New potential antimalarial agents: therapeutic-index evaluation of pyrroloquinazolinediamine and its prodrugs in a rat model of severe malaria.

Antimicrobial Agents and Chemotherapy
Lisa XieDonald R Skillman

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

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Aug 2, 2014·European Journal of Medicinal Chemistry·Ajay KumarDhirender Kaushik
Mar 1, 2012·PLoS Medicine·Dejan ZurovacRobert W Snow
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Mar 21, 2019·Animal Models and Experimental Medicine·Sylvester Aghahowa, Kenka Okolocha

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