Design, synthesis and larvicidal activity of novel imidazo[2,1‐ b ][1,3,4]thiadiazole carboxamides against Anopheles arabiensis and in silico target exploration

BACKGROUND Widespread resistance among malaria vectors to conventional insecticides, coupled with the limited availability of insecticides with novel mechanisms of action, necessitates the discovery of new chemical scaffolds for vector control. Anopheles arabiensis is an important malaria vector in sub‐Saharan Africa and poses additional control challenges due to its behavioral adaptability and rising insecticide resistance. This study aimed to design, synthesize, characterize, and evaluate novel 6‐(4‐substituted phenyl)imidazo[2,1‐ b ][1,3,4]thiadiazole‐2‐carboxamide derivatives ( 6a–6i ) as potential larvicidal agents. RESULTS Novel derivatives were synthesized and evaluated against third‐instar A. arabiensis larvae. At 4 μg/ mL , mortality ranged from 18% to 97% after 48 h. Compound 6e , bearing a sulfolane substituent, was the most active, producing 93% and 97% mortality at 24 and 48 h, respectively, comparable to temephos (99% at both time points). Its median lethal concentration ( LC 50 ) values were 1.17 and 1.03 μg/ mL , respectively, compared with 1.41 and 1.21 μg/ mL for temephos, corresponding to an efficiency ratio of 0.9 at both time points. Structure–activity relationship ( SAR) analysis indicated that the C‐6 trifluoromethyl group and polar hydrogen‐bond‐accepting substituents were favorable. Molecular docking identified adenosine kinase as a potential target, with recurrent interactions involving Gly64, Asn221, and Leu133. CONCLUSION The findings identify imidazo[2,1‐ b ][1,3,4]thiadiazole as a promising scaffold for developing new larvicidal chemotypes. Compound 6e represents the most promising lead and provides a basis for further optimization and validation of this scaffold for innovative malaria‐vector control strategies.