Structure and Antiparasitic Activity Relationship of Alkylphosphocholine Analogues against Leishmania donovani

Abstract

Miltefosine (Milt) is the only oral treatment for visceral leishmaniasis (VL) but its use is associated with adverse effects, e.g., teratogenicity, vomiting, diarrhoea. Understanding how its chemical structure induces cytotoxicity, whilst not compromising its anti-parasitic efficacy, could identify more effective compounds. Therefore, we systemically modified the compound’s head, tail and linker tested the in vitro activity of three alkylphosphocholines (APC) series against Leishmania donovani strains with different sensitivities to antimony. The analogue, APC12, with an alkyl carbon chain of 12 atoms, was also tested for anti-leishmanial in vivo activity in a murine VL model. All APCs produced had anti-leishmanial activity in the micromolar range (IC50 and IC90, 0.46– > 82.21 µM and 4.14–739.89 µM; 0.01– > 8.02 µM and 0.09–72.18 µM, respectively, against promastigotes and intracellular amastigotes). The analogue, APC12 was the most active, was 4–10 fold more effective than the parent Milt molecule (APC16), irrespective of the strain’s sensitivity to antimony. Intravenous administration of 40 mg/kg APC12 to L. donovani infected BALB/c mice reduced liver and spleen parasite burdens by 60 ± 11% and 60 ± 19%, respectively, while oral administration reduced parasite load in the bone marrow by 54 ± 34%. These studies confirm that it is possible to alter the Milt structure and produce more active anti-leishmanial compounds.

Truncated S-MGBs: towards a parasite-specific and low aggregation chemotype

“…7 Anti-Leishmania assay Compounds were screened in vitro for their antileishmanial activity against the intracellular amastigote stage. 21 Bone marrow derived macrophages (0.5 × 10 5 cells per well) were infected using a 20 : 1 host cell : parasite ratio with luciferaseexpressing L. donovani LV82 luc1 (MHOM/ET/67:LV82). The medium was changed at 24 post-infection to remove free parasites and infected cells were treated with medium alone (controls, n = 6) or doubling dilutions of DMSO (n = 3, starting at 2% or 2.5% v/v) or MGB compounds (n = 3 or 6, starting at 25 or 20 μg mL −1 , prepared using a 1 mg mL −1 DMSO stock solution).…”

Selective Anti-Leishmanial Strathclyde Minor Groove Binders Using an N-Oxide Tail-Group Modification

“…The compounds were screened in vitro for their antileishmanial activity against the intracellular amastigote stage [ 23 , 24 ]. Briefly, bone marrow-derived macrophages (0.5 × 10 5 cells per well) were infected using a 20:1 host cell: parasite ratio with luciferase-expressing L. donovani LV82 luc1 (MHOM/ET/67:LV82).…”

Integral Role of Water in the Solid-State Behavior of the Antileishmanial Drug Miltefosine

“…There are four different medicines specified on the 22nd list of WHO Model List of Essential Medicines as treatments for leishmaniasis: amphotericin B, pentavalent antimonials, paromomycin, and miltefosine . Miltefosine is the first and only oral medication to be successfully utilized as a treatment for visceral leishmaniasis but is teratogenic and causes toxicity due to the amphiphilic and zwitterionic structure of the drug (Figure ) which irritates the gastrointestinal epithelial lining. , …”

“…For example, hydrate forms of active pharmaceutical ingredients can cause problems for the storage and shelf life of the drug if dehydration takes place. Water can also cause reaction with other excipients within the tablets. , Therefore, in this work, we investigate the structure of miltefosine and structural analogues (14- and 12-carbon alkyl chain analogues) with biological activity to understand the role of water in the materials and determine whether it is possible to prepare an anhydrous form.…”

“…4 Miltefosine is the first and only oral medication to be successfully utilized as a treatment for visceral leishmaniasis but is teratogenic and causes toxicity due to the amphiphilic and zwitterionic structure of the drug (Figure 1) which irritates the gastrointestinal epithelial lining. 5,6 Miltefosine is hygroscopic, 7 which suggests it is most stable when surrounded by water molecules. There are many studies of miltefosine at the air/water interface 8,9 as micelles 10,11 and as liquid crystals; 12 however, the studies focusing on the solidstate structure of miltefosine are limited.…”