Title:Synthesis and Biological Evaluation of Coumarin Carboxamides as Selective and
Potent Inhibitors of Carbonic Anhydrases IX and XII
Volume: 22
Issue: 14
Author(s): Pavitra S. Thacker, Arifuddin Mohammed*, Claudiu T. Supuran*, Prerna L. Tiwari, Nerella S. Goud, Danaboina Srikanth and Andrea Angeli
Affiliation:
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad
500037, Telangana State, India
- Synergy Community Welfare Research Center (SCWRC), Head office, Panacea, Synergy India
Foundation, 4th Floor TSWREIS building, Masab Tank Hyderabad 500028, India
- Università degli Studi di Firenze,
Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
Keywords:
Carbonic anhydrases, hCA IX, hCA XII, coumarin, carboxamides, sulfonamides.
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.
Results: 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.