Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Abstract

BackgroundDespite 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.MethodsThe 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.ResultsIn 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.ConclusionsThe data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.

Colombian Contributions Fighting Leishmaniasis: A Systematic Review on Antileishmanials Combined with Chemoinformatics Analysis

“…Considering Colombia as a country with a significant number of pathogenic Leishmania species in circulation, these facts are very critical, bearing in mind that parasite sensitivity to antileishmanial agents relies on Leishmania species [70,71]. For instance, a study evaluated dehydroabietylamine derivatives and found species-dependent susceptibility for several of them [72], being consistent with other reports [73,74]. Indeed, owing to the role of intraand inter-species Leishmania susceptibility [71,75,76], the incorporation of drug-resistant strains during antileishmanial research programs have been strongly recommended [77].…”

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years

“…High-throughput screening has been employed by several researchers either as phenotypic screens [32,102,121,122] or target-specific, such as Leishmania protein disulfide isomerase [40,123]. Several compound classes have been identified with potent antileishmanial activity, including substituted 1,2-dioxanes [124], mono-arylimidamides [125], pterocarpanquinones [126], C-10b-substituted dihydropyrrolo [1,2-b]isoquinolines [127], amino-substituted 1H-phenalen-1-ones [128], and chalcones [129]. For example, Ortalli et al (2018) synthesized 31 novel chalcone compounds, with 16 compounds showing activity against L. donovani promastigotes [129].…”

Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

“…The assays were performed in triplicate in 96-well plates (Costar, New York, United States). Inhibition parasite growth was assessed by a fluorescent assay, Resazurin (Sigma-Aldrich) (Faiões et al, 2018). Briefly, 50 µM of resazurin was added per well, and then the samples were incubated for an additional 2 h. The fluorescence was measured using a Spectra Max GEMINI XPS spectrofluorometer (Molecular Devices, Silicon Valley, United States) at excitation and emission wavelengths of 560 and 590 nm, respectively.…”