Second-generation pterocarpanquinones: synthesis and antileishmanial activity

• Published in: Journal of Venomous Animals and Toxins including Tropical Diseases
• Main Authors: Viviane dos Santos Faiões, Lívia C. R. M. da Frota, Edézio Ferreira Cunha-Junior, Julio C. F. Barcellos, Thayssa Da Silva, Chaquip Daher Netto, Silvia Amaral Gonçalves Da-Silva, Alcides J. M. da Silva, Paulo R. R. Costa, Eduardo Caio Torres-Santos
• Format: Article in Journal/Newspaper
• Language: English
• Published: SciELO 2018
• Subjects: Leishmania; Pterocarpanquinone; LQ-118; Phenotypic assay; Leishmaniasis; Drug discovery; Arctic medicine. Tropical medicine; RC955-962; Toxicology. Poisons; RA1190-1270; Zoology; QL1-991; Arctic
• Online Access: https://doi.org/10.1186/s40409-018-0174-7; https://doaj.org/article/c21f424e40fb4359a7e39bbe4c79cc09

Abstract 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 ...