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

I. R. Iaubasarova1,2, L. S. Khailova1, P. A. Nazarov1, T. I. Rokitskaya1, D. N. Silachev1, T. I. Danilina1, E. Y. Plotnikov1, S. S. Denisov1,3, R. S. Kirsanov1, G. A. Korshunova1, E. A. Kotova1, D. B. Zorov1, and Y. N. Antonenko1,a*

1Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

2Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia

3Department of Biochemistry, University of Maastricht, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands

* To whom correspondence should be addressed.

Received June 7, 2020; Revised July 22, 2020; Accepted July 25, 2020
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.
KEY WORDS: mitochondria, uncoupler, protonophore, membrane potential, respiration

DOI: 10.1134/S000629792012010X