The S,S enantiomer of the bisquinoline trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine,
Ro 47-7737, is significantly more potent against
chloroquine-resistant Plasmodium falciparum than the R,R enantiomer and the previously described racemate. Both the enantiomers and the racemate are more potent inhibitors of
heme polymerization than
chloroquine, and their activities are probably mediated by inhibition of this parasite-specific process. The S,S enantiomer,
Ro 47-7737, was studied in more detail and proved to be a potent
antimalarial in the treatment of P. vivax ex vivo and P. berghei in vivo. Its suppression of P. berghei growth in a mouse model (50% effective dose, 2.3 mg/kg of
body weight) was equal to that of
chloroquine and
mefloquine, and
Ro 47-7737 was found to be more potent than these two drugs in the Rane test, in which the curative effect of a single dose is monitored. The dose at which 50% of animals were permanently cured (34 mg/kg) was markedly superior to those of
chloroquine (285 mg/kg) and
mefloquine (> 250 mg/kg). When administered orally at 50 mg/kg,
Ro 47-7737 also showed a faster clearance of parasites than either
chloroquine or
mefloquine, and unlike the other two compounds,
Ro 47-7737 showed no recrudescence. In a study to compare prophylactic efficacies of oral doses of 50 mg/kg,
Ro 47-7737 provided protection for 14 days compared to 3 days for
mefloquine and 1 day for
chloroquine. The good curative and prophylactic properties of the compound can be explained in part by its long terminal half-life. The ability to generate parasite resistance to
Ro 47-7737 was also assessed. With a rodent model, resistance could be generated over eight passages. This rate of resistance generation is comparable to that of
mefloquine, which has proved to be an effective
antimalarial for many years. Toxicity liabilities, however, ruled out this compound as a candidate for
drug development.