Search

The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacterial and parasitic infections, most notably, coccidiosis in poultry and in ruminants. We have investigated the effects of treatment of Toxoplasma gondii in infected human foreskin fibroblasts (HFF) with DCQ. This induced distinct alterations in the parasite mitochondrion within 24 h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC 50 ) of 1.1 nM and the high selectivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with T. gondii oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than T. gondii infection alone, and did not prevent vertical transmission. Thus, three quinoline- O -carbamate derivatives of DCQ, anticipated to have better physicochemical properties than DCQ, were assessed in vitro. One such compound, RMB060, displayed an exceedingly low IC 50 of 0.07 nM, when applied concomitantly with the infection of host cells and had no impact on HFF viability at 10 µM. As was the case for DCQ, RMB060 treatment resulted in the alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6 h after the commencement of treatment. After 48 h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features reminiscent of bradyzoites. The exposure of infected cultures to 300 nM RMB060 for 52 days did not result in the complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. The treatment of mice infected with T. gondii oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.

Vesicles are widely investigated as carrier systems for active pharmaceutical ingredients (APIs). For topical delivery, they are especially effective since they create a "depot-effect" thereby concentrating the APIs in the skin. Artemisone, clofazimine and decoquinate were selected as a combination therapy for the topical treatment of cutaneous tuberculosis. Delivering APIs into the skin presents various challenges. However, utilising niosomes, liposomes and transferosomes as carrier systems may circumvent these challenges. Vesicles containing 1% of each of the three selected APIs were prepared using the thin-film hydration method. Isothermal calorimetry, differential scanning calorimetry and hot-stage microscopy indicated no to minimal incompatibility between the APIs and the vesicle components. Encapsulation efficiency was higher than 85% for all vesicle dispersions. Vesicle stability decreased and size increased with an increase in API concentration; and ultimately, niosomes were found the least stable of the different vesicle types. Skin diffusion studies were subsequently conducted for 12 h on black human female skin utilising vertical Franz diffusion cells. Transferosomes and niosomes delivered the highest average concentrations of clofazimine and decoquinate into the skin, whereas artemisone was not detected and no APIs were present in the receptor phase. Finally, efficacy against tuberculosis was tested against the Mycobacterium tuberculosis H37Rv laboratory strain. All the dispersions depicted some activity, surprisingly even the blank vesicles portrayed activity. However, the highest percentage inhibition (52%) against TB was obtained with niosomes containing 1% clofazimine.

Purpose: The aim of this study was to formulate nano-emulsions comprising natural oils and the active pharmaceutical ingredients (APIs) clofazimine (CLF), artemisone (ATM) and decoquinate (DQ) in order to determine effectiveness of the nano-emulsions for topical delivery of the APIs. The APIs alone do not possess suitable physicochemical properties for topical drug delivery., Methods: Nano-emulsions were formulated with olive and safflower oils encapsulating the APIs. Skin diffusion and tape stripping studies were performed. By using the lactate dehydrogenase (LDH) assay, in vitro toxicity studies were carried out on immortalized human keratinocytes (HaCaT) cell line to determine cytotoxicities due to the APIs and the nano-emulsions incorporating the APIs., Results: The nano-emulsions were effective in delivering the APIs within the stratum corneum-epidermis and the epidermis-dermis, were non-cytotoxic towards HaCaT cell lines (p < 0.05) and inhibited Mycobacterium tuberculosis in vitro., Conclusion: Natural oil nano-emulsions successfully deliver CLF, ATM and DQ and in principle could be used as supplementary topical treatment of cutaneous tuberculosis (CTB). Graphical Abstract ᅟ.

