Synthesis of methyl ether analogues of sildenafil (Viagra) possessing tyrosinase inhibitory potential.
The microwave-assisted synthesis and characterization of the ten new sildenafil (Viagra; 1) analogues 6-15 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 microM, resp.) below those of the standard inhibitors L-mimosine and kojic acid (IC50 = 3.68 and 16.67 microM, 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.
Khan
Khalid Mohammed
KM
H.E.J. Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi, Karachi-75270, Pakistan.
Maharvi
Ghulam Murtaza
GM
Perveen
Shahnaz
S
Khan
Mahmud Tareq Hassan
MT
Abdel-Jalil
Raid J
RJ
Shah
Syed Tasadaque Ali
ST
Fecker
Miriam
M
Choudhary
Muhammad Iqbal
MI
Voelter
Wolfgang
W
D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013450:Sulfones
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D014442:Monophenol Monooxygenase