Planejamento e síntese de cinamamidas como novos larvicidas frente ao vetor Aedes aegypti

Abstract

Aedes aegypti is a vector that has caused great concern in society in recent decades, due to the spread of arbovirus epidemics caused by it. Currently, its population control has been occurring through the application of insecticides, which, however, have not been effective due to generalized resistance among populations of this vector. Given this, the present study aimed at the in silico design and synthesis of cinnamamides. For this approach, the target fishing method was used, followed by virtual screening. Subsequently, the compounds were synthesized via the Steglich reaction and properly characterized using 1H NMR, DEPT-Q, and FTIR techniques. Regarding the in silico study, the results were validated and demonstrated that this chemotherapeutic can be a good candidate for larvicide, as it presents a structure that is within the norms foreseen for a selective and environmentally safe insecticide. In addition, they showed a pronounced affinity for the enzymes chitinase (O17411), 3-hydroxykynurenine transaminase (6MFB), and acetylcholinesterase (Q6A2E2) expressed by the vector larvae. Regarding the synthesis, the synthesized molecules presented yields between 47-100%. Regarding the preliminary larvicidal activity, two compounds from the chemotheque were active, namely (AF18) and (AF09), and two partially active compounds (AF08 and AF17), a weakly active compound (AF15), and nine inactive compounds. Also, the lethal concentration that eliminates 50% of the population (LC50) was determined for the active and partially active compounds (AF18, AF09, AF08, and AF17), which presented the following values of LC50 41.6, 55.9, 105.2, and 105.8 µg/ml, respectively. In a structure-activity relationship study, it was found that the physical-chemical properties highlighted, the number of rotating bonds, and the partition coefficient were crucial for larvicidal activity. Morphologically, larvae exposed to one of the most active compounds, AF09, showed a mass reduction, midgut deformity, and deformations in the siphon region and anal papillae. Which assumes that the biological targets that may be involved are digestive enzymes. However, enzymatic inhibition studies are essential to elucidate the mechanism of action.