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.

Evaluation of ATM Kinase Inhibitor KU-55933 as Potential Anti-Toxoplasma gondii Agent

“…Interestingly, this toxicity did not impair tachyzoite replication inside the host cell, but could affect our interpretation of data relative to blocking T. gondii replication. Recently, a novel plasmodial topoisomerase I venom was designed on CPT derivative topotecan structure (Cortopassi et al, 2014). They demonstrated that a compound named LQB223 has a high selectivity for P. falciparum topoisomerase I in comparison with human counterpart and reduced Plasmodium berghei parasitemia in mice.…”

Old drug repurposing for neglected disease: Pyronaridine as a promising candidate for the treatment of Echinococcus granulosus infections

“…Some studies have reported the potential of topo I inhibitors against parasites including Plasmodium spp. [29,30], Leishmania spp. [31,32], Cryptosporidium parvum [33], and Trypanosoma spp.…”

Síntese De N-Tosil Aza-Carbapterocarpanos E Espiro Iso-Indolinas Com Potencial Ação Antitumoral

“…Baseado no potencial farmacológico, diversos pterocarpanos e análogos aza-pterocarpanos e aza-carbapterocarpanos, foram sintetizados pela professora Camilla D. Buarque em sua tese de Doutorado, sob orientação do professor Paulo R.R. Costa no Laboratório de Química Bioorgânica (LQB-IPPN-UFRJ) (BUARQUE et al, 2010(BUARQUE et al, , 2011(BUARQUE et al, , 2014(BUARQUE et al, , 2015CORTOPASSI et al, 2014).…”

“…Dentre os compostos sintetizados, destacou-se o LQB-223 (Figura 9), um Ntosil-aza-carbapterocarpano que apresentou atividade antiproliferativa semelhante ao antineoplásico doxorrubicina em linhagens de células de melanoma (MDA-MB435), ação anticâncer em linhagens de leucemia (HL-60) e câncer de cólon (HCT-8), uma potente atividade antileshimanial in vitro e antimalarial em ensaios in vivo (BUARQUE et al, 2010(BUARQUE et al, , 2011(BUARQUE et al, , 2014CORTOPASSI et al, 2014;LEMOS et al, 2016;MENDES et al, 2018;SILVA et al, 2017). (BUARQUE et al, 2014).…”

“…O grupo arilsulfonamida (como o grupo tosila) remete uma grande importância para a ação farmacológica de inúmeros compostos biologicamente ativos, assim como do LQB-223, conforme evidenciado previamente em nosso grupo de pesquisa e de acordo com dados na literatura (MENDES, 2018) (BUARQUE et al, 2011(BUARQUE et al, , 2014CORTOPASSI et al, 2014), propusemos então a síntese de N-tosil-orto-iodoanilinas substituídas para a síntese de novos análogos do LQB-223 com substituintes no anel D (Esquema 20).…”