Synthesis of new 3-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-benzenesulfonamides with strong inhibition properties against the tumor associated carbonic anhydrases IX and XII

Murat Bozdag; Ahmed Mahmoud Alafeefy; Abdul Malik Altamimi; Fabrizio Carta; Claudiu T Supuran; Daniela Vullo

doi:10.1016/j.bmc.2017.03.054

Synthesis of new 3-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-benzenesulfonamides with strong inhibition properties against the tumor associated carbonic anhydrases IX and XII

Bioorg Med Chem. 2017 May 15;25(10):2782-2788. doi: 10.1016/j.bmc.2017.03.054. Epub 2017 Mar 29.

Authors

Murat Bozdag¹, Ahmed Mahmoud Alafeefy², Abdul Malik Altamimi³, Fabrizio Carta⁴, Claudiu T Supuran⁵, Daniela Vullo⁶

Affiliations

¹ Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy; Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
² Chemistry Department, Kulliyyah of Science, International Islamic University, Kuantan, Malaysia.
³ Pharmaceutical Chemistry Dept., College of Pharmacy, Prince Sattam Bin Abdulaziz University, Saudi Arabia.
⁴ Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
⁵ Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
⁶ Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: daniela.vullo@unifi.it.

PMID: 28389112
DOI: 10.1016/j.bmc.2017.03.054

Abstract

We report a series of novel metanilamide-based derivatives 3a-q bearing the 2-mercapto-4-oxo-4H-quinazolin-3-yl moiety as tail. All compounds were synthesized by means of straightforward condensation procedures and were investigated in vitro for their inhibition potency against the human (h) carbonic anhydrase (CA; EC 4.2.1.1.1) isoforms I, II, IX and XII. Among all compounds tested the 6-iodo 3g and the 7-fluoro 3i derivatives were the most potent inhibitors against the tumor associated CA IX and XII isoform (K_Is 1.5 and 2.7nM respectively for the hCA IX and K_Is 0.57 and 1.9nM respectively for the hCA XII). The kinetic data reported here strongly support compounds of this type for their future development as radiotracers in tumor pathologies which are strictly dependent on the enzymatic activity of the hCA IX and XII isoforms.

Keywords: Carbonic anhydrase inhibitors (CAIs); Imaging; Quinazolines; Tumors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis*
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / metabolism
Humans
Kinetics
Neoplasms / enzymology
Neoplasms / pathology
Protein Binding
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Quinazolines / chemistry
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / metabolism

Substances

Carbonic Anhydrase Inhibitors
Protein Isoforms
Quinazolines
Sulfonamides
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII