Computational details
Numerous physicochemical parameters for absorption, distribution,
metabolism and excretion (ADME) were evaluated for all the designed R,
RI and RII frameworks employing
Molinspiration Property Calculation Service126 and
DruLiTo software.127 The computed parameters were
employed to confirm if the designed derivatives satisfy the Lipinski’s
rule of five, the Ghose’s rule, and the Veber
criteria.128-131 Compounds violating more than one of
Lipinski’s rules might have difficulties with bioavailability. Those
violating Ghose’s rules could show absorption problems or low
permeation; and those following Veber criteria may have better chances
of suitable oral bioavailability.
Since all these conditions are general rules and not rigorous
regulations, viable drugs have also to fulfill other vital requirements,
such as synthetic accessibility (SA) and
safety.132-135 The SA of the designed compounds was
determined with the SYLVIA-XT 1.4 program (Molecular Networks, Erlangen,
Germany).136 It delivers a value between 1 and 10. The
smaller the value the easier to synthesize is the compound. The SYLVIA
program has been certified for ranking virtual compounds during drug
discovery processes137. Additionally,
LD50 and Ames mutagenicity (M) were employed in this
work to assess the toxicity of R, RI and
RII and its derivatives. The Toxicity Estimation
Software Tool (T.E.S.T.), version 4.1, was employed to obtain these
parameters.138 This software constructs predictions
based on quantitative structure-activity relationships (QSAR), which are
envisioned for screening new compounds. The LD50 and M
descriptors were determined with the consensus method, which makes
predictions as the average of the toxicities obtained with several QSAR
methodologies.139 There is a general understanding
that the consensus method commonly offers higher accuracy and coverage
than other protocols. Selection and elimination scores, expressed in
terms of toxicity, manufacturability and ADME properties were used to
make the first selection of derivatives.140-142
Gaussian 09 package was employed for electronic structure
calculations143. Geometry optimizations and frequency
calculations were carried out using the Density Functional Theory (DFT).
The M05-2X approach was used in conjunction with 6-311+G(d,p) basis set
and the solvation model density (SMD) using water to mimic a polar
environment.144 Local minima were identified by the
absence of imaginary frequencies. Unrestricted calculations were used
for open shell systems. M05-2X is a global hybrid exchange-correlation
general gradient approximations functional designed for noncovalent
interactions, kinetics and thermochemistry.145 It has
also been recommended for calculating reaction energies involving free
radicals146. Furthermore, the M05-2X functional has
been widely used for estimating pKa values, bonding dissociation
energies, and the free radical scavenging activity of numerous
antioxidant molecules147-151.
Ionization energies (IE) and electron affinities (EA) were calculated in
the framework of the electron propagator theory
(EPT),152, 153 which usually delivers values closer to
those derived from experimental results than other methodologies. The
partial third‐order quasiparticle theory (P3)154 was
chosen since it has been reported to have lower mean errors, compared to
other methods.155 However, for the EPT approximations
(including P3) to be valid, pole strength (PS) values are needed to be
larger than 0.80-0.85 156 Electrophilicity, ω, was
also estimated for electron transfer reactions157-159to analyze the chemical behavior of the designed R, RIand RII derivatives. In a chemical reaction, involving
two molecules, that with the higher ω is expected to act as the
electrophile, while the other will behave as the nucleophile. This index
was calculated following the equation: