Allylpolyalkoxybenzene Inhibitors of Galactonolactone Oxidase from Trypanosoma cruzi

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Andrey A. Chudin¹, Igor D. Zlotnikov¹, Sergey S. Krylov², Victor V. Semenov², and Elena V. Kudryashova^1,a*

¹Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia

²Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia

^* To whom correspondence should be addressed.

Received November 30, 2022; Revised December 20, 2022; Accepted December 20, 2022

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Inhibition of biosynthetic pathways of compounds essential for Trypanosoma cruzi is considered as one of the possible action mechanisms of drugs against Chagas disease. Here, we investigated the inhibition of galactonolactone oxidase from T. cruzi (TcGAL), which catalyzes the final step in the synthesis of vitamin C, an antioxidant that T. cruzi is unable to assimilate from outside and must synthesize itself, and identified allylbenzenes from plant sources as a new class of TcGAL inhibitors. Natural APABs (apiol, dillapiol, etc.) inhibited TcGAL with IC₅₀ = 20-130 µM. The non-competitive mechanism of TcGAL inhibition by apiol was established. Conjugation of APABs with triphenylphosphonium, which ensures selective delivery of biologically active substances to the mitochondria, increased the efficiency and/or the maximum percentage of TcGAL inhibition compared to nonmodified APABs.

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KEY WORDS: galactonolactone oxidase, Chagas disease, inhibitors, apiol, allylpolyalkoxybenzenes, triphenylphosphonium derivatives, dillapiol, myristicin, eugenol, estragole

DOI: 10.1134/S000629792301011X

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