Novel sulfonamides bearing pyrrole and pyrrolopyrimidine moieties as carbonic anhydrase inhibitors: Synthesis, cytotoxic activity and molecular modeling

Mostafa M Ghorab; Mariangela Ceruso; Mansour S Alsaid; Yassin M Nissan; Reem K Arafa; Claudiu T Supuran

doi:10.1016/j.ejmech.2014.09.059

Novel sulfonamides bearing pyrrole and pyrrolopyrimidine moieties as carbonic anhydrase inhibitors: Synthesis, cytotoxic activity and molecular modeling

Eur J Med Chem. 2014 Nov 24:87:186-96. doi: 10.1016/j.ejmech.2014.09.059. Epub 2014 Sep 19.

Authors

Mostafa M Ghorab¹, Mariangela Ceruso², Mansour S Alsaid³, Yassin M Nissan⁴, Reem K Arafa⁴, Claudiu T Supuran⁵

Affiliations

¹ Pharmacognosy Department, College of Pharmacy, King Saud University, P.O.Box 2457, Riyadh 11451, Saudi Arabia; Drug Radiation Research Department, National Center for Radiation Research & Technology, Atomic Energy Authority, Cairo, Egypt. Electronic address: mmsghorab@yahoo.com.
² Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Firenze, Italy.
³ Pharmacognosy Department, College of Pharmacy, King Saud University, P.O.Box 2457, Riyadh 11451, Saudi Arabia.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Al-Aini st., P.O.Box 11562, Cairo, Egypt.
⁵ Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Firenze, Italy; Università degli Studi di Firenze, Polo Scientifico, Dipartimento NEUROFABA, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 25255434
DOI: 10.1016/j.ejmech.2014.09.059

Abstract

Novel pyrrole and pyrrolopyrimidine scaffold-based sulfonamides were designed and synthesized. The carbonic anhydrase (CA) inhibition ability of all derivatives was assessed against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated isoforms hCA IX and XII. Some of these sulfonamides were 6-8 fold more potent than the reference drug acetazolamide (AZA, Ki = 5.7 nM)) against hCA XII showing subnanomolar activity. The in vitro cytotoxicity of these derivatives was evaluated against MCF-7, where some derivatives were more cytotoxic than doxorubicin (IC50 = 8.02 μM) displaying IC50 values between 6.46 and 7.56 μM. Docking of these sulfonamides with CA XII was performed and their binding modes were comparable with that of AZA.

Keywords: Carbonic anhydrase; Cytotoxic activity; Pyrroles; Pyrrolopyrimidines; Sulfonamides.

Publication types

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

MeSH terms

Antigens, Neoplasm / chemistry
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Carbonic Anhydrase I / chemistry
Carbonic Anhydrase II / chemistry
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemical synthesis*
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / chemistry*
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Female
Flow Cytometry
Humans
Models, Molecular
Molecular Structure
Pyrimidines / chemistry*
Pyrroles / chemistry*
Structure-Activity Relationship
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacology*
Tumor Cells, Cultured

Substances

Antigens, Neoplasm
Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Pyrimidines
Pyrroles
Sulfonamides
pyrrolopyrimidine
Carbonic Anhydrase I
Carbonic Anhydrase II
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII