Natural inspired ligustrazine-based SLC-0111 analogues as novel carbonic anhydrase inhibitors

• Published in: European journal of medicinal chemistry 2022-01, Vol.228, p.114008-114008, Article 114008
• Main Authors: Elimam, Diaaeldin M., Eldehna, Wagdy M., Salem, Rofaida, Bonardi, Alessandro, Nocentini, Alessio, Al-Rashood, Sara T., Elaasser, Mahmoud M., Gratteri, Paola, Supuran, Claudiu T., Allam, Heba Abdelrasheed
• Format: Article
• Language: English
• Subjects: Anticancer agents; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - pharmacology; Carbonic anhydrase inhibitors; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - metabolism; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Ligustrazine; MCF-7 Cells; Models, Molecular; Molecular Structure; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; Pyrazines - chemistry; Pyrazines - pharmacology; SLC-0111 analogues; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Tail approach; Ureido benzenesulfonamides
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.114008

Ligustrazine is the principle bioactive alkaloid in the widely-used Chinese herb Chuan Xiong rhizome. Herein, a series of novel derivatives has been designed as human carbonic anhydrases inhibitors (hCAIs) starting from the natural product Ligustrazine inserted as a tail instead of the 4-fluorophenyl tail of SLC-0111, a front-runner selective hCA IX inhibitor currently in clinical trials as antitumor/antimetastatic agent. Other derivatives were designed via incorporation of different linkers, of amide and ester type, or incorporation of different zinc anchoring groups such as secondary sulfamoyl and carboxylic acid functionalities. The newly designed molecules were prepared following different synthetic pathways, and were assessed for their inhibitory actions against four isoforms: the widespread cytosolic (hCA I and II), and the transmembrane tumor-related (hCA IX and XII). The primary sulfonamides efficiently inhibited the target hCA IX and hCA XII in the nanomolar range (KIs: 6.2–951.5 nM and 3.3–869.3 nM, respectively). The most selective hCA IX inhibitors 6c and 18 were assessed for their potential anticancer effects, and displayed anti-proliferative activity against MCF-7 cancer cell line with IC50s of 11.9 and 36.7 μM, respectively. Molecular modelling studies unveiled the relationship between structural features and inhibitory profiles against the off-target hCA II and the target, tumor-related isoforms hCA IX and XII. [Display omitted] •New series of Ligustrazine-based sulfonamides were designed and synthesized.•Inhibitory activities of all derivatives were evaluated toward hCA I, II, IX and XII isoforms.•The primary sulfonamides efficiently inhibited hCA IX and XII in the sub-micromolar ranges.•Compounds 6c and 18 were examined for its potential anticancer and pro-apoptotic activities.•A molecular modelling study was performed to unveil the plausible binding interactions.