Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, VPO-Ghudda, Bathinda 151401, Punjab, India.
Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, VPO-Ghudda, Bathinda 151401, Punjab, India.
Bioorg Med Chem. 2024 Nov 15;114:117933. doi: 10.1016/j.bmc.2024.117933. Epub 2024 Oct 3.
In the realm of enzymology, Carbonic anhydrase (CA) emerges as a pivotal protagonist orchestrating the rapid conversion of carbon dioxide and water into bicarbonate ions and hydrogen ions, respectively. Carbonic anhydrase inhibitors (CAIs) are the class of drugs that target various isoforms of the enzyme, and these inhibitors play a crucial role in the treatment and management of multiple diseases such as cancer, glaucoma, high altitude sickness, rheumatoid arthritis, obesity, epilepsy, and sleep apnea. Several structural classes of CAIs developed till date possess unique architects of the pharmacophoric requirements around the central core moiety for the selective targeting of various isoforms of the CA. Recent advancements in drug design and development, along with technologies that aid in structure determination, have led to the development of several isoform-selective inhibitors of CA enzymes. However, their clinical development was hampered by the lack of desired therapeutic efficacy, isoform selectivity and safety profile. This review covers the most recent approaches used by different researchers concerned with the development of isoform-selective carbonic anhydrase inhibitors belonging to distinct structural classes like sulphonamides, carbazoles, selenols, coumarin, organotelluride, topiramate, thiophene, triazole, uracil-modified benzylic amines, and thiourea etc. In addition, their structure-activity relationships, biological evaluation, and in silico studies inlcuding the forthcoming avenues of advancements have been discussed. This review serves as a valuable resource for developing potent and efficacious CAIs with remarkable therapeutic implications; offering insights into their potency, specificity, and potential clinical applications.
在酶学领域，碳酸酐酶（CA）是一种关键的酶，它可以快速将二氧化碳和水分别转化为碳酸氢根离子和氢离子。碳酸酐酶抑制剂（CAI）是一类靶向该酶各种同工型的药物，这些抑制剂在治疗和管理多种疾病方面发挥着重要作用，如癌症、青光眼、高原病、类风湿性关节炎、肥胖症、癫痫和睡眠呼吸暂停等。迄今为止，已经开发出几类碳酸酐酶抑制剂，它们具有独特的药效团结构，围绕着中央核心部分，以选择性地靶向各种碳酸酐酶同工型。最近在药物设计和开发方面的进展以及辅助结构确定的技术，导致了几种同工型选择性碳酸酐酶抑制剂的发展。然而，它们的临床开发受到缺乏所需的治疗效果、同工型选择性和安全性的阻碍。本综述涵盖了不同研究人员在开发属于不同结构类别（如磺酰胺类、咔唑类、硒醇类、香豆素类、有机碲化物类、托吡酯类、噻吩类、三唑类、尿嘧啶修饰的苄基胺类和硫脲类等）的同工型选择性碳酸酐酶抑制剂方面所使用的最新方法。此外，还讨论了它们的构效关系、生物评价和包括即将到来的进展在内的计算研究。本综述为开发具有强大疗效的有效碳酸酐酶抑制剂提供了有价值的资源，为其效力、特异性和潜在的临床应用提供了深入了解。
