wileyonlinelibrary.com/journal/cbdd Chem Biol Drug Des. 2018;91:902–914.
© 2017 John Wiley & Sons A/S
Received: 13 August 2017
Revised: 21 October 2017
Accepted: 17 November 2017
Synthesis of novel norsufentanil analogs via a four- component
Ugi reaction and in vivo, docking, and QSAR studies of their
Faculty of Chemistry, Shahid Beheshti
University, Tehran, Iran
Department of Phytochemistry, Medicinal
Plants and Drugs Research Institute, Shahid
Beheshti University, Tehran, Iran
Laboratory of Bioinformatics and Drug
Design (LBD), Institute of Biochemistry
and Biophysics, University of Tehran,
Department of Pharmacology and
Toxicology, Shahid Beheshti University of
Medical Sciences, Tehran, Iran
UoN Chair of Oman`S Medicinal Plants
and Marine Natural, University of Nizwa,
Peyman Salehi, Department of
Phytochemistry, Medicinal Plants and
Drugs Research Institute, Shahid Beheshti
University, Tehran, Iran.
Research Council of Shahid Beheshti
University, Grant/Award Number: 600-1858
Novel substituted amino acid tethered norsufentanil derivatives were synthesized by
the four- component Ugi reaction. Norsufentanil was reacted with succinic anhydride
to produce the corresponding carboxylic acid. The resulting carboxylic acid has un-
dergone a multicomponent reaction with different aldehydes, amines, and isocya-
nides to produce a library of the desired compounds. In all cases, amide bond rotation
was observed in the NMR spectra. In vivo analgesic activity of the synthesized com-
pounds was evaluated by a tail flick test. Very encouraging results were obtained for
a number of the synthesized products. Some of the synthesized compounds such as
5a, 5b, 5h, 5j, and 5r were found to be more potent than sufentanil, sufentanil citrate,
and norsufentanil. Binding modes between the compounds and mu and delta- opioid
receptors were studied by molecular docking method. The relationship between the
molecular structural features and the analgesic activity was investigated by a quanti-
tative structure–activity relationship model. The results of the molecular modeling
studies and the in vivo analgesic activity suggested that the majority of the synthe-
sized compounds were more potent than sufentanil and norsufentanil.
amide bond rotation, analgesic, docking, norsufentanil, opioid, QSAR, sufentanil, tail flick, Ugi reaction
Synthetic opioid analgesics that contain norsufentanil
(Figure 1) structure are a class of important and widely used
drugs to relieve pain after different treatments.
first synthesis of fentanyl by Paul Johnson in 1956, great ef-
forts have been made to develop this group of analgesics.
Accordingly, a large group of new derivatives possessing an-
algesic properties such as sufentanil and alfentanil (Figure 1)
has been synthesized in recent years. As an example, sufent-
anil is five to 10 times stronger than fentanyl and 500 to 1,000
times stronger than morphine.
In general, structure–activity relationship studies of the
molecules containing norsufentanil scaffold indicated that
their analgesic activity is the result of the interaction between
this moiety of the molecule with opioid receptors in the target
Linking some other functional groups to norsufentanil
caused an improvement in its pharmacokinetic properties.
For example, adding thienylethyl group afforded sufentanil
which resulted in a very fast penetration to cerebrospinal fluid
through the blood–brain barrier and a very high affinity for
mu- opioid receptors (MOR). Also, adding the polar tetrazoli-
none ring changes the in vivo drug behavior.