Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii In Vitro and in Pregnant Mice Infected with T. gondii Oocysts

Abstract

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 (IC50) 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 IC50 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.

Organometallic Derivatives of Decoquinate Targeted toward Toxoplasma gondii

“…Increased efficacy of O-alkylated DCQ derivatives relative to DCQ alone has been studied previously, with Ocarbamate derivatives reaching nanomolar IC 50 values. 24 Such organometallic derivatives could be of interest in the future.…”

“…Of interest was the significant efficacy of the O -alkylated O -PhVDCQ derivative, potentially opening a new avenue of investigation in the pursuit of an effective organometallic derivative of DCQ. Substitution of groups to the cyclic ketone may yield improved efficacy, as has been reported elsewhere …”

“…The rationale behind synthesizing ferrocenyl analogs of DCQ stems from previously published studies by Jaouen, Biot, and co-workers, which showed that ferrocenyl analogs of tamoxifen and chloroquine had improved bioactivities compared to the original parent compounds. − Further studies showed that the ferrocenyl component made a difference by producing reactive oxygen species, increasing lipophilicity of the molecule, and provided additional mechanisms of action compared to that of the original drug. − At our end, we have, over the past few years, used this strategy to unveil novel lead compounds against different parasitic diseases such as schistosomiasis or fungal agents. ,,, …”

“…Substitution of groups to the cyclic ketone may yield improved efficacy, as has been reported elsewhere. 24 ■ EXPERIMENTAL SECTION Ferrocenylmethyl-DCQ (FcMDCQ). In an inert atmosphere, DCQ (100 mg, 0.239 mmol) and K 2 CO 3 (99 mg, 0.718 mmol) were stirred in dry acetonitrile (60 mL).…”

“…17−22 At our end, we have, over the past few years, used this strategy to unveil novel lead compounds against different parasitic diseases such as schistosomiasis or fungal agents. 13,16,23,24 With this in mind, we have synthesized and characterized analogs of DCQ, containing ferrocenyl moieties. In addition to this, ruthenocenyl and benzyl derivatives were also synthesized.…”