; Piper nigrum; Piper nigrum - chemistry; Piperidines; Piperine; piperine analogs; Polyunsaturated Alkamides - chemistry; Polyunsaturated Alkamides - pharmacology; Protease; Proteinase; Rutin; semi-synthesis; Semisynthesis; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Tropical diseases; Vector-borne diseases
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27092841

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