Effects of 4-Alkoxy/Amino-7-Chloroquinolines on <i>Aedes aegypti</i> and <i>Artemia salina</i> Larvae: The Search for Safer Larvicides to Combat Epidemiological Dengue in the Americas

<i>Aedes aegypti</i>, the main transmitter of arboviruses responsible for several arboviruses, such as dengue, is highly prevalent in Latin America, especially in Brazil. Controlling this vector is urgent for public health, since it is more advantageous to prevent than to treat the diseases it causes. The use of chemical control methods, such as larvicides, is strategic. In this sense, the search for environmentally safer larvicides has driven the development of compounds with activity against <i>Ae. aegypti</i> and low toxicity to nontarget organisms. In this study, a rational design of ten 4-alkoxy/amino-7-chloroquinolines was carried out to investigate their larvicidal and toxic properties, from prediction to <i>in vitro</i> assays. Larvicidal tests revealed seven bioactives against <i>Ae. aegypti</i> (LC₅₀ ≤ 69.18 ppm), of which compound <b>3</b> was very active (LC₅₀ = 2.51 ppm) and compound <b>6'</b> was very highly active (LC₅₀ = 0.02 ppm), surpassing the standard larvicide Spinosad (LC₅₀ = 0.05 ppm). Structural analysis indicated that the -O-pentyl and -O-ethyl-Cl moieties at the 4-position of 7-chloroquinolines improved larvicidal activity when compared to 4,7-dichloroquinoline. Regarding the <i>in vitro</i> ecotoxicity study, bioactives <b>1</b>, <b>6'</b>, <b>7'</b>, and <b>9'</b> showed moderate toxicity on <i>Artemia salina</i> larvae (LC₅₀ = 101.68-314.58 μg·mL^-1). The best results demonstrated that compound <b>6'</b>, potentially nonmutagenic, nonhepatotoxic, and predicted not to cause skin sensitization, was 15 729 times more toxic to <i>Ae. aegypti</i> than to the nontarget organism <i>A. salina</i>, emerging as a safer larvicide.