Microwave assisted synthesis of novel acridine–acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII. Issue 16 (15th August 2016)

• Record Type: Journal Article
• Authors: Ulus, Ramazan; Aday, Burak; Tanç, Muhammet; Supuran, Claudiu T.; Kaya, Muharrem
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 16(2016)
• Page Start: 3548
• Page End: 3555
• Publication Date: 2016-08-15
• Subjects: CA carbonic anhydrase -- hCA human carbonic anhydrase -- Quinacrine (RS)-N′-(6-Chloro-2-methoxy-acridin-9-yl)-N, N-diethylpentane-1, 4-diamine -- Proflavine acridine-3, 6-di-amine -- Amsacrine N-(4-(acridin-9-ylamino)-3-methoxyphenyl)methanesulfonamide -- IR infrared -- NMR nuclear magnetic resonance -- HRMS high resolution mass spectroscopy -- SAR structure–activity relationship -- DMSO dimethyl sulfoxide -- TLC thin layer chromatography -- mp melting point -- ESI electron spray ionization -- TEA trimethylamine -- THF tetrahydrofuran -- mM milimolar -- μM micro molar -- nM nanomolar -- KI inhibition constant -- W watt -- Hz hertz -- MHz megahertz -- ppm parts per million -- s singlet -- d doublet -- t triplet -- q quadruplet -- m multiplet -- brs broad singlet -- dd double of doublet -- pAMBS p-aminomethylbenzene sulfonamide; Carbonic anhydrase -- Acridine -- Acetazolamide -- Enzyme inhibition -- Isoforms CA I, II, IV and VII; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.05.064
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 4-Amino- N -(5-sulfamoyl-1, 3, 4-thiadiazol-2-yl)benzamide was condensed with cyclic-1, 3-diketones (dimedone and cyclohexane-1, 3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine–acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KI s in the range of 29.7–708.8 nM (hCA IV), and of 1.3–90.7 nM (hCA VII). For hCA I and II the KI s were in the range of 6.7–335.2 nM (hCA I) and of 0.5–55.4 nM (hCA II). The structure–activity relationships (SAR) for the inhibition of these isoforms with the acridine–acetazolamide conjugates reported here were delineated.