Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Submitted by Sandra Infurna ([email protected]) on 2017-02-09T14:30:16Z No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2016.pdf: 2057722 bytes, checksum: b905a7232a9bd50caaeeaa9c5415f825 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-02-09T14:45:46Z (GMT) No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2016.pdf: 2057722 bytes, checksum: b905a7232a9bd50caaeeaa9c5415f825 (MD5)Made available in DSpace on 2017-02-09T14:45:46Z (GMT). No. of bitstreams: 1 edesio_cunhajr_etal_IOC_2016.pdf: 2057722 bytes, checksum: b905a7232a9bd50caaeeaa9c5415f825 (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Universidade do Estado do Rio de Janeiro. Laboratório Imunol. Aplicada e Bioq. de Proteínas e Prod. Naturais. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Universidade do Estado do Rio de Janeiro. Laboratório Imunol. Aplicada e Bioq. de Proteínas e Prod. Naturais. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Departamento de Patologia e Laboratórios. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Laboratório Imunol. Aplicada e Bioq. de Proteínas e Prod. Naturais. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Laboratório de Química. Macaé, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Pesquisas de Produtos Naturais. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Laboratório Imunol. Aplicada e Bioq. de Proteínas e Prod. Naturais. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and anti-leukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

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 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