On the Basicity of 8‑Phenylsulfanyl Quipazine Derivatives: New Potential Serotonergic Agents
- Publication date
- 2015
- Publisher
Abstract
A protonation
state of serotonergic ligands plays a crucial role in their pharmacological
activity. In this research, the basicity of 8-phenylsulfanyl quipazine
derivatives as new potential serotonergic agents was studied. The
most favorable protonation sites were determined in the gas and aqueous
phases. In water, a solvation effect promoting the protonation of
the N3 atom overcomes a positive charge delocalization phenomenon
favoring a N1 atom protonation. The most stable conformations of neutral
and protonated molecules in gas and water were found. It was demonstrated
that a diprotonation reaction may occur. The most favorable among
the diprotonated structures is the molecule with the N1 and N3 atoms
protonated. A calculation of the p<i>K</i><sub>a</sub> and
p<i>K</i><sub>a2</sub> in water of a set of monosubstituted
8-phenylsulfanyl quipazine derivatives was performed using B3LYP/6-31G(d)
and the SMD continuum solvation model. Enthalpic and entropic contributions
to the p<i>K</i><sub>a</sub> and p<i>K</i><sub>a2</sub> in gas and water were separated for a rationalization of
a substituent effect on values of the p<i>K</i><sub>a</sub> and p<i>K</i><sub>a2</sub>. The relationship of the proton
affinity and the solvation enthalpy in water with some reactivity
descriptors, such as the Fukui function, the molecular electrostatic
potential (MEP), and the global softness, was investigated. The order
of the p<i>K</i><sub>a</sub> values is the most controlled
by the entropy. The diprotonation reaction, despite having an unfavorable
enthalpy in water, is driven entropically. Final state effects in
the diprotonated species were analyzed with the triadic formula. Results
of a calculation of the theoretical basicity of the 8-phenylsulfanyl
quipazines indicate that they should be monoprotonated on the N3 atom
in the CNS environment. Diprotonation of the studied compounds may
occur in very acidic body fluids such as the gastric juice