Synthesis, carbonic anhydrase inhibition studies and modelling investigations of phthalimide–hydantoin hybrids

Abstract

A novel series of hydantoins incorporating phthalimides has been synthesised by condensation of activated phthalimides with 1-aminohydantoin and investigated for their inhibitory activity against a panel of human (h) carbonic anhydrase (CA, EC 4.2.1.1): the cytosolic isoforms hCA I, hCA II, and hCA VII, secreted isoform hCA VI, and the transmembrane hCA IX, by a stopped-flow CO₂ hydrase assay. Although all newly developed compounds were totally inactive on hCA I and mainly ineffective towards hCA II, they generally exhibited moderate repressing effects on hCA VI, VII, and IX with K_Is values in the submicromolar to micromolar ranges. The salts 3a and 3b, followed by derivative 5, displayed the best inhibitory activity of all the evaluated compounds and their binding mode was proposed in silico. These compounds can also be considered interesting starting points for the development of novel pharmacophores for this class of enzyme inhibitors.

GRAPHICAL ABSTRACT

Keywords:

• Carbonic anhydrase
• inhibitors
• hydantoins
• phthalimides
• docking studies

Author contributions

All authors contributed to the writing and revision of the manuscript. MA synthesised the compounds. MA and AB tested the in vitro enzyme activity. AB and PG performed the computational work. CTS and RZ supervised the entire research and were responsible for the funding of the research.

Disclosure statement

CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Data availability statement

Additional data may be requested from the authors.

Additional information

Funding

This work was supported by the Ministero dell’Istruzione dell’Universita e della Ricerca.