Synthesis and Biological Evaluation of Coumarin Carboxamides as Selective and Potent Inhibitors of Carbonic Anhydrases IX and XII

Abstract

Background: Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the reversible hydration of carbon dioxide to bicarbonate and proton. Inhibition of isoforms IX and XII could aid in the amelioration of cancer. Objective: A series of coumarin carboxamides (6a-j) were synthesized and were assayed against hCA isoforms I, II, IX and XII. Methods: Thin Layer Chromatography (TLC) analysis was done by utilizing Merck silica gel 60 F254 aluminum plates. Stuart Digital Melting Point Apparatus (SMP 30) was used in determining the melting points of the compounds, which are uncorrected. High Resolution Mass Spectra (HRMS) were determined by Agilent QTOF mass spectrometer 6540 series instrument and were performed using ESI techniques at 70eV. Result: All the compounds selectively inhibited isoforms IX and XII as against hCAs I and II. Compounds 6a-e exhibited the best inhibitory profiles against hCA IX (Ki < 25 nM). The isoform hCA XII was effectively inhibited by all compounds showing the Ki values less than 65 nM. The Compounds 6a, 6b, 6g, 6h and 6j exhibited Ki values less than 10 nM. The binding interactions of the most potent compounds, 6a and 6b, were investigated through docking studies with hCAs IX and XII. Conclusion: These compounds may be utilized as useful starting points for the design and development of selective and potent hCA IX and XII inhibitors.

Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies

“…The terminal amidic NH forms a hydrogen with the carbonyl oxygen of Leu206 (corresponding to Thr88 of hCA XII), the carboxylic function binds the terminal NH2 of Gln224 (that corresponds to Gln89 of hCA XII), while the phenolic OH is H-bound to the terminal C=O of Gln203 (corresponding to Lys69 of hCA XII). It is known from the literature that the binding regions reported for coumarins are the most variable among hCAs, which can be exploited to obtain selective inhibitors [34][35][36][37][38]. To further confirm this observation and to obtain a more detailed explanation of the activity profiles of the studied compounds, the sequence similarity of the hCA I, II, IX, and XII isoforms was evaluated.…”

“…Therefore, these residues could be responsible for isoform selectivity. Residue variation between hCA XII and hCA IX, moreover, can explain the selectivity profile shown by ligands 16, 17, and 19 toward hCA IX; in fact, MD simulation indicates that the promising activity of these compounds as inhibitors of hCA XII is mainly It is known from the literature that the binding regions reported for coumarins are the most variable among hCAs, which can be exploited to obtain selective inhibitors [34][35][36][37][38]. To further confirm this observation and to obtain a more detailed explanation of the activity profiles of the studied compounds, the sequence similarity of the hCA I, II, IX, and XII isoforms was evaluated.…”

Coumaryl‐sulfonamide moiety: Unraveling their synthetic strategy and specificity toward hCA IX/XII, facilitating anticancer drug development

“…The coumarin molecule has always remained the central focus for drug development research and many patents have also been filed including several small molecules and their hybrids (sulfocoumarins, sulfones, sulfonamides, slenols, and coumarins); additionally, the coumarin along with carboxamide have been reported as potent inhibitors of h CA IX and XII with K i values less than 10 nM. [ 7,8 ] Lately, a group of researchers have designed and synthesized coumarin‐pyridine scaffolds against the target human carbonic anhydrases ( h CA) IX and XII, and have screened with different concentration ranges against the isoforms h CA I & II for a better understanding of the specificity of coumarin toward the target‐the overexpressed isoforms h CA IX & XII in the cancer cell. [ 9 ] With all the above findings the current efforts could parallelly assist the drug development against the cancer target h CA along with the structure–activity relationship for the small molecule conjugation chemistry.…”