Isolation, leishmanicidal evaluation and molecular docking simulations of piperidine alkaloids from Senna spectabilis

Rosimeire Borges Moreira Lacerda; Thamires Rodrigues Freitas; Mário Machado Martins; Thaise Lara Teixeira; Cláudio Vieira da Silva; Pamela Aparecida Candido; Ronaldo Junio de Oliveira; Claudio Viegas Júnior; Vanderlan da Silva Bolzani; Amanda Danuello; Marcos Pivatto

doi:10.1016/j.bmc.2018.10.032

Isolation, leishmanicidal evaluation and molecular docking simulations of piperidine alkaloids from Senna spectabilis

Bioorg Med Chem. 2018 Dec 1;26(22):5816-5823. doi: 10.1016/j.bmc.2018.10.032. Epub 2018 Nov 2.

Affiliations

¹ Núcleo de Pesquisa em Produtos Naturais (NuPPeN), Instituto de Química, Universidade Federal de Uberlândia, 38400-902 Uberlândia, MG, Brazil.
² Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, 38400-902 Uberlândia, MG, Brazil.
³ Laboratório de Biofísica Teórica, Departamento de Física, Instituto de Ciências Exatas, Naturais e Educação, Universidade Federal do Triângulo Mineiro, 38064-200 Uberaba, MG, Brazil; Núcleo de Desenvolvimento de Compostos Bioativos (NDCBio), Departamento de Química, Instituto de Ciências Exatas, Naturais e Educação, Universidade Federal do Triângulo Mineiro, 38064-200 Uberaba, MG, Brazil.
⁴ Laboratório de Pesquisa em Química Medicinal (PeQuiM), Instituto de Química, Universidade Federal de Alfenas, 37133-840 Alfenas, MG, Brazil.
⁵ Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais (NuBBE), Departamento de Química Orgânica, Instituto de Química, Universidade Estadual Paulista, P.O. Box 355, 14801-970 Araraquara, SP, Brazil.
⁶ Núcleo de Desenvolvimento de Compostos Bioativos (NDCBio), Departamento de Química, Instituto de Ciências Exatas, Naturais e Educação, Universidade Federal do Triângulo Mineiro, 38064-200 Uberaba, MG, Brazil.
⁷ Núcleo de Pesquisa em Produtos Naturais (NuPPeN), Instituto de Química, Universidade Federal de Uberlândia, 38400-902 Uberlândia, MG, Brazil; Núcleo de Desenvolvimento de Compostos Bioativos (NDCBio), Departamento de Química, Instituto de Ciências Exatas, Naturais e Educação, Universidade Federal do Triângulo Mineiro, 38064-200 Uberaba, MG, Brazil. Electronic address: pivatto@ufu.br.

PMID: 30413343
DOI: 10.1016/j.bmc.2018.10.032

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 and 3/4) 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 ligands 1-4 to the amino acids in the active site of L. amazonensis arginase. Alkaloid 2 (IC₅₀ 15.81 μg mL^-1) was the most effective against L. amazonensis. Compounds 2 and 4, with larger side chain, were more effective against the parasite than compounds 1 and 3. The cell viability test on Vero cells revealed that compound 2 (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 compound 3 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.

Keywords: (–)-Cassine; (–)-Spectaline; Fabaceae; Leishmanicidal activity; Piperidine alkaloids; Senna spectabilis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkaloids / chemistry
Alkaloids / isolation & purification
Alkaloids / pharmacology*
Antiprotozoal Agents / chemistry
Antiprotozoal Agents / isolation & purification
Antiprotozoal Agents / pharmacology*
Dose-Response Relationship, Drug
Leishmania / drug effects*
Leishmaniasis / drug therapy*
Molecular Docking Simulation
Molecular Structure
Parasitic Sensitivity Tests
Piperidines / chemistry
Piperidines / isolation & purification
Piperidines / pharmacology*
Senna Plant / chemistry*
Structure-Activity Relationship

Substances

Alkaloids
Antiprotozoal Agents
Piperidines
piperidine