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

Abstract

e 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 antileukemic 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

“… ND Not Determined a reference [ 14 ] b reference [ 13 ] e c reference [ 12 ] d Selective Index (SI) = CC 50 in Macrophages/IC 50 in intracellular amastigotes …”

“…al ., which establishes some generic hit selection criteria for infectious diseases, namely that the hit compound should ideally be synthesized in up to five steps with an acceptable yield and acceptable solubility [ 31 ]. Recent studies have shown that LQB-118 (the first generation of pterocarpanquinones) is a suitable structure for the development of promising drugs for the oral treatment of leishmaniasis [ 12 ]; thus, the second generation was produced and its activity spectrum was tested on two species that cause tegumentary leishmaniasis ( L. amazonensis and L. braziliensis ) and a species that causes visceral leishmaniasis ( L. infantum ). In this work, we answered two pertinent questions about the structure of the first generation pterocarpanquinones: (i) the configuration of the position of rings B (pyran) and C (furan) of the pterocarpan core and (ii) the presence of oxygen in the B ring.…”

“…We have also demonstrated that LQB-118 is effective in treating experimental visceral ( Leishmania infantum ) and cutaneous ( L . amazonensis and L. braziliensis ) leishmaniasis via oral delivery, and therapeutic safety in a repeated toxicity study [ 12 – 14 ]. The death of L. amazonensis parasites involved oxidative stress with the hallmarks of apoptosis, similar to cancer-induced death [ 15 ].…”

Preparative chiral separation and absolute configuration of the synthetic pterocarpanquinone LQB‐118

“…This molecule was found to induce apoptosis in Leishmania amazonensis and L. braziliensis besides controlling cutaneous and visceral lesions in infected mice and hamisters . LQB‐118 is currently under preclinical investigation for visceral leishmaniasis . However, all the biological assays conducted so far were carried out with the racemic mixture.…”

“…6 LQB-118 is currently under preclinical investigation for visceral leishmaniasis. 8 However, all the biological assays conducted so far were carried out with the racemic mixture. Even though the latest synthetic protocol 9 developed for LQB-118 was highly regio-and stereoselective, leading to the formation of syn adducts, both enantiomers were formed.…”