Carbonic anhydrase inhibitors: Synthesis, molecular docking, cytotoxic and inhibition of the human carbonic anhydrase isoforms I, II, IX, XII with novel benzenesulfonamides incorporating pyrrole, pyrrolopyrimidine and fused pyrrolopyrimidine moieties

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

doi:10.1016/j.bmc.2014.05.009

Carbonic anhydrase inhibitors: Synthesis, molecular docking, cytotoxic and inhibition of the human carbonic anhydrase isoforms I, II, IX, XII with novel benzenesulfonamides incorporating pyrrole, pyrrolopyrimidine and fused pyrrolopyrimidine moieties

Bioorg Med Chem. 2014 Jul 15;22(14):3684-95. doi: 10.1016/j.bmc.2014.05.009. Epub 2014 May 14.

Authors

Mostafa M Ghorab¹, Mansour S Alsaid², Mariangela Ceruso³, Yassin M Nissan⁴, Claudiu T Supuran⁵

Affiliations

¹ Pharmacognosy Department, College of Pharmacy, King Saud University, PO 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 Pharmacognosy Department, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
³ Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Al-Aini st., PO 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: 24878360
DOI: 10.1016/j.bmc.2014.05.009

Abstract

A series of novel pyrroles, pyrrolopyrimidines, pyrazolopyrrolopyrimidine, triazolopyrrolopyrimidines, tetrazolopyrrolopyrimidine, triazinopyrrolopyrimidines and pyrrolopyrimidotriazepines bearing the biologically active benzenesulfonamide moiety were synthesized by using pyrrole-o-amino-carbonitrile as key intermediate. All the synthesized compounds were evaluated for their in vitro carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects against the human (h) isoforms hCA I, II, IX and XII. Among the tested derivatives, compounds 16, 18 and 20-24 showed potent activity as inhibitors for the tumor associated transmembrane isoforms (hCA IX and XII) in the nanomolar and subnanomolar range, with high selectivity. All compounds underwent cytotoxic activity assays on human breast cancer cell line (MCF-7) showing effective activity, comparable to that of the clinically used drug doxorubicin.

Keywords: Carbonic anhydrase inhibitors; Cytotoxic activity; Molecular docking; Pyrrolopyrimidines; Sulfonamide.

Publication types

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

MeSH terms

Benzenesulfonamides
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Molecular Structure
Pyrimidines / chemistry*
Pyrroles / chemistry*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Carbonic Anhydrase Inhibitors
Isoenzymes
Pyrimidines
Pyrroles
Sulfonamides
pyrrolopyrimidine
Carbonic Anhydrases