SAR of 4-Alkoxybenzoic Acid Inhibitors of the Trypanosome Alternative Oxidase

  • ACS Med Chem Lett. 2018 Jul 31;9(9):923-928. doi: 10.1021/acsmedchemlett.8b00282.
Alejandro Meco-Navas  1 ,  Godwin U Ebiloma  2  3 ,  Ana Martín-Domínguez  1 ,  Irene Martínez-Benayas  1 ,  Eduardo J Cueto-Díaz  1 ,  Amani Saud Alhejely  2 ,  Emmanuel O Balogun  4 ,  Machi Saito  3 ,  Miho Matsui  3 ,  Natsumi Arai  3 ,  Tomoo Shiba  3 ,  Shigeharu Harada  3 ,  Harry P de Koning  2 ,  Christophe Dardonville  1
Affiliations
  • 1. Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
  • 2. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
  • 3. Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • 4. Department of Biochemistry, Ahmadu Bello University, Zaria 2222, Nigeria.
PMID: 30258542 DOI: 10.1021/acsmedchemlett.8b00282
Abstract

The SAR of 4-hydroxybenzaldehyde inhibitors of the trypanosome alternative oxidase (TAO), a critical enzyme for the respiration of bloodstream forms of trypanosomes, was investigated. Replacing the aldehyde group with a methyl ester resulted in a 10-fold increase in TAO inhibition and activity against T. brucei. Remarkably, two analogues containing the 2-hydroxy-6-methyl scaffold (9e and 16e) displayed single digit nanomolar TAO inhibition, which constitute the most potent 4-alkoxybenzoic acid derivatives described to date. 9e was 50-times more potent against TAO and 10-times more active against T. brucei compared to its benzaldehyde analogue 1. The farnesyl derivative 16e was as potent a TAO inhibitor as ascofuranone with IC50 = 3.1 nM. Similar to ascofuranone derivatives, the 2-hydroxy and 6-methyl groups seemed essential for low nanomolar TAO inhibition of acid derivatives, suggesting analogous binding interactions with the TAO active site.