bMalaria kills approximately 1 million people a year, mainly in sub-Saharan Africa. Essential steps in the life cycle of the parasite are the development of gametocytes, as well as the formation of oocysts and sporozoites, in the Anopheles mosquito vector. Preventing transmission of malaria through the mosquito is necessary for the control of the disease; nevertheless, the vast majority of drugs in use act primarily against the blood stages. The study described herein focuses on the assessment of the transmissionblocking activities of potent antierythrocytic stage agents derived from the 4(1H)-quinolone scaffold. In particular, three 3-alkylor 3-phenyl-4(1H)-quinolones (P4Qs), one 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), and one 1,2,3,4-tetrahydroacridin-9(10H)-one (THA) were assessed for their transmission-blocking activity against the mosquito stages of the human malaria parasite (Plasmodium falciparum) and the rodent parasite (P. berghei). Results showed that all of the experimental compounds reduced or prevented the exflagellation of male gametocytes and, more importantly, prevented parasite transmission to the mosquito vector. Additionally, treatment with ICI 56,780 reduced the number of sporozoites that reached the Anopheles salivary glands. These findings suggest that 4(1H)-quinolones, which have activity against the blood stages, can also prevent the transmission of Plasmodium to the mosquito and, hence, are potentially important drug candidates to eradicate malaria.
There were an estimated 154 million to 289 million cases and 610,000 to 971,000 deaths from malaria in 2010 (1). Plasmodium falciparum, the deadliest of the five malaria species that infect humans, mainly affects children under the age of 5 years in Africa (2-6). In areas where malaria is endemic, such as Africa, Southeast Asia, and South America, P. falciparum has developed resistance to many commercially available antimalarials, such as chloroquine (CQ), mefloquine (MFQ), and sulfadoxine-pyrimethamine (SP) (7). Currently, artemisinin derivatives, which have potent activity against blood stages and early-stage gametocytes, are the only drugs that are effective for treating drug-resistant P. falciparum (8,9). However, recent evidence suggests that parasite resistance to artemisinin and its derivatives is emerging in Southeast Asia (4, 10), thus indicating the need for new drugs to combat this disease.Development of new antimalarials has traditionally been focused on the asexual blood stages, which are responsible for the proliferation of the parasite in the human host and for the clinical symptoms of the disease (11). However, gametocytes (i.e., the sexual stages), as well as the mosquito stages (i.e., ookinetes, oocysts, and salivary gland sporozoites), are important drug targets, because they are necessary for disease transmission (12). Currently, there are a limited number of antimalarials that are effective against the sexual and the vector stages of malaria parasites. Therefore, we investigated the transmission-blocking activity of 4(...