Synthesis of New Antimalarial Agents.

摘要

This study is concerned with the preparation of: (a) peroxides based on qinghaosu, (b) peptide pro-drug derivatives of primaquine, and (c) thymidylate synthetase inhibitors as potentially new antimalarial agents. During this study, thirty (30) target compounds were prepared and submitted for antimalarial evaluation. The thirty compounds included twenty-four (24) qinghaosu analogs, three (3) primaquine derivative, and three (3) thymidylate synthetase inhibitors. Twenty-one of the qinghaosu analogs and all three of the thymidylate synthetase inhibitors were evaluated in the malaria in vitro drug screen. All but three of the qinghaosu analogs showed activity in this screen, whereas the thymidylate synthetase inhibitors were inactive. The three peptide pro-drug derivatives of primaquine were tested for radical curative activity against Plasmodium cynomologi in rhesus monkeys, All three compounds showed cures greater than that expected for the primaquine content of each pro-drug. Twenty-three target compounds were evaluated for blood schizonticidal suppressive activity against P. berghei in mice, and ten compounds were tested for causal prophylactic activity against P. berghei yoelii in mice. None of the compounds tested showed significant activity in these screens.