TY - JOUR
T1 - SAR of 4-alkoxybenzoic acid inhibitors of the trypanosome alternative oxidase.
AU - Navas, Alejandro Meco
AU - Ebiloma, Godwin
AU - Domínguez, Ana Martín
AU - Benayas, Irene Martínez
AU - Cueto-Díaz, Eduardo J.
AU - Alhejely, Amani Saud
AU - Balogun, Emmanuel Oluwadare
AU - Saito, Machi
AU - Matsui, Miho
AU - Arai, Natsumi
AU - Shiba, Tomoo
AU - Harada, Shigeharu
AU - De Koning, Harry P.
AU - Dardonville, Christophe
PY - 2018/7/31
Y1 - 2018/7/31
N2 - 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.
AB - 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.
U2 - 10.1021/acsmedchemlett.8b00282
DO - 10.1021/acsmedchemlett.8b00282
M3 - Article
SN - 1948-5875
VL - 9
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 9
M1 - 923-928
ER -