Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety

Abstract

New dihydro-pyrrol-2-one compounds, featuring dual sulfonamide groups, were synthesized through a one-pot, three-component approach utilizing trifluoroacetic acid as a catalyst. Computational analysis using density functional theory (DFT) and condensed Fukui function explored the structure− reactivity relationship. Evaluation against human carbonic anhydrase isoforms (hCA I, II, IX, XII) revealed potent inhibition. The widely expressed cytosolic hCA I was inhibited across a range of concentrations (K I 3.9−870.9 nM). hCA II, also cytosolic, exhibited good inhibition as well. Notably, all compounds effectively inhibited tumor-associated hCA IX (K I 1.9−211.2 nM) and hCA XII (low nanomolar). Biological assessments on MCF7 cancer cells highlighted the compounds' ability, in conjunction with doxorubicin, to significantly impact tumor cell viability. These findings underscore the potential therapeutic relevance of the synthesized compounds in cancer treatment.

Design, synthesis, and in vitro and in silico studies of morpholine derived thiazoles as bovine carbonic anhydrase-II inhibitors

“… 9 CA-I, CA-II, CA-III, CA-VII, and CA-XIII are cytosolic isoforms; CA-VA and CA-VB are mitochondrial isoforms; CA-IV, CA-IX, CA-XII, CA-XIV, and CA-XV are membrane-associated isoforms; and CA-VI is the isoform found in saliva. 10,11 …”

“…CA-II primarily regulates the concentration of bicarbonate in the eyes and CA-II inhibitors are effective in lowering the elevated intraocular pressure commonly observed in individuals with glaucoma. 10,17 Additionally, CA-II is also present in malignant brain tumors, as well as in renal, gastritis, and pancreatic carcinomas. 18,19 CA-II inhibitors have also been explored as a supplementary treatment in cancer chemotherapy.…”

Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors

“…The primary sulfonamides (−SO 2 NH 2 ) are the prototypical CA inhibitor (CAI) moieties and have a long-standing history in clinical practice spanning over 70 years to date. Such a group is widely recognized for its capability to directly inhibit the catalytic action of CAs through coordination of the zinc ion. , …”