Antimalarial Activities of New Pyrrolo[3,2-f]Quinazoline-1,3-Diamine Derivatives

Abstract

WR227825 is an antimalarial pyrroloquinazolinediamine derivative with a high potency but a low therapeutic index. A series of carbamate, carboxamide, succinimide, and alkylamine derivatives of WR227825 were prepared to search for compounds with an improved therapeutic index. The new acetamides and imide showed potent cell growth inhibition against four clones of Plasmodium falciparum (D-6, RCS, W-2, and TM91C235), with a 50% inhibitory concentration of ϳ0.01 ng/ml, and were highly active against Plasmodium berghei, with 100% cure at doses from <0.1 mg/kg of body weight to 220 mg/kg. The carbamates and alkyl derivatives, however, showed weak activity against Plasmodium falciparum cell growth but were highly efficacious in tests against P. berghei by the Thompson test. The best compounds, bis-ethylcarbamate (compound 2a) and tetraacetamide (3a) derivatives, further demonstrated high potency against the sporozoite Plasmodium yoelii in mice and P. falciparum and Plasmodium vivax in aotus monkeys. Against the AMRU-1 strain of P. vivax, which has four dihydrofolate reductase mutations and is highly resistant to antifolates, tetra-acetamide 3a cured the monkeys at doses of 1 and 3 mg/kg. Compound 2a cured only one out of two monkeys at 3 mg/kg. The results indicated that the new derivatives 2a and 3a not only have retained/improved the antimalarial efficacy of the parent compound WR227825 but also were less toxic to the animals used in the tests.Malaria is one of the most common diseases in countries of Africa, Southeast Asia, and South America (12,27,28,31,32). The increasing prevalence of multiple-drug-resistant strains of Plasmodium falciparum in most areas where malaria is endemic has significantly reduced the efficacy of current antimalarial drugs for the prophylaxis and treatment of this disease (17,19). Furthermore, the usefulness of many newer antimalarial drugs was impaired by their side effects. Lethal hemolysis side effects were observed in glucose-6-phosphate dehydrogenase-deficient recipients of 8-aminoquinoline drugs (2, 3), namely, primaquine and tafenoquine. Central nervous system toxicity was a problematic side effect in the patients treated with mefloquine (22, 24). Therefore, there is an eminent need for new and safe antimalarial drugs to combat this disease in areas of malaria endemicity.Pyrroloquinazolinediamine (PQZ) derivatives were reported to possess anticancer, antimicrobial, and antimalarial activities (13). Among the PQZ derivatives, WR227825 (compound 1) is one of the most potent antimalarial agents ever reported (26). This compound not only displayed high in vitro efficacy against P. falciparum, with a 50% inhibitory concentration (IC 50 ) of ϳ0.01 ng/ml, but was also highly active against Plasmodium berghei in a rodent model, with a 100% curative oral dose of Ͻ1 to 20 mg/kg of body weight. However, WR227825 also exhibited high host toxicity, with a subcutaneous 50% lethal dose in mice at less than 20 mg/kg, and produced deaths in aotus monkeys at doses less than 2 mg/kg (33). The PQZ was ...

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

“…These two derivatives were also highly active in Aotus monkeys (oral curative dose, 1 mg/kg). Furthermore, PQD-A4 and PQD-BE showed no host toxicity at oral doses of 3 mg/ kg/day for 3 days in Aotus monkeys and 10 mg/kg/day for 7 days in Rhesus monkeys (13).…”

Adaptation of a Thai Multidrug-Resistant C2A Clone of Plasmodium falciparum to Aotus Monkeys and Its Preliminary in vivo Antimalarial Drug Efficacy-Resistance Profile

“…6 For more than 40 years, the Panamanian Aotus ( Aotus lemurinus. lemurinus ) has been used to adapt new strains of malaria [7][8][9] study its biology, [10][11][12] pathogenesis of its infection, [13][14][15] and to test the efficacy and pharmacokinetics of antimalarial compounds [16][17][18][19][20][21][22][23][24][25][26][27] against these new strains. More recently, this model has also been used to test the efficacy and immunogenicity of antimalarial vaccines through the use of repeated challenge, 28 plasmid DNA vaccines, [29][30][31][32] temperature-sensitive mutants, 33 synthetic peptides, 34 recombinant proteins, [35][36][37] and even to test the immunogenicity of hepatitis B DNA vaccines.…”

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

“…At a single oral dose, PQD-A4 and PQD-BE were about 12-fold and 6-fold safer than PQD. As expected, PQD-A4 was even slower than PQD-BE since PQD-A4 generated three metabolites and each metabolite had an elimination half-life of more than 12 h. Although the PQD concentration in plasma was significantly less from PQD-A4 and PQD-BE administration, the efficacies of derivatives were not affected because the derivatives (PQD-A4 and PQD-BE) and their intermediate metabolites (PQD-A1 and PQD-A2) all have antimalarial potencies similar to that of PQD (11). An increased therapeutic index was the aspiration for the approaches in the design as well as the evaluation criteria.…”