Vector-borne diseases are causes of global health concern and mosquitoes are the primary transmitters of health-threatening pathogens. Botanicals are sources of compounds structurally modifiable into versatile hits for novel plant-based insecticides. Carlina oxide (1) is a natural compound isolated from Carlina acaulis L. (Asteraceae) with promising insecticidal potential, whose industrial production is limited by the absence of a plant supply chain. Herein, a one-step synthesis producing 1 in 81% yield was developed and a structure-activity relationship (SAR) study for the larvicidal activity on Aedes albopictus (Skuse, 1894) and Anopheles stephensi (Liston, 1901) was performed. The most promising analogue (5) displayed an encouraging larvicidal action (LC50 < 6.0 μg mL-1), safety profile on human keratinocytes (IC50 > 100 μg mL-1) and non-target organisms if compared to 1. Untargeted metabolomic analysis on mosquito larvae revealed that 1 and 5 target the carbohydrates and amino acid metabolism.

Chemistry Interdisciplinary Project research center School of Pharmacy University of Camerino Via Madonna delle Carceri 62032 Camerino Italy

Czech Agrifood Research Center Dunovská 507 16106 Prague 6 Ruzyně Czech Republic

Department of Agricultural and Environmental Sciences Production Landscape Agroenergy University of Milan Via Celoria 2 20133 Milan Italy

Department of Plant Biotechnology College of Life Sciences and Biotechnology Korea University 02841 Seoul Republic of Korea

Department of Plant Protection Czech University of Life Sciences Prague Kamycká 129 16500 Prague 6 Suchdol Czech Republic

School of Biosciences and Veterinary Medicine Immunopathology and Molecular Medicine Unit University of Camerino Via Madonna delle Carceri 9 62032 Camerino Italy

School of Biosciences and Veterinary Medicine University of Camerino Via Gentile 3 Da Varano 62032 Camerino Italy

School of Pharmacy University of Camerino Via Madonna delle Carceri 9 C 62032Camerino Italy

School of Science and Technology Chemistry Division University of Camerino 62032 Camerino Italy

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