Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Herein, the synthesis of some analogs of sildenafil (Viagra) (21) is described, employing MW irradiations in key steps such as, SNAr reaction on important precursor bromopyrazole (7). Compound 7 was synthesized by the bromination followed by the amidation of readily available 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid (5). Compounds 9 and 10 were obtained as SNAr reaction products, apparently through the proposed dipolar high-energy transition states TS-1 and TS-2 under MW irradiation, respectively. In contrast, conventional heating failed to produce similar results, even after prolonged heating. Compound 10, upon chlorosulfonation followed by the coupling of various nucleophiles, yielded a series of compounds 12-20 as analogs of sildenafil (21). Compounds 12-21 were subjected to tyrosinase inhibition studies and SAR studies were carried out. This study reflected that the inhibition was enhanced with increase of carbon chain. In case of the compound 17, the -OH group was replaced with -CH2-CH2-OH with a resulting increase in inhibition against tyrosinase. Compound 17 was found to be more potent than the potent reference inhibitor LM and KA. The 2D and 3D hydrogen bonding descriptors that help to study QSPR were also calculated. Energetically most stable conformations of these compounds were analyzed. Their kinetic, potential and total energies were also calculated through MD simulation.
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PMID:A facile and improved synthesis of sildenafil (Viagra) analogs through solid support microwave irradiation possessing tyrosinase inhibitory potential, their conformational analysis and molecular dynamics simulation studies. 1578 47

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.
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PMID:Synthesis of methyl ether analogues of sildenafil (Viagra) possessing tyrosinase inhibitory potential. 1719 95