Novel benzoxaborole, nitroimidazole and aminopyrazoles with activity against experimental cutaneous leishmaniasis

Abstract

ObjectivesDrugs for Neglected Diseases initiative (DNDi) has identified three chemical lead series, the nitroimidazoles, benzoxaboroles and aminopyrazoles, as innovative treatments for visceral leishmaniasis. The leads discovered using phenotypic screening, were optimised following disease- and compound-specific criteria. Several leads of each series were progressed and preclinical drug candidates have been nominated. Here we evaluate the efficacy of the lead compounds of each of these three chemical classes in in vitro and in vivo models of cutaneous leishmaniasis.MethodsThe in vitro activity of fifty-five compounds was evaluated against the intracellular amastigotes of L. major, L. aethiopica, L. amazonensis, L. panamensis, L. mexicana and L. tropica. The drugs demonstrating potent activity (EC50 < 5 μM) against at least 4 of 6 species were subsequently evaluated in vivo in different L. major – BALB/c mouse models using a 5 or 10-day treatment with either the oral or topical formulations. Efficacy was expressed as lesion size (measured daily using callipers), parasite load (by quantitative PCR – DNA) and bioluminescence signal reduction relative to the untreated controls.ResultsThe selected drug compounds (3 nitroimidazoles, 1 benzoxaborole and 3 aminopyrazoles) showed consistent and potent activity across a range of Leishmania species that are known to cause CL with EC50 values ranging from 0.29 to 18.3 μM. In all cases, this potent in vitro antileishmanial activity translated into high levels of efficacy with a linear dose-response against murine CL. When administered at 50 mg/kg/day, DNDI-0690 (nitroimidazole), DNDI-1047 (aminopyrazole) and DNDI-6148 (benzoxaborole) all resulted in a significant lesion size reduction (no visible nodule) and an approximate 2-log-fold reduction of the parasite load as measured by qPCR compared to the untreated control.ConclusionsThe lead compounds DNDI-0690, DNDI-1047 and DNDI-6148 showed excellent activity across a range of Leishmania species in vitro and against L. major in mice. These compounds offer novel potential drugs for the treatment of CL.

Activity of Amphotericin B-Loaded Chitosan Nanoparticles against Experimental Cutaneous Leishmaniasis

“…Although this does not mimic the in vivo situation, for which a comprehensive investigation would be necessary, it is in line with the longer dosing periods used. The standard in vivo drug efficacy for CL has been established as dosing over a 10-day period—where daily systemic administration with paromomycin demonstrated a significant reduction in nodule size and parasite load [ 36 , 37 ]. The release of AmB from AmB-CH-TPP nanoparticles or AmB-CH-Dex nanoparticles was conducted using dialysis.…”

“…We aimed to improve the potential of chitosan nanoparticles for the treatment of CL through the first in-depth study on this disease using: (a) the ionotropic gelation method to prepare nanoparticles of both positive and negative charge, using sodium tripolyphosphate (TPP), an FDA-approved additive for use in food substances [ 34 ] which has shown to play a role in nanoparticle stability during storage [ 15 , 35 ] or dextran sulphate (biodegradable, biocompatible and previously used to produce chitosan nanoparticles [ 35 ]) for gelation, respectively, with a clear aim of preparing particles <100 nm with enhanced drug delivery to Leishmania infected skin [ 24 ], (b) to determine the activity and dose-response effect in vivo in a murine model of CL infection using three methodologies [ 36 , 37 ], (c) to relate activity to drug accumulation and distribution in the skin [ 22 ] and (d) to compare the activity of these formulations against CL when administered by both the intravenous and topical routes, with the topical formulations optimized and analysed for appropriate skin permeation and distribution [ 37 ].…”

Pharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous Leishmaniasis

“…In a mouse model of L. major CL, oral DNDI-0690 exerted a linear dose-response effect (50% effective dose = 5 mg/kg, 90% effective dose = 21 mg/kg, maximal efficacy > 95% for a dose of 50 mg/kg), while topical solutions applied directly to the skin lesion were <50% active (19).…”

Infectivity and Drug Susceptibility Profiling of Different Leishmania-Host Cell Combinations

“…To deliver drugs that effectively treat Leishmania with lower adverse effects and higher accessibility, several organizations, including the Drugs for Neglected Diseases initiative (DNDi), have started fueling the global Leishmania drug pipeline with new potential chemotherapeutics. DNDi-6148 and DNDi-0690 are in phase I clinical trials, and several others are undergoing preclinical studies [14,15], following development from a phenotypic approach. Furthermore, with the absence of a clinically validated Leishmania drug target, a cell-based approach is regarded as an efficient way to fill in the pipeline.…”