Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action

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• 作者：Francesco Mincione^a ; Francesca Benedini^b ; Stefano Biondi^b ; Alessandro Cecchi^c ; Claudia Temperini^c ; Giuseppe Formicola^d ; Ilaria Pacileo^d ; Andrea Scozzafava^c ; Emanuela Masini^d ; ^{emnuela.masini@unifi.it"" rel=""nofollow} ; Claudiu T. Supuran^c ; ^{claudiu.supuran@unifi.it"" rel=""nofollow}
• 关键词：Carbonic anhydrase ; Sulfonamide ; Nitrate ester ; NO ; Antiglaucoma drug ; X-ray crystallography
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：1 June 2011
• 年：2011
• 卷：21
• 期：11
• 页码：3216-3221
• 全文大小：866 K

文摘

Several aromatic/heterocyclic sulfonamide scaffolds have been used to synthesize compounds incorporating NO-donating moieties of the nitrate ester type, which have been investigated for the inhibition of five physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms: hCA I (offtarget), II, IV and XII (antiglaucoma targets) and IX (antitumor target). Some of the new compounds showed effective in vitro inhibition of the target isoforms involved in glaucoma, and the X-ray crystal structure of one of them revealed factors associated with the marked inhibitory activity. In an animal model of ocular hypertension, one of the new compounds was twice more effective than dorzolamide in reducing elevated intraocular pressure characteristic of this disease, anticipating their potential for the treatment of glaucoma.