Discovery of 4-sulfamoyl-phenyl-β-lactams as a new class of potent carbonic anhydrase isoforms I, II, IV and VII inhibitors: The first example of subnanomolar CA IV inhibitors

Srinivas Angapelly; P V Sri Ramya; Andrea Angeli; Simona Maria Monti; Martina Buonanno; Mallika Alvala; Cladiu T Supuran; Mohammed Arifuddin

doi:10.1016/j.bmc.2016.11.027

Discovery of 4-sulfamoyl-phenyl-β-lactams as a new class of potent carbonic anhydrase isoforms I, II, IV and VII inhibitors: The first example of subnanomolar CA IV inhibitors

Bioorg Med Chem. 2017 Jan 15;25(2):539-544. doi: 10.1016/j.bmc.2016.11.027. Epub 2016 Nov 19.

Authors

Srinivas Angapelly¹, P V Sri Ramya¹, Andrea Angeli², Simona Maria Monti³, Martina Buonanno³, Mallika Alvala⁴, Cladiu T Supuran⁵, Mohammed Arifuddin⁶

Affiliations

¹ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Govt of India, Balanagar, Hyderabad 500037, India.
² Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
³ Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Napoli, Italy.
⁴ Molecular Modeling Facility, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Govt. of India, Balanagar, Hyderabad 500037, India.
⁵ Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.
⁶ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Govt of India, Balanagar, Hyderabad 500037, India. Electronic address: arif@niperhyd.ac.in.

PMID: 27919611
DOI: 10.1016/j.bmc.2016.11.027

Abstract

A series of benzenesulfonamides incorporating 1,3,4-trisubstituted-β-lactam moieties was prepared from sulfanilamide Schiff bases and in situ obtained ketenes, by using the Staudinger cycloaddition reaction. The new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) involved in various physiological/pathological conditions, hCA I, II, IV and VII. Excellent inhibitory activity was observed against all these isoforms, as follows: hCA I, involved in some eye diseases was inhibited with K_Is in the range of 7.3-917nM; hCA II, an antiglaucoma drug target, with K_Is in the range of 0.76-163nM. hCA IV, an isoform involved in several pathological conditions such as glaucoma, retinitis pigmentosa and edema was potently inhibited by the lactam-sulfonamides, with K_Is in the range of 0.53-51.0nM, whereas hCA VII, a recently validated anti-neuropathic pain target was the most inhibited isoform by these derivatives, with K_Is in the range of 0.68-9.1nM. The structure-activity relationship for inhibiting these CAs with the new lactam-sulfonamides is discussed in detail.

Keywords: Carbonic anhydrase; Isoform CA I, II, IV, VII; Sulfonamide; β-Lactam.

Publication types

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

MeSH terms

Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Lactams / chemical synthesis
Lactams / chemistry
Lactams / pharmacology*
Molecular Structure
Structure-Activity Relationship

Substances

Carbonic Anhydrase Inhibitors
Isoenzymes
Lactams
Carbonic Anhydrases