Screening procedure using chicks infected with the sporozoites of Plasmodium gallinaceum in an antimalarial drug development programme.

Of 10 000 compounds tested for tissue schizontocidal activity in a Plasmodium gallinaceum-chick model, 157 were also tested in a definitive mouse test (DMT) and 277 in a rhesus monkey test (RMT). The results in the avian model were 78% and 55% in agreement with those of the DMT and RMT, respectively. This result is not as good as that for a tissue schizontocidal mouse screen previously reported, which showed 93% and 80% agreement with DMT and RMT, respectively. More than three-quarters of the compounds tested in DMT and RMT were 8-aminoquinolines, a chemical class known to have tissue schizontocidal activity.

Anticancer agents and antitrypanosomiasis activity in mice.

Of 303 compounds (66 active against cancer and 237 inactive against cancer) obtained from the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, 25 were found to be active against Trypanosoma rhodesiense infections of ICR/Ha Swiss mice. Fifteen of these 25 compounds also had anticancer properties. The percentage of anticancer compounds found to have antitrypanosomiasis properties was 22.7. This percentage compares with 6% antitrypanosomiasis compounds among compounds selectecd by other methods.

The development of a "high volume tissue schizonticidal drug screen" based upon mortality of mice inoculated with sporozoites of Plasmodium berghei.

A biological test system has been developed to assess the prophylactic activity of compounds against sporozoite-induced Plasmodium berghei malaria in mice. The procedure was designed to serve as the foundation of an effort to develop tissue schizonticidal drugs in a manner parallel to that of a previous system employed in the U.S. Arym Antimalarial Drug Development Program to screen compounds for blood schizonticidal activity. In tests with 35 known antimalarial compounds, the new screen was found to be in agreement 93% and 80%, respectively, when assessed compound activity was compared with results obtained in a definitive mouse causal prophylactic test and a rhesus monkey radical curative system.

A new chemical series active against African trypanosomes: benzyltriphenylphosphonium salts.

Antitrypanosomal activity for benzyltriphenylphosphonium salts is reported for the first time. Testing was conducted using Trypanosoma rhodesiense infected mice. Of 70 phosphorus-containing compounds tested, 21 were active. Sixteen of these active chemical species were benzyltriphenylphosphonium salts. Four were nonbenzyl triphenyl compounds. The remaining active drug was a benzyldiphenylphosphonium salt.

Activity of antitumor drugs against African trypanosomes.

Of 49 compounds known to have antitumor properties, 6 were found to have significant activity against Trypanosoma rhodesiense infections in mice. Activity against the African trypanosomes has not been reported previously for any of these six compounds. In order of decreasing activity these compounds were: (i) imidazole-4-carboxamide, 5-(3,3-dimethyl-1,1-triazene), (ii) inosine diglycolaldehyde, (iii) cis-diamminedichloro-platinum, (iv) streptozotocin, (v) coralyne sulfate, and (vi) 5-fluoro-2'-deoxyuridine. The percentage of "hits" (12.2%) from these known antitumor agents was approximately twice as great as when other means are employed for the selection of compounds for this test system.

Screening large numbers of compounds in a model based on mortality of Trypanosoma rhodesiense infected mice.

A test system has been developed to evaluate the trypanosomicidal activity of large numbers of candidate drugs. Based on mortality of mice with blood induced Trypanosoma rhodesiense infections, it serves as a primary screen or as a secondary and confirmatory test for active compounds. Over 5,500 selected compounds have been tested; more than 6% were active.