Antimalarial Activities of Various 9-Phenanthrenemethanols with Special Attention to WR-122,455 and WR-171,669

Abstract

Pilot appraisals of the activities of 16 specially selected 9-phenanthrenemethanols against acute infections with Plasmodium falciparum in owl monkeys showed that all were more active than the reference compound, 455, the most active derivative, and WR-171,669, ranked sixth, were selected for study in human volunteers. To assist this undertaking, appraisals of both compounds in owl monkeys infected with various strains of P. falciparum were expanded. These assessments showed: (i) that 455 of activities against infections with chloroquineresistant and pyrimethamine-resistant strains of P. falciparum in owl monkeys. These examinations showed that, as a class, the 9-phenanthrenemethanols were fully effective in the face of resistance to the above drugs and identified six derivatives which, as measured by curative doses, were at least as active as chloroquine against infections with a chloroquine-susceptible strain of P. falciparum.The current report records the results of the pilot evaluations referred to above. It also presents the results of broader assessments of the antmalarial properties of two members of the pilot group, WR-122,455 and WR-171,669, the most active of the 9-phenanthrenemethanols with, respectively, 2-piperidyl and alkylaminoalkyl substituents on the 9-methanol (see Table 1 for structures). These assessments were undertaken to support and guide projected trials of WR-122,455 and WR-171,669 in human volunteers. They were aimed at strengthening the pilot appraisals, determining the influence of the dosage regimen on the activities of both compounds, and ascertaining whether 455 had tissue schizonticidal as well as blood schizonticidal activity.

Development of halofantrine resistance and determination of cross-resistance patterns in Plasmodium falciparum

“…As such, it possesses more structural similarities to mefloquine and quinine than it does to the 4-aminoquinoline antimalarial agents. A number of workers have shown HF to be highly active against both chloroquinesusceptible and -resistant isolates of P. falciparum (10,11,26,32,33). This result is in agreement with the present findings, HF being effective against both isolates, with greater antimalarial activity against the chloroquine-resistant K1 isolate than against the chloroquine-susceptible T9.96 isolate.…”

“…DISCUSSION HF is a 9-phenanthrenemethanol member of the aminoalcohols (10,26,27). As such, it possesses more structural similarities to mefloquine and quinine than it does to the 4-aminoquinoline antimalarial agents.…”

Antimalarial Activities of Various 4-Pyridinemethanols with Special Attention to WR-172,435 and WR-180,409

“…Second, WR-172,435 and WR-180,409 effect parasite clearance slightly more rapidly tharr mefloquine (25) and much more rapidly than the two phenanthrenemethanols (26) in the various owl monkey models. Third, there is every reason to believe that the toxicological and pharmacological properties of these 4-pyridinemethanols in humans will be as different from those of the quinolinemethanols and phenanthrenemethanols as the latter are from each other.…”

“…On the basis of these pilot appraisals and a critical comparative study which showed that WR- (25,26). Second, WR-172,435 and WR-180,409 effect parasite clearance slightly more rapidly tharr mefloquine (25) and much more rapidly than the two phenanthrenemethanols (26) in the various owl monkey models.…”

Drug Evaluation in the Plasmodium Falciparum - Aotus Model

“…1 Evaluation of these two agents in human V-olunteers infected with the :ulti-drug resistant strain of P. falciparum showed that while both drugs cured such infections, both evoked gastrointestinal sy4nptcxjs. 2 Data ff-cci another laboratory indicated that the biquinate salt of halofantrine might enhance the bioavailability of this drug.…”