New Potential Antimalarial Agents: Therapeutic-Index Evaluation of Pyrroloquinazolinediamine and Its Prodrugs in a Rat Model of Severe Malaria

Abstract

Tetra-acetamide pyrroloquinazolinediamine (PQD-A4) and bis-ethylcarbamyl pyrroloquinazolinediamine (PQD-BE) are new derivatives of pyrroloquinazolinediamine (PQD) and are being investigated as potential chemotherapeutic agents for the treatment of malaria. Comparative studies to assess the therapeutic indices of PQD-A4, PQD-BE, and PQD were conducted in Plasmodium berghei-infected rats following daily intragastric dosing for three consecutive days. Artesunate (AS), a standard drug for treatment of severe malaria, was used as a comparator. The minimum doses required to clear malaria parasitemia were 156 mol/kg of body weight for AS and 2.4 mol/kg for PQD, PQD-4A, and PQD-BE. The maximum tolerated dose (MTD) of AS was 625 mol/kg, and its therapeutic index was calculated to be 4. The MTDs of PQD-A4, PQD-BE, and PQD were found to be 190, 77, and 24 mol/kg, respectively, yielding therapeutic indices of 80, 32, and 10, respectively. Although PQD-A4 and PQD-BE are only half as potent as PQD based on their curative effects, the two new derivatives, PQD-4A and PQD-BE, are 8.0-fold and 3.2-fold safer, respectively, than their parent compound when they are dosed for three consecutive days. Oral PQD-A4 and PQD-BE are 44 to 70 times more potent on an mg basis than intravenous AS. As assessed from the therapeutic index over 3 days, PQD-A4, PQD-BE, and PQD administered orally are 20.0, 8.0, and 2.5 times safer than AS given intravenously. The results indicate that PQD-4A is a promising candidate for antimalarial treatment.

Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats

“…In this study, the decrease of body weight was calculated as a sole index of anorexic toxicity to evaluate the GI toxicity of the PQD drugs in rats ( Table 1). The index results showed that (i) anorexic toxicity was dose dependent for the three PQDs; (ii) GI toxicity was significantly reduced by the derivatives, PQD-A4 and PQD-BE, compared to PQD at any dose level; and (iii) the GI toxicity of PQD was about 3.8-and 8.8-fold higher than those of PQD-BE and PQD-A4, respectively, which had similar safety margins (3.2-and 8.0-fold), as shown in our therapeutic-index study, with the same multiple doses (27).…”

“…The two derivatives showed exceptionally less toxicity and higher therapeutic indices than their parent drug, which successfully reduced side effects associated with PQD in our previous study (27) and in the present studies. However, the two derivatives of PQD also reduced the bioavailability by one-half compared to PQD in rats.…”

“…The series bioavailability studies showed that the limitation of bioavailability was more affected at higher dose levels (Ͼ20 mg/kg) and was dose dependent. This could be a reason why the efficacy was not affected very much at therapeutic dose levels (low doses of Ͻ10 mg/kg) in malaria-infected rats (27).…”

“…Oral PQD-A4 and PQD-BE are 44 to 70 times more potent on an mg basis than intravenous artesunate (AS), which is in current use as first-line antimalarial agent. As assessed from the therapeutic index over 3 days, PQD-A4, PQD-BE, and PQD administered orally are 20, 8, and 2.5 times safer than AS given intravenously (27). In the present study, the pharmacokinetic (PK) differences between these two derivatives have been investigated and the superiority of the two derivatives to PQD in this respect has been fully evaluated.…”

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

“…Recently, the tetraacetyl prodrug 71 showed markedly superior efficacy and safety in a mouse model of severe malaria relative to artesunate (42). [276] …”