Design, synthesis and biological evaluation of benzimidazole carbamide derivatives - potential autophagy inducers
- Bioorg Med Chem. 2026 Jul:138:118646. doi: 10.1016/j.bmc.2026.118646.
- 1. Department of Organic Chemistry, Lobachevsky State University, Gagarina av. 23, Nizhny Novgorod 603950, Russia.
- 2. Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia. Electronic address: [email protected].
- 3. Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia.
- 4. Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
- 5. Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia; Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, 119571 Moscow, Russia.
- 6. Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
- 7. Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia; Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the RAS 117997, Moscow, Russia.
- 8. Department of Organic Chemistry, Lobachevsky State University, Gagarina av. 23, Nizhny Novgorod 603950, Russia. Electronic address: [email protected].
Herein, we report a convenient synthetic approach and an in vitro evaluation of benzimidazole carbamide derivatives as potential Autophagy activators. Two compounds exhibited autophagy-inducing activity at concentrations ≥100 μM. The most favorable activity-toxicity profile was observed for a benzimidazole derivative lacking a carbamide fragment. Mechanistic studies indicated that the compounds predominantly act via the AMPK pathway, while generally showing low selectivity toward individual components of this signaling cascade. Notably, the derivative bearing a pyridyl substituent in the carbamide moiety and a methylated benzimidazole core preferentially targeted AMPK within the signaling cascade. Overall, the synthesized benzimidazoles can be considered mild Autophagy activators and relatively broad modulators of cellular signaling.