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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

Abstract

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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Abbreviations

AMPA:

α-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid

cGMP:

cyclic guanosine monophosphate

EIMS:

electron impact mass spectra

HYBOT:

hydrogen bond thermodynamics

KA:

kojic acid

LM:

l-mimosine

MD:

molecular dynamic

MED:

male erectile dysfunction

SAR:

structure activity relationship

MM:

molecular mechanics

MMFF:

molecular mechanics force field

MW:

microwave

NMR:

nuclear magnetic resonance

PDE5:

phosphodiesterase type 5

PPO:

polyphenol oxidase

QSPR:

quantitative structure properties relationships

RMS:

root mean square

SEM:

standard error of the mean

SNAr:

aromatic nucleophilic substitution reaction

TS:

transition state.

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Correspondence to Khalid M. Khan.

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Khan, K.M., Maharvi, G.M., Khan, M.T.H. et al. 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. Mol Divers 9, 15–26 (2005). https://doi.org/10.1007/s11030-005-1299-5

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  • DOI: https://doi.org/10.1007/s11030-005-1299-5

Keywords

  • bromination
  • energy minimization
  • hydrogen bonding
  • molecular modeling
  • sildenafil
  • solid state
  • tyrosinase