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

Made available in DSpace on 2019-10-04T12:32:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-12-01 Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) 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 mu g 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 mu g 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. Univ Fed Uberlandia, Inst Quim, Nucleo Pesquisa Prod Nat NuPPeN, BR-38400902 Uberlandia, MG, Brazil Univ Fed Uberlandia, Inst Ciencias Biomed, BR-38400902 Uberlandia, MG, Brazil Univ Fed Triangulo Mineiro, Inst Ciencias Exatas Nat & Educ, Dept Fis, Lab Biofis Teor, BR-38064200 Uberaba, MG, Brazil Univ Fed Alfenas, Inst Quim, Lab Pesquisa Quim Med PeQuiM, BR-37133840 Alfenas, MG, Brazil Univ Estadual Paulista, Inst Quim, Dept Quim Organ, Nucleo Bioensaios Biossintese & Ecofisiol Prod Na, POB 355, BR-14801970 Araraquara, SP, Brazil Univ Fed Triangulo Mineiro, Inst Ciencias Exatas Nat & Educ, Dept Quim, Nucleo Desenvolvimento Compostos Bioativos NDCBio, BR-38064200 Uberaba, MG, Brazil Univ Estadual Paulista, Inst Quim, Dept Quim Organ, Nucleo Bioensaios Biossintese & Ecofisiol Prod Na, POB 355, BR-14801970 Araraquara, SP, Brazil FAPEMIG: APQ-02481-14 CNPq: 449846/2014-8 FAPEMIG: REDE-113/10 FAPEMIG: CEX-RED-00010-14