Design, synthesis, molecular modeling, and evaluation of larvicidal efficacy of novel triazole derivatives against Culex pipiens L., referring to their potential mechanism.
TL;DR
The results demonstrated that chalcone and pyrazole derivatives exhibited significantly potent larvicidal activity compared to thiazole derivatives, which allow the discovery of novel mosquito control agents and support ongoing efforts to develop more effective strategies for vector control.
Abstract
A new series of triazole-based heterocyclic compounds was synthesized by good and efficient methods. The key triazole intermediate was further reacted with different aromatic aldehydes to afford chalcone derivatives, which were then converted into pyrazoline derivatives. Additional transformation of the thiosemicarbazide intermediate with different chloroacyl reagents yielded hydrazineyl thiazol analogues. The synthesized compounds exhibited high to moderate activity against the third larval instar of Culex pipiens. All triazole derivatives had median lethal concentrations (LC50) < 19 μg /mL at 48 h post-treatment, which are lower than that recommended by the World Health Organization (WHO) for the selection of promising larvicides. The results demonstrated that chalcone and pyrazole derivatives exhibited significantly potent larvicidal activity compared to thiazole derivatives. The most effective compounds were 4a (4.23 μg /mL) > 4b (5.70 μg /mL) >4c (6.11 μg /mL) > 10 (6.47 μg /mL) > 12 (6.98 μg /mL) compared to the least potent 6 (18.79 μg /mL). The molecular docking and biochemical analysis were performed for acetylcholinesterase (AChE) and cytochrome monooxygenase 450 (CYP450) to demonstrate the mode of action and detoxifying response of larvae to the tested compounds. The treated larvae showed a significant oxidation response to the tested compounds, where CYP450 activity reached 57.34 ± 2.03 and 46.89 ± 1.45 (μ mole/min/mg protein) after treatment with 4a and 4b, respectively, compared to 10.73 ± 1.45 (μ mole/min/mg protein) of control. While AChE activity showed less response to toxicity with 4a (367.91 ± 3.76 μg AchBr/min/mg protein) and 4b (359.21 ± 1.15 μg AchBr/min/mg protein) relative to control (169.3 ± 0.33 μg AchBr/min/mg protein). Results of molecular docking assessment were highly consistent with those obtained from biochemical and larvicidal activity, where tested derivatives showed superior affinity with CYP450 than AChE. In silico ADME and toxicophore analyses using SwissADME and ProTox-3 confirmed favorable drug-likeness parameters and supported the safety profile of the synthesized compounds, specifically 4a and 4c. These findings allow the discovery of novel mosquito control agents and support ongoing efforts to develop more effective strategies for vector control.