Isolation, leishmanicidal evaluation and molecular docking simulations of piperidine alkaloids from Senna spectabilis. Issue 22 (1st December 2018)

• Record Type: Journal Article
• Authors: Lacerda, Rosimeire Borges Moreira; Freitas, Thamires Rodrigues; Martins, Mário Machado; Teixeira, Thaise Lara; da Silva, Cláudio Vieira; Candido, Pamela Aparecida; Oliveira, Ronaldo Junio de; Júnior, Claudio Viegas; Bolzani, Vanderlan da Silva; Danuello, Amanda; Pivatto, Marcos
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 22(2018)
• Page Start: 5816
• Page End: 5823
• Publication Date: 2018-12-01
• Subjects: Fabaceae -- Senna spectabilis -- Piperidine alkaloids -- (–)-Cassine -- (–)-Spectaline -- Leishmanicidal activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.10.032
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Natural alkaloid (–)-3- O -acetylcassine (green) with leishmanicidal activity, isolated from Senna spectabilis flowers. Highlights: The novel alkaloid (–)-3- O -acetylcassine was isolated from Senna spectabilis flowers. All the alkaloids displayed significant leishmanicidal activity against L. amazonensis . In silico evaluation suggested how the alkaloids bind in the active site of L. amazonensis arginase. Abstract: Leishmaniasis is one of the most important neglected tropical diseases (NTDs) that are especially common among low-income populations in developing regions of Africa, Asia, and the Americas. Many natural products, particularly alkaloids, have been reported to have inhibitory activity against arginase, the key enzyme in the pathology caused by Leishmania sp. In this way, piperidine alkaloids (–)-cassine (1 ), (–)-spectaline (2 ), (–)-3- O -acetylcassine (3 ), and (–)-3- O -acetylspectaline (4 ) were isolated from Senna spectabilis flowers. These compounds (1 /2 and3 /4 ) initially present as homologous mixtures were separated by high performance liquid chromatography and evaluated against the promastigote phase of Leishmania amazonensis . In addition, molecular docking simulations were implemented in order to probe the binding modes of the ligands1 –4 to the amino acids in the active site of L. amazonensis arginase. Alkaloid2 (IC50 15.81 μg mL −1 ) was the most effective against L. amazonensis . Compounds2 and4, with larger side chain, were more effective against the parasite than compounds1 and3 . The cell viability test on Vero cells revealed that compound2 (CC50 66.67 μg mL −1 ) was the most toxic. The acetyl group in the 3- O position of the parent structures reduced the leishmanicidal activity and the toxicity of the alkaloids. Further, molecular docking suggested that Asn143 is essential for arginase to interact with (–)-spectaline-derived compounds, which agreed with the IC50 measurements. Our findings revealed that S. spectabilis is an important source of piperidine alkaloids with leishmanicidal activity. Moreover, the natural compound3 has been isolated for the first time. Experimental investigation combined with theoretical study advances knowledge about the enzyme binding site mode of interaction and contributes to the design of new bioactive drugs against Leishmania infection.