A novel hydrogen sulfide-releasing nicorandil derivative:
synthesis and vasodilator activity
Leonardo S. Neto1*, Victor P. Ziviani1, Natália R. C. Nóbrega2, Daniela E. F. R. Costa2,
Daniella Bonaventura2, Rosemeire B. Alves1, Ângelo de Fátima1
1
Grupo de Estudos em Química Orgânica e Biológica (GEQOB), Departamento de Química, Instituto de
Ciências Exatas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, 31270-901.
2
Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais
(UFMG), Belo Horizonte, 31270-901.
*e-mail corresponding author: [email protected]
Keywords: nicorandil, hydrogen sulfide-releasing, vasodilator activity
INTRODUCTION
Together with nitric oxide (NO) and carbon
monoxide (CO), hydrogen sulfide (H2S) is now
recognized as the third endogenous gaseous
1
transmitter . In recent years, some drugs are being
synthesized as H2S-releasing hybrids containing the
moiety ADTOH, which is responsible for the
2
production of H2S . Nicorandil (NIC) is a NOreleasing drug employed in the treatment of angina
3
4
pectoris also presenting anti-inflammatory activities
(Figure 1).
coupling of 5 with the phenol 3 furnished the
carbamate 6. The Boc group of adduct 6 was
removed under acid conditions providing the
intermediate 7 in 69% yield. Finally, the treatment of
7 with nicotinic acid and the coupling reagent
PyBOP produced the desired hybrid 8 in 96% yield.
The in vitro vasodilator activity of hybrid 8
(named as NHS) was assayed and it was compared
with the activities of NIC and ADTOH (Figure 2).
Figure 1. Structure of H2S-releasing nicorandil and
nicorandil. The ADTOH moiety is highlight in blue.
To further explore the potential of H2S-releasing
nicorandil derivative, the aims of this study are the
synthesis of such derivative and evaluation of its
potential as vasodilator agent.
RESULTS AND DISCUSSION
The synthetic strategy used to prepare the
nicorandil derivative is show in the Scheme 1.
Figure 2. Dose-dependent vasodilator activity of nicorandil
(NIC), hybrid 8 (NHS), ADTOH and MNH (main metabolite
of NIC).
Nicorandil, ADTOH and hybrid 8 were able to
cause 100% of vascular relaxation but they have
different release profiles of NO or H2S.
CONCLUSION
The synthesis of 8 was performed from transanethole in 5 steps and 11% overall yield. The
replacing NO-releasing moiety by the H2S-releasing
moiety altered the relaxation profile of the
compounds.
ACKNOWLEDGEMENTS
Scheme 1.
derivative.
Synthesis
of
H2S-releasing
nicorandil
The heating of trans-anethole (1) with sulfur
furnished the compound 2, which was converted into
phenol 3 by demethylation reaction. The preparation
of fragment 5 was carried out reacting the bromide 4
with di-tert-butyl-dicarbonate (Scheme 1). Then, the
This work was financially support by CNPq, CAPES
and FAPEMIG.
REFERENCES
1
Bhatia, M. et al. Brit. J. Pharmacol. 2005, 145, 141.
2
Wallace, J.L. Trends Pharmacol. Sci. 2007, 28, 501.
3
Tobin, K.J. J. Am. Osteopath. Assoc. 2010, 110, 364.
4
Dutra, M.M.G.B. et al. Pharmacol. Biochem. Behav. 2013, 106, 85
16th Brazilian Meeting on Organic Synthesis – 16th BMOS – November 15-18, 2015 - Búzios, Brazil