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. 2013 Dec;57(12):6187-95.
doi: 10.1128/AAC.00492-13. Epub 2013 Sep 30.

4-(1H)-Quinolones and 1,2,3,4-Tetrahydroacridin-9(10H)-ones Prevent the Transmission of Plasmodium Falciparum to Anopheles Freeborni

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4-(1H)-Quinolones and 1,2,3,4-Tetrahydroacridin-9(10H)-ones Prevent the Transmission of Plasmodium Falciparum to Anopheles Freeborni

Fabián E Sáenz et al. Antimicrob Agents Chemother. .
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Abstract

Malaria 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 transmission-blocking activities of potent antierythrocytic stage agents derived from the 4(1H)-quinolone scaffold. In particular, three 3-alkyl- or 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.

Figures

Fig 1
Fig 1
Structures of the compounds tested in this study.
Fig 2
Fig 2
Summary of the methods used in this study. (A) Assessment of gametocytocidal and gametocidal activity of experimental compounds. To test the gametocytocidal activity of the compounds, early-stage (stages I, II, and III) and late-stage (stages III, IV, and V) gametocytes were treated with the compounds in duplicate for three consecutive days at 0.1, 1.0, and 10.0 μM concentrations. The gametocytemia on day 14 p.i. was used as a measure of the effect of the experimental compounds on gametocyte development. Gametocidal activity was determined by assessing the effect of the test compounds (1.0 μM) on male gamete exflagellation on day 15 p.i. and subsequent oocyst development in the mosquito midgut. The number of oocysts per midgut on day 25 p.i. was used as a measure of gametocidal activity. (B) Assessment of sporozontocidal activity of the test compounds. On day 15 p.i., untreated gametocyte cultures were fed to noninfected A. freeborni females. On day 25 p.i., mosquitoes were exposed to a noninfected blood meal containing 1.0 μM the test compound, and on day 35 p.i., salivary glands were checked for infections.
Fig 3
Fig 3
Transmission-blocking technique. PEG400, polyethylene glycol 400.
Fig 4
Fig 4
Stage V gametocytemia on day 14 p.i. following treatment with 0.1, 1.0, and 10.0 μM compound. Treatment of early-stage (ES; stages I to III) and late-stage (LS; stages III to V) gametocytes with 0.1, 1.0, or 10.0 μM compound did not significantly affect gametocyte development compared to that for the untreated controls. Only the control drug DHA significantly diminished the number of stage V gametocytes compared to that for the untreated controls (P < 0.05). Interestingly, primaquine did not have a significant effect on the number of stage V gametocytes. *, statistically significant difference.
Fig 5
Fig 5
Effect of test compounds on exflagellation when gametocytes were treated during the early stage (ES; stages I to III) and late stage (LS; stages III to IV). Treatment of early-stage gametocytes with 0.1 μM THA-93, P4Q-105, P4Q-146, and ICI 56,780 significantly reduced male gamete exflagellation compared to that for the untreated control (Dunnett's multiple-comparison test, P < 0.001). Treatment of early-stage gametocytes with 1.0 μM and 10.0 μM all test compounds significantly reduced exflagellation compared to that for the untreated control (Dunnett's multiple-comparison test, P < 0.001). Late-stage gametocyte treatment with 0.1 μM and 1.0 μM P4Q-105, P4Q-146, and ICI 56,780 significantly reduced male gamete exflagellation compared to that for the untreated control (Dunnett's multiple-comparison test, P < 0.05). Treatment of late-stage gametocytes with 10.0 μM all test compounds significantly reduced exflagellation compared to that for the untreated control (Dunnett's multiple-comparison test, P < 0.001). *, statistically significant difference.
Fig 6
Fig 6
P4Q-146 and ICI 56,780 block the transmission of P. berghei to A. stephensi in vivo. (A) ICI 56,780 blocks the transmission at 1, 3, and 10 mg/kg; (B) THA-93 and P4Q-95 do not prevent P. berghei transmission to A. stephensi; (C) P4Q-146 blocks transmission at 1, 3, and 10 mg/kg.
Fig 7
Fig 7
ICI 56,780 blocks transmission for up to 12 h posttreatment in P. berghei-infected mice. Animals with ∼3% parasitemia were treated with a single dose of 1 mg/kg ICI 56,780 (per os), and then adult female A. stephensi mosquitoes were allowed to feed at 1, 6, 12, or 24 h posttreatment. ICI 56,780 completely blocked transmission up to 12 h posttreatment, as assessed by a lack of oocyst development in mosquitoes 8 days after feeding on treated animals.

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