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

Author(s): 
Xie, Lisa H.
Li, Qigui
Lin, Ai J.
Smith, Kirsten
Zhang, Jing
Skillman, Donald S.
Item Type: 
Journal Article
Publication Title: 
Antimicrobial Agents and Chemotherapy
Journal Abbreviation: 
Antimicrob. Agents Chemother.
Publication Date: 
5/6/2015
Publication Year: 
2006
Pages: 
1649-1655
Volume: 
50
Issue: 
5
ISSN: 
0066-4804
DOI: 
10.1128/AAC.50.5.1649-1655.2006
Library Catalog: 
PubMed
Extra: 
PMID: 16641431 PMCID: PMC1472225

Turabian/Chicago Citation

Lisa H. Xie, Qigui Li, Ai J. Lin, Kirsten Smith, Jing Zhang and Donald S. Skillman. 5/6/2015. "New potential antimalarial agents: therapeutic-index evaluation of pyrroloquinazolinediamine and its prodrugs in a rat model of severe malaria." Antimicrobial Agents and Chemotherapy 50: 5: 1649-1655. 10.1128/AAC.50.5.1649-1655.2006.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1128/AAC.50.5.1649-1655.2006 | issn = 0066-4804 | volume = 50 | pages = 1649-1655 | last = Xie | first = Lisa H. | coauthors = Li, Qigui, Lin, Ai J., Smith, Kirsten, Zhang, Jing, Skillman, Donald S. | title = New potential antimalarial agents: therapeutic-index evaluation of pyrroloquinazolinediamine and its prodrugs in a rat model of severe malaria | journal = Antimicrobial Agents and Chemotherapy | date = 5/6/2015 | pmid = | pmc = }} </ref>