Spirocyclic sulfonamides with carbonic anhydrase inhibitory and anti-neuropathic pain activity

Y Kalisha Vali; Rambabu Gundla; Om V Singh; Yasinalli Tamboli; Lorenzo Di Cesare Manelli; Carla Ghelardini; Abdul-Malek S Al-Tamimi; Fabrizio Carta; Andrea Angeli; Claudiu T Supuran

doi:10.1016/j.bioorg.2019.103210

Spirocyclic sulfonamides with carbonic anhydrase inhibitory and anti-neuropathic pain activity

Bioorg Chem. 2019 Nov:92:103210. doi: 10.1016/j.bioorg.2019.103210. Epub 2019 Aug 17.

Affiliations

¹ Department of Chemistry, School of Technology, GITAM University, Hyderabad 502102, Telangana, India.
² School of Chemical Sciences, SRTM University, Nanded 431606, Maharashtra, India. Electronic address: yasinmedchem@gmail.com.
³ NEUROFARBA Department, Section of Pharmacology and Toxicology, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Alkharj 11942, Saudi Arabia.
⁵ University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
⁶ University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy; Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, "Petru Poni" Institute of Macromolecular Chemistry, Iasi, Romania. Electronic address: andrea.angeli@unifi.it.
⁷ University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 31473472
DOI: 10.1016/j.bioorg.2019.103210

Abstract

A novel series of 4-oxo-spirochromane bearing primary sulfonamide group were synthetized as Carbonic Anhydrase inhibitors (CAIs) and tested for their management of neuropathic pain. Indeed, CAs have been recently validated as novel therapeutic targets in neuropathic pain. All compounds, here reported, showed strong activity against hCA II and hCA VII with K_I values in the low or sub-nanomolar range. Two compounds (6d and 6l) showed good neuropathic pain attenuating effects and longer duration than drug reference acetazolamide in an animal model of oxaliplatin induced neuropathy.

Keywords: Carbonic Anhydrase inhibitors (CAIs); Carbonic Anhydrases (CAs); Metalloenzymes; Neuropathic pain.

MeSH terms

Analgesics / chemical synthesis
Analgesics / chemistry
Analgesics / pharmacology*
Animals
Carbonic Anhydrase II / antagonists & inhibitors*
Carbonic Anhydrase II / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Male
Mice
Molecular Structure
Neuralgia / chemically induced
Neuralgia / drug therapy*
Oxaliplatin / administration & dosage
Spiro Compounds / chemical synthesis
Spiro Compounds / chemistry
Spiro Compounds / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Analgesics
Carbonic Anhydrase Inhibitors
Spiro Compounds
Sulfonamides
Oxaliplatin
Carbonic Anhydrase II
CA2 protein, human
Carbonic Anhydrases
carbonic anhydrase VI