title: Theoretical and experimental studies of new modified isoflavonoids as potential inhibitors of topoisomerase I from Plasmodium falciparum.
abstract: DNA topoisomerase I from Plasmodium falciparum (PfTopoI), a potential selective target for chemotherapy and drug development against malaria, is used here, together with human Topo I (HssTopoI), for docking, molecular dynamics (MD) studies and experimental assays. Six synthetic isoflavonoid derivatives and the known PfTopoI inhibitors camptothecin and topotecan were evaluated in parallel. Theoretical results suggest that these compounds dock in the binding site of camptothecin and topotecan inside both enzymes and that LQB223 binds selectively in PfTopoI. In vitro tests against P. falciparum blood parasites corroborated the theoretical findings. The selectivity index (SI) of LQB223 ≥ 98 suggests that this molecule is the most promising in the group of compounds tested. In vivo experiments in mice infected with P. berghei showed that LQB223 has an antimalarial activity similar to that of chloroquine.
authors.affiliation: Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Modelagem Aplicada a Defesa Química e Biológica, Instituto Militar de Engenharia, Rio de Janeiro, Brazil.
authors.forename: Wilian A
authors.initials: WA
authors.lastname: Cortopassi
authors.affiliation: Laboratório de Malária, Centro de Pesquisas René Rachou, Fundação Instituto Oswaldo Cruz, Belo Horizonte, Brazil; Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Julia
authors.initials: J
authors.lastname: Penna-Coutinho
authors.affiliation: Laboratório de Malária, Centro de Pesquisas René Rachou, Fundação Instituto Oswaldo Cruz, Belo Horizonte, Brazil; Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Anna C C
authors.initials: AC
authors.lastname: Aguiar
authors.affiliation: Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: André S
authors.initials: AS
authors.lastname: Pimentel
authors.affiliation: Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Camilla D
authors.initials: CD
authors.lastname: Buarque
authors.affiliation: Laboratório de Química Bioorgânica, Núcleo de Pesquisas de Produtos Naturais, Rio de Janeiro, Brazil.
authors.forename: Paulo R R
authors.initials: PR
authors.lastname: Costa
authors.affiliation: Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Bruna R M
authors.initials: BR
authors.lastname: Alves
authors.affiliation: Laboratório de Modelagem Aplicada a Defesa Química e Biológica, Instituto Militar de Engenharia, Rio de Janeiro, Brazil.
authors.forename: Tanos C C
authors.initials: TC
authors.lastname: França
authors.affiliation: Laboratório de Malária, Centro de Pesquisas René Rachou, Fundação Instituto Oswaldo Cruz, Belo Horizonte, Brazil; Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Antoniana U
authors.initials: AU
authors.lastname: Krettli
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007529:Isoflavones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010271:Parasites / Q000187:drug effects; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D013816:Thermodynamics; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019772:Topotecan / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D007529:Isoflavones; D059003:Topoisomerase Inhibitors; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin