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.
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.
Khan
Khalid M
KM
H.E.J. Research Institute of Chemistry, International Centerfor Chemical Sciences, University of Karachi, Karachi, Pakistan. hassaan2@super.net.pk
Maharvi
Ghulam M
GM
Khan
Mahmud T H
MT
Perveen
Shahnaz
S
Choudhary
Muhammad I
MI
Atta-Ur-Rahman
D007202:Indicators and Reagents; D008872:Microwaves; D008958:Models, Molecular; D008968:Molecular Conformation; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors / Q000528:radiation effects; D010879:Piperazines / Q000138:chemical synthesis*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014665:Vasodilator Agents / Q000138:chemical synthesis
D007202:Indicators and Reagents; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D014442:Monophenol Monooxygenase