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Abstract

The microwave-assisted synthesis and characterization of the ten new sildenafil (Viagra®; 1) analogues 615 are described. A detailed structure–activity-relationship (SAR) study revealed that compounds 10 (=4-ethoxy-N-hydroxy-3-(7-methoxy-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide) and 12 (=S-(2-hydroxyethyl) 4-ethoxy-3-(7-methoxy-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonothioate) are extremely potent mushroom tyrosinase inhibitors, with IC50 values (3.59 and 2.15 μM, resp.) below those of the standard inhibitors L-mimosine and kojic acid (IC50=3.68 and 16.67 μM, resp.). Compounds 10 and 12 are, thus, the currently most-effective inhibitors of tyrosinase, and bear great potential to be used for the treatment of various skin disorders such as hyperpigmentation, which is associated with high production of melanocytes.