N-Quinary heterocycle-4-sulphamoylbenzamides exert anti-hypoxic effects as dual inhibitors of carbonic anhydrases I/II.

• N -quinary heterocycles-4-sulfamoylbenzamides were potent dual hCA I / II inhibitors. • The quinary heterocycles reinforced the interaction between the titled compounds and hCA I/II. • The selected compounds 2b and 6d possessed powerful anti-hypoxia activities in vivo. • The selected compounds 2b and 6d showed no obvious toxicity in vivo. Acute mountain sickness (AMS) affects approximately 25–50% of newcomers to high altitudes. Two human carbonic anhydrase isoforms, hCA I and II, play key roles in developing high altitude illnesses. However, the only FDA-approved drug for AMS is acetazolamide (AAZ), which has a nearly 100 times weaker inhibitory activity against hCA I (K i = 1237.10 nM) than hCA II (K i = 13.22 nM). Hence, developing potent dual hCA I/II inhibitors for AMS prevention and treatment is a critical medical need. Here we identified N -quinary heterocycle-4-sulphamoylbenzamides as potent hCA I/II inhibitors. The newly designed compounds 2b , 5b , 5f , 6d , and 6f possessed the desired inhibitory activities (hCA I: Ki = 16.95–52.71 nM; hCA II: K i = 8.61–18.64 nM). Their hCA I inhibitory capacity was 22– to 76-fold stronger than that of AAZ. Relative to the control group for survival in a mouse model of hypoxia, 2b and 6d prolonged the survival time of mice by 21.7% and 29.3%, respectively, which was longer than those of AAZ (6.5%). These compounds did not display any apparent toxicity in vitro and in vivo. In addition, docking simulations suggested that the quinary aromatic heterocycle groups stabilised the interaction between hCA I/II and the inhibitors, which could be further exploited in structure optimization studies. Hence, future functional studies may confirm 2b and 6d as potential clinical candidate compounds with anti-hypoxic activity against AMS. [ABSTRACT FROM AUTHOR]