title: Synthesis, antimalarial activity in vitro, and docking studies of novel neolignan derivatives.
abstract: The absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors have left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventional antimalarial drugs result in a worrisome scenario making the search for new drugs a priority. In the present study, the activities of nine neolignan derivatives were evaluated as follows: (i) against blood forms of chloroquine-resistant Plasmodium falciparum (clone W2), using the tritiated hypoxanthine incorporation and anti-HRPII assays; (ii) for cytotoxic activity against cultured human hepatoma cells (HepG2); and (iii) for intermolecular interaction with the P. falciparum cysteine protease of falcipain-2 (F2) by molecular docking. The neolignan derivatives 9 and 10 showed activity against the blood form of the chloroquine-resistant P. falciparum clone W2 and were not cytotoxic against cultured human hepatoma cells. A molecular docking study of these two neolignans with FP2 revealed several intermolecular interactions that should guide the design of future analogs.
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, PA, Brazil.|Laboratório de Pesquisa em Malária, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Glaécia A N
authors.initials: GAN
authors.lastname: Pereira
authors.affiliation: Laboratório de Síntese Orgânica, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, PA, Brazil.
authors.forename: Gisele C
authors.initials: GC
authors.lastname: Souza
authors.affiliation: Laboratório de Síntese Orgânica, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, PA, Brazil.
authors.forename: Lourivaldo S
authors.initials: LS
authors.lastname: Santos
authors.affiliation: Laboratório de Síntese Orgânica, Instituto de Química, UNICAMP, Campinas, SP, Brazil.
authors.forename: Lauro E S
authors.initials: LES
authors.lastname: Barata
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, PA, Brazil.
authors.forename: Carla C F
authors.initials: CCF
authors.lastname: Meneses
authors.affiliation: Laboratório de Malária, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil.
authors.forename: Antoniana U
authors.initials: AU
authors.lastname: Krettli
authors.affiliation: Laboratório de Pesquisa em Malária, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Cláudio Tadeu
authors.initials: CT
authors.lastname: Daniel-Ribeiro
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, PA, Brazil.
authors.forename: Cláudio Nahum
authors.identifier: http://orcid.org/0000-0001-6576-4229
authors.initials: CN
authors.lastname: Alves
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006860:Hydrogen Bonding; D017705:Lignans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D017705:Lignans; D015800:Protozoan Proteins; D002738:Chloroquine; D003546:Cysteine Endopeptidases; C416224:falcipain 2
keywords: antiplasmodial activity; docking; falcipain-2; neolignan derivatives