As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The emergence of Plasmodium falciparum (Pf) parasite strains tolerant of the artemisinin component and resistant to the other drug component in artemisinin combination therapies (ACTs) used for treatment now markedly complicates malaria control. Thus, development of new combination therapies are urgently required. For the non-artemisinin component, the quinolone ester decoquinate (DQ) that possesses potent activities against blood stage Pf and acts on a distinct target, namely the Pf cytochrome bc1 complex, was first considered. However, DQ has poor drug properties including high lipophilicity and exceedingly poor aqueous solubility (0.06 μg/ml), rendering it difficult to administer. Thus, DQ was chemically modified to provide the secondary amide derivative RMB005 and the quinoline O-carbamate derivatives RMB059 and RMB060. The last possesses sub-nanomolar activities against multidrug resistant blood stages of Pf, and P. berghei sporozoite liver stages. Here we present the results of ADME analyses in vitro and pharmacokinetic analyses using C57BL/6 mice. The amide RMB005 had a maximum mean whole blood concentration of 0.49 ± 0.02 µM following oral administration; however, the area under the curve (AUC), elimination half-life (t1/2) and bioavailability (BA) were not significantly better than those of DQ. Surprisingly, the quinoline O-carbamates which can be recrystallized without decomposition were rapidly converted into DQ in human plasma and blood samples. The maximum concentrations of DQ reached after oral administration of RMB059 and RMB060 were 0.23 ± 0.05 and 0.11 ± 0.01 µM, the DQ elimination half-lives were 4.79 ± 1.66 and 4.66 ± 1.16 h, and the DQ clearance were 19.40 ± 3.14 and 21.50 ± 3.38 respectively. Under these assay conditions, the BA of DQ could not be calculated Overall although RMB059 and -060 are labile in physiological medium with respect to the DQ parent, the potential to apply these as prodrugs is apparent from the current data coupled with their ease of preparation. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), the leading cause of death due to an infectious agent, requires prolonged and costly drug treatments. With the rise in incidence of MDR and XDR TB, newer more efficacious treatments which are better able to permeate into the deeper recesses of the human lung where bacteria reside are urgently required. To this end, two new promising drug candidates, the decoquinate derivative RMB041 and the phenoxazine PhX1, were assessed for their abilities to permeate into specific murine organs. In particular, PhX1 permeation into the lungs and heart was notably efficient, as reflected in the high relative AUC values of 9669 ± 120.2 min/nmol/mg and 12450 ± 45.2 min/nmol/mg for lung and heart tissue, respectively. However, neither compound maintained a free concentration in the lung which exceeded the compound's respective MIC90 values, indicating the importance of correcting for organ specific binding. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is currently the leading cause of mortality due to an infectious disease, despite the existence of multiple effective first-line and second-line drugs. The current anti-TB regimen requires a prolonged treatment period of around 6 months and is only efficacious against drug-sensitive strains of Mycobacterium tuberculosis (Mtb). With a rise in cases of multi-drug resistant and extensively drug resistant strains of Mtb , newer treatments comprising compounds with novel mechanisms of action are required. Although decoquinate (DQ) is inactive against Mtb , its derivatives are of interest to anti-TB drug discovery because of their potential to permeate the mycobacterial cell wall, Mtb -infected macrophages, and granulomatous lesions by passive diffusion. The compounds also display mechanisms of action which are unlike those of currently used quinolones, potentially displaying activity against new targets. Three such derivatives bearing an alkyl group at N-1 and an amide group at C-3 (RMB 041, -043, and -073) displayed potent in vitro activities against Mtb H37Rv (90% minimum inhibitory concentrations, MIC90 = 1.61, 4.18, and 1.88 μM, respectively) and high selectivity indices (10–25). In this study, we evaluated the drug-like properties (in vitro microsomal stability, microsomal/plasma protein binding, kinetic solubility, lipophilicity, and passive permeability) and pharmacokinetic (PK) parameters of these compounds after intravenous and oral administration to male C57BL/6 mice. The compounds showed markedly improved kinetic solubilities compared to that of the parental DQ and were metabolically stable in vitro. The maximum concentrations reached after oral administration were 5.4 ± 0.40, 5.6 ± 1.40, and 2.0 ± 0.03 μM; elimination half-lives were 23.4 ± 2.50, 6.2 ± 0.80, and 11.6 ± 1.30 h; and bioavailabilities were 21.4 ± 1.0, 22.1 ± 2.2, and 5.9 ± 1.3 for RMB041, -043, and -073, respectively. These compounds therefore display promising drug-like properties, and their PK/toxicity profiles (including long half-lives both in vitro and in vivo) support their potential as candidates for further investigation in animal models of Mtb infection. [ABSTRACT FROM AUTHOR]

Available anti-malarial tools have over the ten-year period prior to 2012 dramatically reduced the number of fatalities due to malaria from one million to less than six-hundred and thirty thousand. Although fewer people now die from malaria, emerging resistance to the first-line anti-malarial drugs, namely artemisinins in combination with quinolines and arylmethanols, necessitates the urgent development of new anti-malarial drugs to curb the disease. The quinolones are a promising class of compounds, with some demonstrating potent in vitro activity against the malaria parasite. This review summarizes the progress made in the development of potential anti-malarial quinolones since 2008. The efficacy of these compounds against both asexual blood stages and other stages of the malaria parasite, the nature of putative targets, and a comparison of these properties with anti-malarial drugs currently in clinical use, are discussed. [ABSTRACT FROM AUTHOR]