Single-dose treatment for cutaneous leishmaniasis with an easily synthesized chalcone entrapped in polymeric microparticles

Abstract

<jats:title>Abstract</jats:title><jats:p>Cutaneous leishmaniasis (CL) is a major health problem in many countries and its current treatment involves multiple parenteral injections with toxic drugs and requires intensive health services. Previously, the efficacy of a single subcutaneous injection with a slow-release formulation consisting of poly(lactide-co-glycolide) (PLGA) microparticles loaded with an antileishmanial 3-nitro-2-hydroxy-4,6-dimethoxychalcone (CH8) was demonstrated in mice model. In the search for more easily synthesized active chalcone derivatives, and improved microparticle loading, CH8 analogues were synthesized and tested for antileishmanial activity <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. The 3-nitro-2′,4′,6′-trimethoxychalcone (NAT22) analogue was chosen for its higher selectivity against intracellular amastigotes (selectivity index = 1489, as compared with 317 for CH8) and more efficient synthesis (89% yield, as compared with 18% for CH8). NAT22 was loaded into PLGA / polyvinylpyrrolidone (PVP) polymeric blend microspheres (NAT22-PLGAk) with average diameter of 1.9 <jats:italic>μ</jats:italic>m. Although NAT22-PLGAk showed similar activity to free NAT22 in killing intracellular parasites <jats:italic>in vitro</jats:italic> (IC<jats:sub>50</jats:sub> ~ 0.2 <jats:italic>μ</jats:italic><jats:sc>m</jats:sc>), <jats:italic>in vivo</jats:italic> studies in <jats:italic>Leishmania amazonensis</jats:italic> – infected mice demonstrated the significant superior efficacy of NAT22-PLGAk to reduce the parasite load. A single intralesional injection with NAT22-PLGAk was more effective than eight injections with free NAT22. Together, these results show that NAT22-PLGAk is a promising alternative for single-dose localized treatment of CL.</jats:p>

Synthesis and evaluation of hybrid sulfonamide‐chalcones with potential antileishmanial activity

“…were obtained from BALB/c mice after culturing bone marrow stem cells with GM-CSF. [55] Differentiated cells were plated at 5 × 10 [56] The concentration that inhibited growth by 50% (IC 50 ) of each compound was calculated by nonlinear regression analysis using GraphPad Prism 7 software.…”

“…Parasite viability was fluorimetrically assessed in the last 4 h of culture by reduction of Alamar blue. [ 56 ] The concentration that inhibited growth by 50% (IC 50 ) of each compound was calculated by nonlinear regression analysis using GraphPad Prism 7 software.…”

Microparticles in the Development and Improvement of Pharmaceutical Formulations: An Analysis of In Vitro and In Vivo Studies

“…In another study, Sousa-Batista et al [ 36 ] prepared CH8 analogues to develop PLGA microparticles and evaluated their antileishmanial activity in vitro and in vivo. Results similar to those mentioned above were found for PLGA/polyvinylpyrolidone (PVP) microspheres loaded with the NAT22 analog.…”

Chalcones identify cTXNPx as a potential antileishmanial drug target

“…Whilst CH8 (1b; Fig 1) showed good activity, drug development was challenged by a difficult synthesis in which flavone formation accompanied aldol condensation. Consequently, a trimethoxylated analogue NAT22 (1c; Fig 1), that could be prepared far more efficiently through simple aldol condensation of the commercially available trimethoxyacetophenone with 3-nitrobenzaldehyde, was used as the parent chalcone [31]. Importantly, this showed similar anti-leishmanial activity to chalcone CH8 (1b) in vitro and in vivo against L. amazonensis [31].…”