基于4-苯胺基喹唑啉的苯磺酰胺作为碳酸酐酶同工酶I、II、IX和XII的纳摩尔抑制剂：设计、合成及生物学研究
4-Anilinoquinazoline-based benzenesulfonamides as nanomolar inhibitors of carbonic anhydrase isoforms I, II, IX, and XII: design, synthesis, , and biological studies.
作者信息
Nada Hossam, Elkamhawy Ahmed, Abdellattif Magda H, Angeli Andrea, Lee Chang Hoon, Supuran Claudiu T, Lee Kyeong
机构信息
BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
出版信息
J Enzyme Inhib Med Chem. 2022 Dec;37(1):994-1004. doi: 10.1080/14756366.2022.2055553.
Human carbonic anhydrase inhibitors (hCAIs) are a key therapeutic class with a multitude of novel applications such as anticonvulsants, topically acting antiglaucoma, and anticancer drugs. Herein, a new series of 4-anilinoquinazoline-based benzenesulfonamides were designed, synthesised, and biologically assessed as potential hCAIs. The target compounds are based on the well-tolerated kinase scaffold (4-anilinoquinazoline). Compounds (89.4 nM), (91.2 nM), and (60.9 nM) exhibited 2.8, 2.7, and 4 folds higher potency against hCA I when compared to the standard (AAZ, ), respectively. A single digit nanomolar activity was elicited by compounds (8.7 nM), (2.4 nM), and (4.6 nM) with 1.4, 5, and 2.6 folds of potency compared to AAZ (12.1 nM) against isoform hCA II, respectively. Structure-activity relationship (SAR) and molecular docking studies validated our design approach that revealed highly potent hCAIs.
人碳酸酐酶抑制剂（hCAIs）是一类关键的治疗药物，有许多新的应用，如抗惊厥药、局部作用的抗青光眼药物和抗癌药物。在此，设计、合成了一系列基于4-苯胺基喹唑啉的新型苯磺酰胺，并对其作为潜在hCAIs进行了生物学评估。目标化合物基于耐受性良好的激酶支架（4-苯胺基喹唑啉）。化合物（89.4 nM）、（91.2 nM）和（60.9 nM）对hCA I的活性分别比标准品（AAZ，）高2.8倍、2.7倍和4倍。化合物（8.7 nM）、（2.4 nM）和（4.6 nM）分别对同工型hCA II产生了个位数纳摩尔活性，与AAZ（12.1 nM）相比，其活性分别为1.4倍、5倍和2.6倍。构效关系（SAR）和分子对接研究验证了我们揭示高效hCAIs的设计方法。
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