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Antimicrobial Agents and Chemotherapy, May 2006, p. 1649-1655, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1649-1655.2006

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

Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910

Received 7 September 2005/ Returned for modification 29 November 2005/ Accepted 11 February 2006

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 µmol/kg of body weight for AS and 2.4 µmol/kg for PQD, PQD-4A, and PQD-BE. The maximum tolerated dose (MTD) of AS was 625 µmol/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 µmol/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.

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• Li, Q., Kozar, M. P., Shearer, T. W., Xie, L. H., Lin, A. J., Smith, K. S., Si, Y., Anova, L., Zhang, J., Milhous, W. K., Skillman, D. R. (2007). Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats. Antimicrob. Agents Chemother. 51: 2898-2904 [Abstract] [Full Text]