Antileishmanial activity evaluation of a natural amide and its synthetic analogs against Leishmania (V.) braziliensis: an integrated approach in vitro and in silico

Author(s):Show less -

da Silva, Minelly A. ^{[1, 2, 3]} ; Fokoue, Harold H. ^[4] ; Fialho, Saara N. ^{[5, 6]} ; dos Santos, Ana Paula de A. ^[5] ; Rossi, Norton R. D. L. P. ^{[2, 5]} ; Gouveia, Aurileya de J. ^[5] ; Ferreira, Amalia S. ^[5] ; Passarini, Guilherme M. ^{[2, 5]} ; Garay, Ana F. G. ^{[5, 7]} ; Alfonso, Jorge J. ^{[5, 7]} ; Soares, Andreimar M. ^{[2, 5, 6, 8]} ; Zanchi, Fernando B. ^{[2, 5, 6]} ; Kato, Massuo J. ^[9] ; Teles, Carolina B. G. ^{[2, 5, 6, 8]} ; Kuehn, Christian C. ^[2]

Affiliation

^[1] Fed Inst Educ Sci & Technol Rondonia IFRO, Porto Velho, Rondonia - Brazil

^[2] Fed Univ Rondonia UNIR, Porto Velho, Rondonia - Brazil

^[3] Inst Fed Rondonia Porto Velho Calama, Av Calama 4985, BR-76820441 Porto Velho, RO - Brazil

^[4] Fundacao Oswaldo Cruz, Farmanguinhos FIOCRUZ RJ, Inst Tecnol Farmacos, Rio De Janeiro - Brazil

^[5] Fundacao Oswaldo Cruz Rondonia FIOCRUZ RO, Porto Velho, Rondonia - Brazil

^[6] Rede Biodiversidade & Biotecnol Amazonia Legal BI, Porto Velho, Rondonia - Brazil

^[7] Ctr Desarrollo Invest Cient CEDIC, Asuncion - Paraguay

^[8] Natl Inst Sci & Technol Epidemiol Western Amazon, Porto Velho, Rondonia - Brazil

^[9] Univ Sao Paulo, Inst Chem, Sao Paulo - Brazil

• Document type: Journal article
• Source: Parasitology Research; v. 120, n. 6, p. 2199-2218, JUN 2021.
• Web of Science Citations: 0

Abstract

Leishmaniasis is considered a neglected disease, which makes it an unattractive market for the pharmaceutical industry; hence, efforts in the search for biologically active substances are hampered by this lack of financial motivation. Thus, in the present study, we report the leishmanicidal activity and the possible mechanisms of action of compounds with promising activity against the species Leishmania (V.) braziliensis, the causative agent of the skin disease leishmaniasis. The natural compound 1a (piplartine) and the analog 2a were the most potent against promastigote forms with growth inhibition values for 50% of the parasite population (IC50) = 8.58 and 11.25 mu M, respectively. For amastigote forms, the ICa50 values were 1.46 and 16.7 mu M, respectively. In the molecular docking study, piplartine showed favorable binding energy (-7.13 kcal/mol) and with 50% inhibition of trypanothione reductase (IC50) = 91.1 mu M. Preliminary investigations of the mechanism of action indicate that piplartine increased ROS levels, induced loss of cell membrane integrity, and caused accumulation of lipid bodies after 24 h of incubation at its lowest effective concentration (IC50), which was not observed for the synthetic analog 2a. The mode of action for the leishmanicidal activity of piplartine (1a) was assigned to involve affinity for the trypanothione reductase of Leishmania (V.) braziliensis TR. (AU)

• FAPESP's process: 14/50316-7 - Dimensions US-Biota São Paulo: Chemically mediated multi-trophic interaction diversity across tropical gradients
• Grantee: Massuo Jorge Kato
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants