Linking 7-Nitrobenzo-2-oxa-1,3-diazole (NBD) to Triphenylphosphonium Yields Mitochondria-Targeted Protonophore and Antibacterial Agent.

Abstract

Appending lipophilic cations to small molecules has been widely used to produce mitochondria-targeted compounds with specific activities. In this work, we obtained a series of derivatives of the well-known fluorescent dye 7-nitrobenzo-2-oxa-1,3-diazole (NBD). According to the previous data [Denisov et al. (2014) Bioelectrochemistry, 98, 30-38], alkyl derivatives of NBD can uncouple isolated mitochondria at concentration of tens of micromoles despite a high pKa value (~11) of the dissociating group. Here, a number of triphenylphosphonium (TPP) derivatives linked to NBD via hydrocarbon spacers of varying length (C5, C8, C10, and C12) were synthesized (mitoNBD analogues), which accumulated in the mitochondria in an energy-dependent manner. NBD-C10-TPP (C10-mitoNBD) acted as a protonophore in artificial lipid membranes (liposomes) and uncoupled isolated mitochondria at micromolar concentrations, while the derivative with a shorter linker (NBD-C5-TPP, or C5-mitoNBD) exhibited no such activities. In accordance with this data, C10-mitoNBD was significantly more efficient than C5-mitoNBD in suppressing the growth of Bacillus subtilis. C10-mitoNBD and C12-mitoNBD demonstrated the highest antibacterial activity among the investigated analogues. C10-mitoNBD also exhibited the neuroprotective effect in the rat model of traumatic brain injury.

• Authors: I R Iaubasarova, L S Khailova, P A Nazarov, T I Rokitskaya, D N Silachev, T I Danilina, E Y Plotnikov, S S Denisov, R S Kirsanov, G A Korshunova, E A Kotova, D B Zorov, Y N Antonenko
• Journal: Biochemistry. Biokhimiia (Biochemistry (Mosc)) Vol. 85 Issue 12 Pg. 1578-1590 (Dec 2020) ISSN: 1608-3040 [Electronic] United States
• PMID: 33705296 (Publication Type: Journal Article)

Chemical References

• 7-nitrobenzo-2-oxa-1,3-diazole
• Anti-Bacterial Agents
• Neuroprotective Agents
• Nitrobenzenes
• Organophosphorus Compounds
• Oxadiazoles
• triphenylphosphine

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Bacillus subtilis (drug effects)
• Brain Injuries (prevention & control)
• Disease Models, Animal
• Energy Metabolism
• Mitochondria, Liver (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Nitrobenzenes (chemistry, pharmacology)
• Organophosphorus Compounds (chemistry, pharmacology)
• Oxadiazoles (chemistry, pharmacology)
• Rats
• Thermogenesis