Synthesis of Novel Hybrids of Quinazoline and Artemisinin with High Activities against <i>Plasmodium falciparum</i>, Human Cytomegalovirus, and Leukemia Cells

Abstract

Many quinazoline derivatives have been synthesized over the last few decades with great pharmacological potential, such as antimalarial, anti-inflammatory, antimicrobial, anticancer, and antiviral. But so far, no quinazoline-artemisinin hybrids have been reported in the literature. In the present study, five novel quinazoline-artemisinin hybrids were synthesized and evaluated for their in vitro biological activity against malarial parasites (<i>Plasmodium falciparum</i> 3D7), leukemia cells (CCRF-CEM and CEM/ADR5000), and human cytomegalovirus. Remarkably, hybrid <b>9</b> (EC₅₀ = 1.4 nM), the most active antimalarial compound of this study, was not only more potent than artesunic acid (EC₅₀ = 9.7 nM) but at the same time more active than the clinically used drugs dihydroartemisinin (EC₅₀ = 2.4 nM) and chloroquine (EC₅₀ = 9.8 nM). Furthermore, hybrids <b>9</b> and <b>10</b> were the most potent compounds with regard to anticytomegaloviral activity (EC₅₀ = 0.15-0.21 μM). They were able to outperform ganciclovir (EC₅₀ = 2.6 μM), which is the relevant standard drug of antiviral therapy, by a factor of 12-17. Moreover, we identified a new highly active quinazoline derivative, compound <b>14</b>, that is most effective in suppressing cytomegalovirus replication with an EC₅₀ value in the nanomolar range (EC₅₀ = 50 nM). In addition, hybrid <b>9</b> exhibited an antileukemia effect similar to that of artesunic acid, with EC₅₀ values in the low micromolar range, and was 45 times more active toward the multidrug-resistant CEM/ADR5000 cells (EC₅₀ = 0.5 μM) than the standard drug doxorubicin.