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

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

  • Bioorg Chem. 2020 Jul;100:103931. doi: 10.1016/j.bioorg.2020.103931.
Chaofu Yang 1,  Jing Wang 2,  Yunyun Cheng 2,  Xu Yang 2,  Yan Feng 2,  Xiaomei Zhuang 2,  Zhenwang Li 3,  Wangyu Zhao 4,  Jiwen Zhang 4,  Xianyu Sun 5,  Xinhua He 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian District, Beijing 100850, China; College of Chemistry & Pharmacy, Shaanxi Key Laboratory of Natural Products& Chemical Biology, Northwest A&F University, Yangling, Shaanxi 712100, China.
  • 2 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian District, Beijing 100850, China.
  • 3 Department of Pharmacy, College of Animal Science and Technique, Heilongjiang Bayi Agricultural University, Xinyang Road 2, Daqing 163319, China.
  • 4 College of Chemistry & Pharmacy, Shaanxi Key Laboratory of Natural Products& Chemical Biology, Northwest A&F University, Yangling, Shaanxi 712100, China.
  • 5 Department of Pharmacy, College of Animal Science and Technique, Heilongjiang Bayi Agricultural University, Xinyang Road 2, Daqing 163319, China. Electronic address: sxianyu@163.com.
  • 6 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian District, Beijing 100850, China. Electronic address: xhhe@ncba.ac.cn.
PMID: 32450385 DOI: 10.1016/j.bioorg.2020.103931
Abstract

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 (Ki = 1237.10 nM) than hCA II (Ki = 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: Ki = 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.

Keywords

Anti-hypoxic activity; Docking simulation; Dual hCA I/II inhibitor; Human carbonic anhydrase; N-quinary heterocycle-4-sulphamoylbenzamide.

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