The Clinical Trial of Eighteen Analogues of Pamaquin (Plasmochin) in Viv Ax Malaria (Chesson Strain) 1

Abstract

In the malarial research program conducted on a national scale during World War II, several drugs were developed which had marked superiority over quinacrine (atabrine) and quinine in their ability to terminate individual attacks of vivax malaria (1). For example, chloroquine (SN-7618) in terms of oral dosage and the resulting plasma concentration can be administered in amounts many times that required to suppress the disease (2). The margin between the therapeutic and toxic dose of chloroquine is several times that which exists for quinine and quinacrine. When these new compounds, however, failed, even at high dosages, to affect the relapse rate it seemed doubtful that further extension of research aimed chiefly towards finding a more effective and less toxic, and primarily suppressive, drug would lead

Resistance to Therapies for Infection by Plasmodium vivax

“…Eighteen candidates advanced to clinical trials. All of them seemed to be effective against relapse, but 8-aminoquinoline toxicity limited therapeutic choices (4). Primaquine had the highest therapeutic index and moved to licensure, production, and rushed use for American troops at war on the Korean Peninsula in 1950 (32).…”

“…Nonetheless, few centers engage in such research because its vital importance to patient and public health has not been adequately appreciated. The experimental challenge data from the clinical screening of 8-aminoquinolines during the 1940s and 1950s show decisively that follow-up to only 28 days is not adequate for assessing clinical efficacy against relapse: more than half of drug failures occurred beyond day 28 (4).…”

Resistance to Chloroquine Unhinges Vivax Malaria Therapeutics

“…In 1948 they wrote, "Quinine was administered concurrently with the drugs [candidate 8-aminoquinolines against relapse]… the synergistic effect of quinine on pamaquin (sic) may also extend to pamaquin analogs…" (3). Today this statement would not be understood by most workers in malaria chemotherapeutics.…”

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

“…There is no available crystal structure of this compound in complex with any of the 6-oxopurine PRTases. Thus, to try to distinguish between the two possibilities above and to try in improve the inhibition of the enzymes, a new series of ANbPs was designed whereby there was only one difference with (9-[1,3-bis(phosphonomethoxy)propan-2-yl]guanine (2). This difference is that the linker was lengthened by one carbon atom between the oxygen atom and the phosphorous atom in both branches of acyclic moiety (18 -23; Scheme 1) giving it a better chance of reaching the predicted sites.…”

“…1 Many of the currently available antimalarial drugs has been discovered serendipitously by screening of a large number of compounds or they are based on natural products used in traditional medicine. 2,3,4 However, the development of resistance to present drugs has become a serious problem. Therefore, to control the spread of malaria requires new drug targets to be identified and new drug leads to be developed into pharmaceuticals.…”