Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases

被引：19

作者：

Ali, Majid ^{[1
,2
,3
]}

Bozdag, Murat ^{[1
]}

Farooq, Umar ^{[3
]}

Angeli, Andrea ^{[1
]}

Carta, Fabrizio ^{[1
]}

Berto, Paola ^{[2
]}

Zanotti, Giuseppe ^{[2
]}

Supuran, Claudiu T. ^{[1
]}

机构：

[1] Univ Firenze, Dipartimento Neurofarba, Sez Sci Farmaceut, Via Ugo Schiff 6, I-50019 Florence, Italy

[2] Univ Padua, Dept Biomed Sci, Via Ugo Bassi 58-B, I-35131 Padua, Italy

[3] COMSATS Univ Islamabad, Dept Chem, Abbottabad Campus, Islamabad 45550, Pakistan

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2020年 / 21卷 / 07期

关键词：

carbonic anhydrase: sulfonamide; tail approach; X-ray crystallography; ISOZYME-II; DRUG DISCOVERY; INHIBITORS; IX; POTENT; MOIETIES; GABA;

D O I：

10.3390/ijms21072560

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on para- or meta- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (K(I)s of 2.8-9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.

引用

页数：15

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