Antimalarial activities and subacute toxicity of RC-12, a 4-amino-substituted pyrocatechol

Abstract

RC-12 [1,2-dimethoxy-4-(bis-diethylaminoethyl)-amino-5-bromobenzeneI was evaluated for prophylactic, radical curative, and suppressive activities against infections with Plasmodium cynomolgi and subacute toxicity in rhesus monkeys. Applied as a prophylactic agent, RC-12, administered in doses of 6.25 to 25.0 mg/kg daily throughout the incubation period, provided near-complete to complete protection against 105 to 106 times the minimum infective dose of sporozoites. Applied as a suppressive agent, daily doses of 100.0 mg of RC-12 per kg did not eradicate blood schizonts regularly; hence, the need for concomitant administration of a blood schizonticide, such as chloroquine, in assessments of radical curative activity. In such appraisals, daily doses of 6.25 to 25.0 mg of RC-12 per kg for 14 days, in combination with 2.5 mg of chloroquine per kg daily for 7 days, effected cure of 69 and 93% of established infections, respectively. The curative activity of RC-12 was related to the total dose and could be achieved with a regimen as brief as 4 days. With respect to outward expressions of toxicity, daily doses of 50.0 mg/kg or lower for 15 to 225 days evoked no reactions. Doses of 100.0 or 200.0 mg/kg, scheduled for 15 days, evoked convulsions and depression and were, respectively, lethal to 4 of 17 and 7 of 7 recipients. Doses of 25.0 mg/kg or lower evoked no discrete reactions. Doses of 50.0 mg/kg and higher evoked hepatomegaly, vacuolation of hepatocytes, and elevations of glutamic oxalacetic and glutamic pyruvic transferase activities in serum, reactions related in intensity to dose but not duration of dosage.

Targeting the Liver Stage of Malaria Parasites: A Yet Unmet Goal

“…It is known that 25 mg/kg po prevented the development and/or maturation of exoerythrocytic stages in P. cynomolgi , thus showing causal prophylaxis. , Schmidt et al reported that even at 6.25 mg/kg the efficacy did not decrease significantly. Nevertheless, as a result of limited activity against blood stages by 129 , coadministration of chloroquine is required for radical cure …”

“…Nevertheless, as a result of limited activity against blood stages by 129, coadministration of chloroquine is required for radical cure. 128 DL-α-Difluoromethylornithine, 130, is a specific irreversible inhibitor of ornithine decarboxylase, a key enzyme in the biosynthesis of polyamines. Compound 130 administered at 1% in drinking water showed prophylactic activity in mice inoculated with P. berghei sporozoites, through the inhibition of early stage exoerythrocytic schizogony.…”

Killing the hypnozoite – drug discovery approaches to prevent relapse inPlasmodium vivax

“…A second chemical class with modest anti-relapse activity in the P. cynomolgi rhesus model is RC-12. 56 RC-12 is an electron rich ring with amine side chains; interestingly, an overlay with primaquine ( Fig. 5) is apparent and putative metabolites of RC-12 can theoretically form iminoquinones.…”

Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12)

“… 13 Compound 1 ( Figure 1 ) is about 1 order of magnitude less effective than primaquine in this model, but it is also 1 order of magnitude less toxic and produced no hemolysis. 14 However, in a small-scale clinical trial where volunteers were infected with mosquito-borne P. vivax sporozoites, 1 did not prevent infections or inhibit relapses of P. vivax . 15 In this trial, volunteers were given a well-tolerated 7-day course of 1 at 10 mg/(kg day), a dose regimen comparable to that which protected against and cured P. cynomolgi infections in the rhesus monkey model.…”

“… 15 In this trial, volunteers were given a well-tolerated 7-day course of 1 at 10 mg/(kg day), a dose regimen comparable to that which protected against and cured P. cynomolgi infections in the rhesus monkey model. 14 Clearly, the dichotomy between the lack of efficacy of 1 against P. vivax hypnozoites in humans 15 and the high efficacy of 1 against P. cynomolgi hypnozoites in rhesus monkeys 14 points to the compelling need to better understand both the pharmacokinetic and the pharmacodynamic profile of 1 and to identify potential active metabolites that might explain these apparent species differences. We now describe our work to elucidate the Phase I metabolism using liver microsomes from various species, the pharmacokinetics in rats, and the in vitro liver-stage activity of 1 and its major metabolites.…”