Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Journal of venomous animals and toxins

Lívia C. R. M. da Frota^2¹  Thayssa Da Silva^3²  Viviane dos Santos Faiões^1³  Edézio Ferreira Cunha-Junior^1⁴  Julio C. F. Barcellos^2⁵ 

[1] Instituto de Pesquisa de Produtos naturais, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ Brazil^2;Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCUZ, Av. Brasil, 4365, Pavilhao Leonidas Deane, sala 405A, Manguinhos, Rio de Janeiro, RJ 21040-900 Brazil Find articles by Eduardo Caio Torres-Santos^5;Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCUZ, Av. Brasil, 4365, Pavilhao Leonidas Deane, sala 405A, Manguinhos, Rio de Janeiro, RJ 21040-900 Brazil^1;Laboratório de Imunofarmacologia Parasitária, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ Brazil^3;Laboratório de Química, Universidade Federal do Rio de Janeiro, campus Professor Aloísio Teixeira, Macaé, RJ Brazil^4

关键词: Leishmania;    Pterocarpanquinone;    LQ-118;    Phenotypic assay;    Leishmaniasis;    Drug discovery;    Neglected diseases;   

DOI  :  10.1186/s40409-018-0174-7

学科分类：药理学

来源: BioMed Central

【 摘 要 】

Background Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones. Methods The second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis , L. braziliensis , and L. infantum . Toxicity was assessed in peritoneal macrophages and selective index calculated by CC₅₀/IC₅₀. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells. Results In this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum . As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production. Conclusions The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.

【 授权许可】

CC BY