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Effect of incorporating a thiophene tail in the scaffold of acetazolamide on the inhibition of human carbonic anhydrase isoforms I, II, IX and XII.
Bioorg Med Chem Lett. 2013 Oct 15; 23(20):5646-9.BM

Abstract

The high resolution crystal structure of 5-(2-thienylacetamido)-1,3,4-thiadiazole-2-sulfonamide complexed to human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoform hCA II is reported. The compound binds in a similar manner with acetazolamide when the sulfamoyl-thiadiazolyl-acetamido fragment of the two compounds is considered, but the thienyl tail was positioned in the subpocket 2, rarely observed by other investigated CA inhibitors. This positioning allows interaction with amino acid residues (such as Asn67, Ile91, Gln92 and Val121 which are variable in other isoforms of medicinal chemistry interest, such as hCA I, IX and XII. Indeed, the investigated sulfonamide was a medium potency hCA I and II inhibitor but was highly effective as a hCA IX and XII inhibitor. This different behavior with respect to acetazolamide (a promiscuous inhibitor of all these isoforms) has been explained by resolving the crystal structure, and may be used to design more isoform-selective compounds.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23993330

Citation

Biswas, Shyamasri, et al. "Effect of Incorporating a Thiophene Tail in the Scaffold of Acetazolamide On the Inhibition of Human Carbonic Anhydrase Isoforms I, II, IX and XII." Bioorganic & Medicinal Chemistry Letters, vol. 23, no. 20, 2013, pp. 5646-9.
Biswas S, McKenna R, Supuran CT. Effect of incorporating a thiophene tail in the scaffold of acetazolamide on the inhibition of human carbonic anhydrase isoforms I, II, IX and XII. Bioorg Med Chem Lett. 2013;23(20):5646-9.
Biswas, S., McKenna, R., & Supuran, C. T. (2013). Effect of incorporating a thiophene tail in the scaffold of acetazolamide on the inhibition of human carbonic anhydrase isoforms I, II, IX and XII. Bioorganic & Medicinal Chemistry Letters, 23(20), 5646-9. https://doi.org/10.1016/j.bmcl.2013.08.019
Biswas S, McKenna R, Supuran CT. Effect of Incorporating a Thiophene Tail in the Scaffold of Acetazolamide On the Inhibition of Human Carbonic Anhydrase Isoforms I, II, IX and XII. Bioorg Med Chem Lett. 2013 Oct 15;23(20):5646-9. PubMed PMID: 23993330.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of incorporating a thiophene tail in the scaffold of acetazolamide on the inhibition of human carbonic anhydrase isoforms I, II, IX and XII. AU - Biswas,Shyamasri, AU - McKenna,Robert, AU - Supuran,Claudiu T, Y1 - 2013/08/13/ PY - 2013/07/16/received PY - 2013/08/05/revised PY - 2013/08/05/accepted PY - 2013/9/3/entrez PY - 2013/9/3/pubmed PY - 2014/5/6/medline KW - Acetazolamide KW - Carbonic anhydrase KW - Isoformselective inhibitor KW - Thiopheneacetamide KW - X-ray crystallography SP - 5646 EP - 9 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 23 IS - 20 N2 - The high resolution crystal structure of 5-(2-thienylacetamido)-1,3,4-thiadiazole-2-sulfonamide complexed to human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoform hCA II is reported. The compound binds in a similar manner with acetazolamide when the sulfamoyl-thiadiazolyl-acetamido fragment of the two compounds is considered, but the thienyl tail was positioned in the subpocket 2, rarely observed by other investigated CA inhibitors. This positioning allows interaction with amino acid residues (such as Asn67, Ile91, Gln92 and Val121 which are variable in other isoforms of medicinal chemistry interest, such as hCA I, IX and XII. Indeed, the investigated sulfonamide was a medium potency hCA I and II inhibitor but was highly effective as a hCA IX and XII inhibitor. This different behavior with respect to acetazolamide (a promiscuous inhibitor of all these isoforms) has been explained by resolving the crystal structure, and may be used to design more isoform-selective compounds. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/23993330/Effect_of_incorporating_a_thiophene_tail_in_the_scaffold_of_acetazolamide_on_the_inhibition_of_human_carbonic_anhydrase_isoforms_I_II_IX_and_XII_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(13)00948-7 DB - PRIME DP - Unbound Medicine ER -